San Francisco, CA, United States
San Francisco, CA, United States

The University of California, San Francisco , is a center of health science research, patient care, and education; located in San Francisco, California, and is widely regarded as one of the world's leading universities in health science.Though one of the 10 campuses of the University of California, it is the only University of California campus dedicated solely to graduate education, and in health and biomedical science. Some of UCSF's treatment centers include kidney transplants and liver transplantation, radiology, neurosurgery, neurology, oncology, ophthalmology, gene therapy, women's health, fetal surgery, pediatrics, and internal medicine. With a work force of 22,800 people and annual economic impact of $2 billion, UCSF is San Francisco's second largest employer.Founded in 1873, the mission of UCSF is to serve as a "public university dedicated to saving lives and improving health." The UCSF Medical Center is consistently ranked among the top 10 hospitals in the United States by U.S. News & World Report, who also ranked UCSF's medical school as one of the top 10 in a number of specialties, including a specialty program in AIDS medical care ranked first in the country. Wikipedia.

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Esensten J.H.,University of California at San Francisco | Bluestone J.A.,University of California at San Francisco | Lim W.A.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2017

Engineered T cells are currently in clinical trials to treat patients with cancer, solid organ transplants, and autoimmune diseases. However, the field is still in its infancy. The design, and manufacturing, of T cell therapies is not standardized and is performed mostly in academic settings by competing groups. Reliable methods to define dose and pharmacokinetics of T cell therapies need to be developed. As of mid-2016, there are no US Food and Drug Administration (FDA)-approved T cell therapeutics on the market, and FDA regulations are only slowly adapting to the new technologies. Further development of engineered T cell therapies requires advances in immunology, synthetic biology, manufacturing processes, and government regulation. In this review, we outline some of these challenges and discuss the contributions that pathologists can make to this emerging field. © 2017 by Annual Reviews. All rights reserved.

Lord C.J.,Cancer Research UK Research Institute | Ashworth A.,University of California at San Francisco
Science | Year: 2017

PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness. © 2017, American Association for the Advancement of Science. All rights reserved.

BACKGROUND: It has been postulated that short wait time before liver transplant (LT) for hepatocellular carcinoma (HCC) results in the inclusion of tumors with aggressive biology, but prolonged wait time could result in a shift to more aggressive tumor behavior. We therefore test the hypothesis that a wait time “sweet spot” exists with a lower risk for HCC recurrence compared to the other 2 extremes. METHODS: This multi-center study included 911 patients from 3 LT centers with short, medium and long wait times (median of 4, 7, and 13 months, respectively) who received MELD exception listing for HCC from 2002-2012. RESULTS: Wait time, defined as time from initial HCC diagnosis to LT, was <6 months in 32.4%, 6-18 months in 53.7%, and >18 months in 13.9%. Waitlist dropout was observed in 18.4% at a median of 11.3 months. Probability of HCC recurrence at 1 and 5 years were 6.4% and 15.5% with wait time <6 or >18 months (n=343) versus 4.5% and 9.8% with wait time of 6-18 months (n=397), respectively (p=0.049). When only pre-LT factors were considered, wait time <6 or >18 months (HR 1.6, p=0.043) and AFP >400 at HCC diagnosis (HR 3.0, p<0.001) predicted HCC recurrence in multivariable analysis. CONCLUSION: This large multi-center study provides evidence of an association between very short (<6 months) or very long (>18 months) wait times and an increased risk for HCC recurrence post-LT. The so-called “sweet spot” of 6-18 months should be the target to minimize HCC recurrence. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Sarkar M.,University of California at San Francisco
American Journal of Gastroenterology | Year: 2017

Objectives:Young women with hyperandrogenism have high risk of metabolic co-morbidities, including increased risk of nonalcoholic fatty liver disease (NAFLD). Whether testosterone (the predominant androgen) is associated with NAFLD independent of metabolic co-factors is unclear. Additionally, whether testosterone confers increased risk of NAFLD in women without hyperandrogenism is unknown.Methods:Among women in the prospective population-based multicenter Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed whether free testosterone levels measured at Year 2 (1987–1988) were associated with prevalent NAFLD at Year 25 (2010–2011) (n=1052). NAFLD was defined using noncontrast abdominal CT scan with liver attenuation≤40 Hounsfield units after excluding other causes of hepatic fat. The association of free testosterone with prevalent NAFLD was assessed by logistic regression.Results:Increasing quintiles of free testosterone were associated with prevalent NAFLD at Year 25 (adjusted odds ratio (AOR) 1.25, 95% confidence interval (CI) 1.04–1.50, P=0.015), independent of insulin resistance, body mass index, waist circumference, and serum lipids. Importantly, the association persisted among n=955 women without androgen excess (AOR 1.27, 95% CI 1.05–1.53, P=0.016). Visceral adipose tissue (VAT) volume partially mediated the association of free testosterone with NAFLD (mediating effect 41.0%, 95% CI 22–119%).Conclusions:Increasing free testosterone is associated with prevalent NAFLD in middle age, even in women without androgen excess. Visceral adiposity appears to play an important role in the relationship between testosterone and NAFLD in women. Testosterone may provide a potential novel target for NAFLD therapeutics, and future studies in pre-menopausal women should consider the importance of testosterone as a risk factor for NAFLD.Am J Gastroenterol advance online publication, 14 March 2017; doi:10.1038/ajg.2017.44. © 2017 American College of Gastroenterology

Bellono N.W.,University of California at San Francisco | Leitch D.B.,University of California at San Francisco | Julius D.,University of California at San Francisco
Nature | Year: 2017

Elasmobranch fishes, including sharks, rays, and skates, use specialized electrosensory organs called ampullae of Lorenzini to detect extremely small changes in environmental electric fields. Electrosensory cells within these ampullae can discriminate and respond to minute changes in environmental voltage gradients through an unknown mechanism. Here we show that the voltage-gated calcium channel Ca V 1.3 and the big conductance calcium-activated potassium (BK) channel are preferentially expressed by electrosensory cells in little skate (Leucoraja erinacea) and functionally couple to mediate electrosensory cell membrane voltage oscillations, which are important for the detection of specific, weak electrical signals. Both channels exhibit unique properties compared with their mammalian orthologues that support electrosensory functions: structural adaptations in Ca V 1.3 mediate a low-voltage threshold for activation, and alterations in BK support specifically tuned voltage oscillations. These findings reveal a molecular basis of electroreception and demonstrate how discrete evolutionary changes in ion channel structure facilitate sensory adaptation. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Kornberg T.B.,University of California at San Francisco
Current Opinion in Genetics and Development | Year: 2017

During development, cells use specialized filopodia called cytonemes to deploy the signaling proteins that coordinate growth and direct morphogenesis. Cytonemes are dynamic structures that can extend long distances across tissues to either deliver or take up signaling proteins. Signaling proteins transfer between cells at the tips of cytonemes where specific contacts termed morphogenetic synapses form. This review summarizes our current understanding of the roles and functions of cytonemes, and it explores some of the conceptual issues relevant to the cytoneme mechanism of contact-dependent cell-cell signaling. © 2017 Elsevier Ltd

Liu J.S.E.,University of California at San Francisco | Hebrok M.,University of California at San Francisco
Genes and Development | Year: 2017

Following differentiation during fetal development, β cells further adapt to their postnatal role through functional maturation. While adult islets are thought to contain functionally mature β cells, recent analyses of transgenic rodent and human pancreata reveal a number of novel heterogeneity markers in mammalian β cells. The marked heterogeneity long after maturation raises the prospect that diverse populations harbor distinct roles aside from glucose-stimulated insulin secretion. In this review, we outline our current understanding of the β-cell maturation process, emphasize recent literature on novel heterogeneity markers, and offer perspectives on reconciling the findings from these two areas. © 2017 Liu and Hebrok.

Altshuler-Keylin S.,University of California at San Francisco | Kajimura S.,University of California at San Francisco
Science Signaling | Year: 2017

Mitochondrial homeostasis is regulated by a balance between mitochondrial biogenesis and degradation. Emerging evidence suggests that mitophagy, a selective form of autophagy that degrades mitochondria, plays a key role in the physiology and pathophysiology of mitochondria-enriched cells, such as brown and beige adipocytes. This review discusses findings regarding the roles of autophagy and mitophagy in cellular development, maintenance, and functions of metabolic organs, including adipose tissue, liver, and pancreas. A better understanding of the molecular links between mitophagy and energy metabolism will help to identify promising targets for the treatment of obesity and obesity-Associated disorders.

Garcia-Gonzalo F.R.,Autonomous University of Madrid | Reiter J.F.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2017

Cilia are plasma membrane protrusions that act as cellular propellers or antennae. To perform these functions, cilia must maintain a composition distinct from those of the contiguous cytosol and plasma membrane. The specialized composition of the cilium depends on the ciliary gate, the region at the ciliary base separating the cilium from the rest of the cell. The ciliary gate’s main structural features are electron dense struts connecting microtubules to the adjacent membrane. These structures include the transition fibers, which connect the distal basal body to the base of the ciliary membrane, and the Y-links, which connect the proximal axoneme and ciliary membrane within the transition zone. Both transition fibers and Y-links form early during ciliogenesis and play key roles in ciliary assembly and trafficking. Accordingly, many human ciliopathies are caused by mutations that perturb ciliary gate function. © 2017 Cold Spring Harbor Laboratory Press. All rights reserved.

Oakes S.A.,University of California at San Francisco
American Journal of Physiology - Cell Physiology | Year: 2017

The unfolded protein response (UPR) is an intracellular signaling network largely controlled by three endoplasmic reticulum (ER) transmembrane proteins, inositol-requiring enzyme 1α, PRK-like ER kinase, and activating transcription factor 6, that monitor the protein-folding status of the ER and initiate corrective measures to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins, conditions often encountered by cancer cells, can lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” Under remediable levels of ER stress, the homeostatic UPR outputs activate transcriptional and translational changes that promote cellular adaptation. However, if the ER stress is irreversible despite these measures, a terminal UPR program supersedes that actively signals cell destruction. In addition to its prosurvival and prodeath outputs, the UPR is now recognized to play a major role in the differentiation and activation of specific immune cells, as well as proinflammatory cytokine production in many cell types. Given the numerous intrinsic and extrinsic factors that threaten the fidelity of the secretory pathway in cancer cells, it is not surprising that ER stress is documented in many solid and hematopoietic malignancies, but whether ongoing UPR signaling is beneficial or detrimental to tumor growth remains hotly debated. Here I review recent evidence that cancer cells are prone to loss of proteostasis within the ER, and hence may be susceptible to targeted interventions that either reduce homeostatic UPR outputs or alternatively trigger the terminal UPR. © 2017 the American Physiological Society.

Samaranch L.,University of California at San Francisco
Gene Therapy | Year: 2017

The present study was designed to characterize transduction of non-human primate brain and spinal cord with AAV5 viral vector after parenchymal delivery. AAV5-CAG-GFP (1 × 1013 vector genomes per milliliter (vg ml-1)) was bilaterally infused either into putamen, thalamus or with the combination left putamen and right thalamus. Robust expression of GFP was seen throughout infusion sites and also in other distal nuclei. Interestingly, thalamic infusion of AAV5 resulted in the transduction of the entire corticospinal axis, indicating transport of AAV5 over long distances. Regardless of site of injection, AAV5 transduced both neurons and astrocytes equally. Our data demonstrate that AAV5 is a very powerful vector for the central nervous system and has potential for treatment of a wide range of neurological pathologies with cortical, subcortical and/or spinal cord affection.Gene Therapy advance online publication, 16 March 2017; doi:10.1038/gt.2017.14. © 2017 The Author(s)

Schmidt R.,University of Sheffield | Berke J.D.,University of California at San Francisco
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2017

Many studies have implicated the basal ganglia in the suppression of action impulses (‘stopping’). Here, we discuss recent neurophysiological evidence that distinct hypothesized processes involved in action preparation and cancellation can be mapped onto distinct basal ganglia cell types and pathways. We examine how movement-related activity in the striatum is related to a ‘Go’ process and how going may be modulated by brief epochs of beta oscillations. We then describe how, rather than a unitary ‘Stop’ process, there appear to be separate, complementary ‘Pause’ and ‘Cancel’ mechanisms. We discuss the implications of these stopping subprocesses for the interpretation of the stop-signal reaction time—in particular, some activity that seems too slow to causally contribute to stopping when assuming a single Stop processes may actually be fast enough under a Pause-then-Cancel model. Finally, we suggest that combining complementary neural mechanisms that emphasize speed or accuracy respectively may serve more generally to optimize speed–accuracy trade-offs. © 2017 The Author(s) Published by the Royal Society. All rights reserved.

Roseberry T.,Gladstone | Roseberry T.,University of California at San Francisco | Kreitzer A.,Gladstone | Kreitzer A.,University of California at San Francisco
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2017

The ability to stop ongoing movement is fundamental to animal survival. Behavioural arrest involves the hierarchical integration of information throughout the forebrain, which ultimately leads to the coordinated inhibition and activation of specific brainstem motor centres. Recent advances have shed light on multiple regions and pathways involved in this critical behavioural process. Here, we synthesize these new findings together with previous work to build a more complete understanding of the circuit mechanisms underlying suppression of ongoing action.We focus on three specific conditions leading to behavioural arrest: goal completion, fear and startle. We outline the circuitry responsible for the production of these behaviours and discuss their dysfunction in neurological disease. © 2017 The Author(s) Published by the Royal Society. All rights reserved.

Bush N.A.O.,University of California at San Francisco | Chang S.,University of California at San Francisco
Journal of Oncology Practice | Year: 2016

Diffuse low-grade gliomas include oligodendrogliomas and astrocytomas. The recent 2016 WHO classification has now updated the definition of these tumors to include molecular characterization, including the presence of isocitrate dehydrogenase mutation and 1p/19q codeletion. In this new classification, the histologic subtype of grade II mixed oligoastrocytoma has been eliminated. Treatment recommendations are currently evolving, mainly because of a change in the prognostic factors that are based on molecular and cytogenetic features. Standard of care includes maximal safe surgical resection. Prior randomized clinical trials stratified treatment arms on the basis of extent of resection and age, with patients stratified into low risk (age younger than 40 years and gross total resection) and high risk (age older than 40 years or subtotal resection). Patients who are low risk may undergo routine magnetic resonance imaging surveillance after resection. On the basis of recently published data, it is now recommended that high-risk patients undergo a combination of both radiation and chemotherapy after surgery. These studies, however, do not address the management of patients with low-grade gliomas in the era of genomic medicine. These treatments can also have great impact on quality of life, and therefore treatment recommendations should be done on an individual basis taking into account the current pathology classification, age, extent of resection, quality of life, and patient preference. Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

Truong H.-H.M.,University of California at San Francisco
Sexually Transmitted Diseases | Year: 2017

ABSTRACT: Exchange sex and higher education were associated with an increased likelihood of international sexual partnerships (ISPs). Exchange sex and older age were associated with an increased likelihood of condomless sex in ISPs. Educational and socioeconomic factors may create unbalanced power dynamics that influence exchange sex and condomless sex in ISPs. © Copyright 2017 American Sexually Transmitted Diseases Association

Sanders S.J.,University of California at San Francisco
Nature Genetics | Year: 2017

Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo–affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Marcucio R.,University of California at San Francisco
eLife | Year: 2017

The proper development of the vocal cords requires embryos to contain a certain number of progenitor cells, and mutations that lead to an overflow of cells can cause malformations of the voice box. © Marcucio.

Collisson E.A.,University of California at San Francisco | Olive K.P.,Columbia University
Cancer Research | Year: 2017

"Pancreatic Cancer: Advances in Science and Clinical Care," a Special Conference of the American Association for Cancer Research, was held in Orlando, FL, on May 12 to 15, bringing together more than 450 basic, translational, clinical, and epidemiologic pancreatic cancer researchers as well as pancreatic cancer patients, survivors, and advocates. Pancreatic cancer remains one of the great challenges in medicine, but the accelerating pace of research and early hints of clinical successes to come were palpable throughout the meeting. Prominent meeting themes included immunology and the tumor microenvironment, heterogeneity of both the epithelial and stromal compartments, personalized medicine efforts to integrate molecular information into clinical practice, new approaches to early detection, and clinical trials using a host of novel targeted therapies. Adding to the vibrant atmosphere of the meeting, a coalition of pancreatic cancer research and support foundations participated, with several innovative initiatives announced by individual organizations. We present here a summary of meeting highlights, a series of "success factors" that will benchmark the progress of the field over the next 2 years, and three challenges to the pancreatic cancer research community as it moves toward to the goal of extending patient survival. © 2017 AACR.

Bourne H.R.,University of California at San Francisco | Vermillion E.B.,University of California at San Francisco
FASEB Journal | Year: 2017

The decrease of federal and state support threatens long-Term sustainability of research in publicly supported academic health centers. In weathering these financial threats, research at the University of California, San Francisco (UCSF), has undergone 3 substantial changes: institutional salary support goes preferentially to senior faculty,whereas theyoungincreasinglydependongrants;privateandgovernmentsupport for researchgrowsapace in clinical departmentsbut declines in basic science departments;andresearch is judgedmoreonits quantity (numbersof investigators and federal and private dollars) than on its goals, achievements, or scientific quality.We propose specific measures to alleviate these problems. Other large public academic health centers probably confront similar issues, but-except forUCSF-such centers have not been subjected to detailed public analysis.

Ishikawa H.,University of California at San Francisco | Marshall W.F.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2017

Ciliaand flagella are microtubule-based organelles whose assembly requires a motile process, known as intraflagellar transport (IFT), to bring tubulin and other components to the distal tip of the growing structure. The IFT system uses a multiprotein complex with components that appear to be specialized for the transport of different sets of cargo proteins. The mechanisms by which cargo is selected for ciliary import and transport by IFT remain an area of active research. The complex dynamics of cilia and flagella are under constant regulation to ensure proper length control, and this regulation appears to involve regulation at the stage of IFT injection into the flagellum, as well as regulation of flagellar disassembly and, possibly, of cargo binding. Cilia and flagella thus represent a convenient model system to study how multiple motile and signaling pathways cooperate to control the assembly and dynamics of a complex cellular structure. © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

Gupta N.,University of California at San Francisco
Current neuropharmacology | Year: 2017

BACKGROUND: Diffuse intrinsic pontine gliomas represent a unique subtype of primary brain tumors occuring in a specific location and age. Their growth demonstrates early invasion and, following diagnosis, rapid growth not responsive to common therapies. Until recently, the genetic and cellular basis of these tumors was unknown. Genetic evidence implicates mutations in the histone genes in the origin of these tumors.METHODS: Surgical biopsies performed on selected patients have resulted in the establishment of anatomically accurate mouse models that have been used to examine patterns of growth and response to new therapeutic agents.RESULTS: Human derived pontine glioma models recapitulate the invasive patterns of growth. The grade of the original tumor affects the latency of tumor growth after implantation.CONCLUSION: The use of human-derived xenograft models allows for improved pre-clinical testing of new therapeutic targets in a tumor- and organ-specific manner.

Barr-Walker J.,University of California at San Francisco
Journal of the Medical Library Association | Year: 2017

Objective: This study assessed public health workers’ evidence-based information needs, based on a review of the literature using a systematic search strategy. This study is based on a thesis project conducted as part of the author’s master’s in public health coursework and is considered a systematized review. Methods: Four databases were searched for English-language articles published between 2005 and 2015: PubMed, Web of Science, Library Literature & Information Science Index, and Library, Information Science & Technology Abstracts (LISTA). Studies were excluded if there was no primary data collection, the population in the study was not identified as public health workers, “information” was not defined according to specific criteria, or evidence-based information and public health workers were not the major focus. Studies included in the final analysis underwent data extraction, critical appraisal using CASP and STROBE checklists, and thematic analysis. Results: Thirty-three research studies were identified in the search, including twenty-one using quantitative methods and twelve using qualitative methods. Critical appraisal revealed many potential biases, particularly in the validity of research. Thematic analysis revealed five common themes: (1) definition of information needs, (2) current information -seeking behavior and use, (3) definition of evidence-based information, (4) barriers to information needs, and (5) public health–specific issues. Conclusions: Recommendations are given for how librarians can increase the use of evidence-based information in public health research, practice, and policy making. Further research using rigorous methodologies and transparent reporting practices in a wider variety of settings is needed to further evaluate public health workers’ information needs. © 2017, Medical Library Association. All rights reserved.

Right ventricular failure (RVF) may still occur despite the benefits of minimally-invasive left ventricular assist device (MI-LVAD) implantation. Our center strategy aims to avoid aggressive postoperative inotrope use by utilizing mechanical support to facilitate RV recovery and adaptation. We herein report first outcomes of patients with minimally-invasive temporary right ventricular assist device (MI-t-RVAD) support for RVF during MI-LVAD implantation.RVF was defined as requiring more than moderate inotopic support after weaning from cardiopulmonary bypass according to INTERMACS adverse event definitions. All patients requiring MI-t-RVAD support for RVF during MI-LVAD implantation between 01/2012 and 04/2016 were retrospectively reviewed. Clinical endpoints were death or unsuccessful RVAD weaning.Overall 10 patients (90% male, mean age 49.6±14.8 years) underwent MI-t-RVAD implantation. Duration of MI-t-RVAD support was 16.2±11.6 days. RVAD weaning and subsequent uneventful awake device explantation was successful in all cases. The 30-day survival was 80%.Our results confirm safety and feasibility of MI-t-RVAD support for acute RVF in the setting of MI-LVAD implantation. The potential benefits of this strategy are more stable hemodynamics in the first postoperative days that usually are crucial for LVAD patients and reduced inotrope requirement. Copyright © 2017 by the American Society for Artificial Internal Organs

Dvorak C.C.,University of California at San Francisco
Blood | Year: 2016

In this issue of Blood, Kim et al demonstrate, in a mouse model of in utero hematopoietic cell transplantation (HCT), a novel approach to enhancing donor hematopoietic stem cell (HSC) engraftment by mobilizing host HSCs from their endogenous niche and then infusing the donor HSCs during the period of maximal mobilization.1 Much like a game of "musical chairs"-where everyone tries to sit down when the music stops-when the agents causing mobilization wear off, the donor HSCs have many more empty niches to potentially occupy, thereby resulting in enhanced multilineage engraftment. © 2016 by The American Society of Hematology.

Young-Wolff K.C.,University of California at San Francisco
Medical Care | Year: 2017

OBJECTIVES:: To examine rates of smoking and tobacco treatment utilization by insurance coverage status (Medicaid, commercial, exchange) among newly enrolled patients in the post Affordable Care Act (ACA) era. METHODS:: We examined new members who enrolled in Kaiser Permanente Northern California through Medicaid, the California exchange, or nonexchange commercial plans (N=122,298) in the first 6 months of 2014 following ACA implementation. We compared these groups on smoking prevalence and tested whether smokers in each group differed on sociodemographic characteristics and in their utilization of tobacco treatment (pharmacotherapy and counseling) in 2014. RESULTS:: Smoking prevalence was higher among Medicaid (22%) than exchange (13%) or commercial (12%) patients (P<0.0001). Controlling for key sociodemographic and clinical characteristics, Medicaid (odds ratio, 1.49; 95% confidence interval, 1.29–1.73) smokers had greater odds of tobacco treatment use than commercial smokers. Other groups at risk for underuse included men, younger patients, Asians, and Latinos. CONCLUSIONS:: In this cohort of newly enrolled patients after ACA implementation, Medicaid patients were more likely to be smokers compared with exchange and commercial patients, but they were also more likely to use tobacco treatment. Low tobacco treatment use among exchange and commercial plan smokers, as well as younger men, Asians and Latinos poses a significant obstacle to improving public health and additional targeted outreach strategies may be needed to engage these patients with available health services. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Taghavi T.,University of California at San Francisco
Pharmacogenetics and Genomics | Year: 2017

OBJECTIVES: Nicotine metabolism rates differ considerably among individuals, even after controlling for variation in the major nicotine-metabolizing enzyme, CYP2A6. In this study, the impact of genetic variation in alternative metabolic enzymes and transporters on nicotine and cotinine (COT) pharmacokinetics and smoking was investigated. METHODS: We examined the impact of UGT2B10, UGT2B17, FMO3, NAT1, and OCT2 variation on pharmacokinetics and smoking (total nicotine equivalents and topography) before and after stratifying by CYP2A6 genotype in 60 African American (AA) smokers who received a simultaneous intravenous infusion of deuterium-labeled nicotine and COT. RESULTS: Variants in UGT2B10 and UGT2B17 were associated with urinary glucuronidation ratios (glucuronide/free substrate). UGT2B10 rs116294140 was associated with significant alterations in COT and modest alterations in nicotine pharmacokinetics. These alterations, however, were not sufficient to change nicotine intake or topography. Neither UGT2B10 rs61750900, UGT2B17*2, FMO3 rs2266782, nor NAT1 rs13253389 altered nicotine or COT pharmacokinetics among all individuals (n=60) or among individuals with reduced CYP2A6 activity (n=23). The organic cation transporter OCT2 rs316019 significantly increased nicotine and COT Cmax (P=0.005, 0.02, respectively) and decreased nicotine clearance (P=0.05). UGT2B10 rs116294140 had no significant impact on the plasma or urinary trans-3′-hydroxycotinine/COT ratio, commonly used as a biomarker of CYP2A6 activity. CONCLUSION: We found that polymorphisms in genes other than CYP2A6 represent minor sources of variation in nicotine pharmacokinetics, insufficient to alter smoking in AAs. The change in COT pharmacokinetics with UGT2B10 rs116294140 highlights the UGT2B10 gene as a source of variability in COT as a biomarker of tobacco exposure among AA smokers. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

OBJECTIVE:: The aim of this study was to establish high-quality, valid standards to improve surgical care of the older adult. BACKGROUND:: The aging population increases demand for high-quality surgical care. Building upon prior guidelines, quality indicators, and pilot projects, the Coalition for Quality in Geriatric Surgery (CQGS) includes 58 diverse stakeholder organizations committed to improving geriatric surgery. METHODS:: Using a modified RAND-UCLA Appropriateness Methodology, 44 of 58 CQGS Stakeholders twice rated validity (primary outcome) and feasibility for 308 standards, ranging from goals and decision-making, pre-operative assessment and optimization, perioperative and postoperative care, to transitions of care beyond the acute care hospital. RESULTS:: Three hundred six of 308 (99%) standards were rated as valid to improve quality of geriatric surgery. There were 4 sections. Section 1 included 157 (57%) standards and focused on goals and decision-making, preoperative optimization, and transitions into and out of the hospital. Section 2 included 84 (27.3%) standards focused on in-hospital care, across the immediate preoperative, intraoperative, and postoperative phases. Section 3 included 59 (19.1%) standards about program management, including personnel and committee structure, credentialing, and education. Section 4 included 8 (2.6%) standards establishing overarching concepts for data collection and patient follow-up. Two hundred ninety of 308 standards (94.2%) were rated as feasible; 18 (5.8%) were rated as uncertain in feasibility. CONCLUSIONS:: CQGS Stakeholders rated the vast majority of standards of care as highly valid (99%) and feasible (94%) for improving the quality of surgical care provided to older adults. Future work will focus on a pilot phase to better understand and address challenges to implementation of the standards. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Robbins H.A.,University of California at San Francisco
AIDS | Year: 2017

OBJECTIVE:: We suggested cervical cancer screening strategies for women living with HIV (WLHIV) by comparing their precancer risks to general population women, and then compared our suggestions to current CDC guidelines. DESIGN:: We compared risks of biopsy-confirmed cervical high-grade squamous intraepithelial neoplasia or worse (bHSIL+), calculated among WLHIV in the Womenʼs Interagency HIV Study, to “risk benchmarks” for specific management strategies in the general population. METHODS:: We applied parametric survival models among 2,423 WLHIV with negative or ASC-US cytology during 2000–2015. Separately, we synthesized published general population bHSIL+ risks to generate 3-year risk benchmarks for a 3-year return (after negative cytology, i.e., “re-screening threshold”), 6–12-month return (ASC-US), and immediate colposcopy (LSIL). RESULTS:: Average 3-year bHSIL+ risks among general population women (“risk benchmarks”) were 0.69% for a 3-year return (after negative cytology), 8.8% for a 6–12-month return (after ASC-US), and 14.4% for colposcopy (after LSIL). Most CDC guidelines for WLHIV were supported by comparing risks in WLHIV to these benchmarks, including: a 3-year return after three negative cytology tests or a negative cytology/oncHPV co-test with CD4≥500 (all 3y-risks≤1.3%); a 1-year return after negative cytology with either positive oncHPV co-test (1y-risk?=?1.0%) or CD4<500 (1y-risk?=?1.1%); and a 6–12-month return after ASC-US (3y-risk?=?8.2% if CD4≥500; 10.4% if CD4?=?350–499). Other suggestions differed modestly from current guidelines, including colposcopy (vs. 6–12mo return) for WLHIV with ASC-US and CD4<350 (3y-risk?=?16.4%) and a lengthened 2-year (vs. 1-year) interval for WLHIV with CD4≥500 after negative cytology (2y-risk?=?0.98%). CONCLUSIONS:: Current cervical cancer screening guidelines for WLHIV are largely appropriate. CD4 count may inform risk-tailored strategies. Copyright © 2017 Wolters Kluwer Health, Inc.

Nolan A.,University of California at San Francisco
International Journal of Gynecological Pathology | Year: 2017

Ovarian sex-cord stromal tumors that have between 10% and 50% granulosa cells in a prominent fibrothecomatous background have been referred to as granulosa theca cell tumors or mixed granulosa theca cell tumors. The classification and prognosis of these tumors is not clear. Most adult granulosa cell tumors of the ovary harbor a mutation in the FOXL2 gene, whereas fibromas and thecomas lack this mutation. The aim of our study was to assess the FOXL2 mutation status of ovarian granulosa theca cell tumors and to correlate the mutation status with morphologic and clinical characteristics. A FOXL2 mutation was detected in 6 of 12 (50%) granulosa theca cell tumors. Tumors with higher cellularity of granulosa cells were more likely to harbor a FOXL2 mutation as were tumors in which the granulosa cells formed large lobules. No conclusions could be drawn regarding the clinical and prognostic significance of the presence of a mutation given the small number of cases and limited clinical follow-up. Our study shows that half of granulosa theca cell tumors harbor the same FOXL2 mutation that characterizes adult granulosa cell tumors but there is no outcome evidence to guide whether mutation status should alter the classification of the tumor or the management of the patient. ©2017International Society of Gynecological Pathologists

Dong X.,University of California at San Francisco
Plastic and Reconstructive Surgery | Year: 2017

BACKGROUND: Cleft Lip with or without Palate (CL/P) is present in approximately 1 in 500-700 live births, representing the most common congenital craniofacial anomaly. Previously, we developed a unique murine model with compound Pbx deficiency that exhibits fully penetrant CL/P. To investigate the possibility of tissue repair at an early gestational stage, we designed a minimally invasive surgical approach suitable for intrauterine repair using Wnt9b-soaked collagen microspheres to restore craniofacial developmental programs for cleft correction. METHODS: Collagen microspheres with diameters ranging from 20–50 microns were fabricated to serve as a delivery vehicle for Wnt9b. At gestational day 11.5, wild type and Pbx-deficient murine embryos were isolated. Microspheres soaked in murine purified Wnt9b protein were microsurgically implanted at the midface λ junction. Embryos were cultured in a 37°C modified Whole Embryo Culture (WEC) system. RESULTS: Targeted release of Wnt9b resulted in augmented Wnt expression at the λ junction. Microsurgical implantation of Wnt9b-soaked microspheres resulted in cleft correction in 27.1% of the Pbx-deficient embryos. The difference in the ratio of the areas of clefting between implanted and non-implanted embryos was significant (p<0.05). CONCLUSION: Ex utero correction of CL/P in our murine model via microsurgical intervention and targeted delivery of Wnt proteins is an innovative and promising strategy. Although further refinement and optimization of this technique will be required to improve efficacy, we believe that this approach will open new avenues towards unconventional prenatal interventions for patients with CL/P, as well as provide future approaches for prenatal repair of other congenital head and neck disorders. ©2017American Society of Plastic Surgeons

Ferrell L.D.,University of California at San Francisco
Modern Pathology | Year: 2017

While non-alcoholic steatohepatitis is a slowly progressive disease, patients may rarely present in acute liver failure. We describe six patients who developed severe hepatic dysfunction following rapid weight loss or malnutrition. Rapid weight loss (18 to 91 kg) occurred after Roux-en-Y gastric bypass in four patients and starvation-like dieting or hypoalbuminemia was noted in two patients. Four patients either died or received an urgent liver transplant. Pathologic findings were characterized by advanced alcoholic steatohepatitis-like features, including extensive/circumferential centrizonal pericellular fibrosis, central scar with perivenular sclerosis/veno-occlusion with superimposed hepatocellular dropout, abundant/prominent hepatocellular balloons, and numerous Mallory–Denk bodies, but there was no history of excess alcohol consumption. This study characterizes clinicopathologic features of aggressive non-alcoholic steatohepatitis following rapid weight loss or malnutrition, which should be included in the differential diagnosis with alcohol when a patient is considered for liver transplantation. The mechanism of liver injury in aggressive steatohepatitis is unknown, but rapid fat mobilization in obese patients may potentially cause oxidative stress to the liver and further study is needed to determine if there is a genetic predisposition to this form of injury and if antioxidants may protect the liver during rapid weight loss/malnutrition.Modern Pathology advance online publication, 3 March 2017; doi:10.1038/modpathol.2017.13. © 2017 United States & Canadian Academy of Pathology USCAP, Inc

Epel E.E.,University of California at San Francisco
Molecular Psychiatry | Year: 2017

Alterations in cellular aging, indexed by leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), might partly account for the increased health risks in persons with depression. Although some studies indeed found cross-sectional associations of depression with LTL and mtDNAcn, the longitudinal associations remain unclear. This 10-year longitudinal study examined between- and within-person associations of depressive symptoms with LTL and mtDNAcn in a large community sample. Data are from years 15, 20 and 25 follow-up evaluations in 977 subjects from the Coronary Artery Risk Development in Young Adults study. Depressive symptoms (years 15, 20, 25) were assessed with the Center for Epidemiologic Studies Depression (CES-D) scale; LTL (years 15, 20, 25) and mtDNAcn (years 15, 25) were measured in whole blood by quantitative PCR. With mixed-model analyses, we explored between- and within-person associations between CES-D scores and cellular aging markers. Results showed that high levels of depressive symptomatology throughout the 10-year time span was associated with shorter average LTL over 10 years (B=−4.2; P=0.014) after covarying for age, sex, race and education. However, no within-person association was found between depressive symptoms and LTL at each year (B=−0.8; P=0.548). Further, we found no between-person (B=−0.2; P=0.744) or within-person (B=0.4; P=0.497) associations between depressive symptomatology and mtDNAcn. Our results provide evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship. In this study, we found no evidence for an association between depressive symptoms and mtDNAcn.Molecular Psychiatry advance online publication, 28 March 2017; doi:10.1038/mp.2017.48. © 2017 Macmillan Publishers Limited, part of Springer Nature.

Nosrati A.,University of California at San Francisco
British Journal of Cancer | Year: 2017

Background:Anti-PD-1 therapy has shown significant clinical activity in advanced melanoma. We developed and validated a clinical prediction scale for response to anti- PD-1 monotherapy.Methods:A total of 315 patients with advanced melanoma treated with pembrolizumab (2 or 10 mg kg-1 Q2W or Q3W) or nivolumab (3 mg kg-1 Q2W) at four cancer centres between 2011 to 2013 served as the setting for the present cohort study. Variables with significant association to response on a univariate analysis were entered into a forward stepwise logistic regression model and were given a score based on ORs to calculate a clinical prediction scale.Results:The developed clinical prediction scale included elevated LDH (1 point), age <65 years (1 point), female sex (1 point), history of ipilimumab treatment (2 points) and the presence of liver metastasis (2 points). The scale had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80) in predicting response to therapy. The predictive performance of the score was maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the goodness-to-fit model demonstrated good calibration.Conclusions:Based on a large cohort of patients, we developed and validated a simple five-factor prediction scale for the clinical activity of PD-1 antibodies in advanced melanoma patients. This scale can be used to stratify patients participating in clinical trials.British Journal of Cancer advance online publication, 21 March 2017; doi:10.1038/bjc.2017.70 © 2017 Cancer Research UK

Yang J.Y.C.,University of California at San Francisco | Sarwal M.M.,University of California at San Francisco
Nature Reviews Genetics | Year: 2017

Ever since the discovery of the major histocompatibility complex, scientific and clinical understanding in the field of transplantation has been advanced through genetic and genomic studies. Candidate-gene approaches and recent genome-wide association studies (GWAS) have enabled a deeper understanding of the complex interplay of the donor–recipient interactions that lead to transplant tolerance or rejection. Genetic analysis in transplantation, when linked to demographic and clinical outcomes, has the potential to drive personalized medicine by enabling individualized risk stratification and immunosuppression through the identification of variants associated with immune-mediated complications, post-transplant disease or alterations in drug-metabolizing genes. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Over 3000 human genes can be expressed from a single allele in one cell, and from the other allele—or both—in neighboring cells. Little is known about the consequences of this epigenetic phenomenon, monoallelic expression (MAE). We hypothesized that MAE increases expression variability, with a potential impact on human disease. Here, we use a chromatin signature to infer MAE for genes in lymphoblastoid cell lines and human fetal brain tissue. We confirm that across clones MAE status correlates with expression level, and that in human tissue data sets, MAE genes show increased expression variability. We then compare mono- and biallelic genes at three distinct scales. In the human population, we observe that genes with polymorphisms influencing expression variance are more likely to be MAE (P<1.1 × 10-6). At the trans-species level, we find gene expression differences and directional selection between humans and chimpanzees more common among MAE genes (P<0.05). Extending to human disease, we show that MAE genes are under-represented in neurodevelopmental copy number variants (CNVs) (P<2.2 × 10-10), suggesting that pathogenic variants acting via expression level are less likely to involve MAE genes. Using neuropsychiatric single-nucleotide polymorphism (SNP) and single-nucleotide variant (SNV) data, we see that genes with pathogenic expression-altering or loss-of-function variants are less likely MAE (P<7.5 × 10-11) and genes with only missense or gain-of-function variants are more likely MAE (P<1.4 × 10-6). Together, our results suggest that MAE genes tolerate a greater range of expression level than biallelic expression (BAE) genes, and this information may be useful in prediction of pathogenicity.Molecular Psychiatry advance online publication, 7 March 2017; doi:10.1038/mp.2017.13. © 2017 Macmillan Publishers Limited, part of Springer Nature.

Hellerstein M.,University of California at San Francisco
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2017

PURPOSE OF REVIEW: Flux-rate measurements of protein synthesis and breakdown (turnover) in muscle represent an ideal class of mechanism-based biomarkers for conditions of altered muscle mass and function. We describe here new metabolic labeling techniques for flux-rate measurements in humans, focusing on skeletal muscle. RECENT FINDINGS: Dynamics of the muscle proteome are accurately measured in humans by combining long-term heavy water labeling with tandem mass spectrometry. Broad proteomic flux signatures or kinetics of targeted proteins are measurable. After interventions, early fractional synthesis rates of skeletal muscle proteins predict later changes in muscle mass. The ‘virtual biopsy’ method for measuring tissue protein turnover rates from body fluids has been validated for skeletal muscle, from labeling of plasma creatine kinase-type M or carbonic anhydrase-3. Label in these proteins in plasma reflects label of cognate proteins in the tissue, and response in plasma predicts longer term outcomes. Skeletal muscle mass can also be measured noninvasively from a spot urine, based on dilution of labeled creatine. This method correlates well with whole body MRI assessment of muscle mass and predicts clinical outcomes in older men. SUMMARY: Flux measurements are available and more interpretable functionally than static measurements for several reasons, which are discussed. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Evangelista L.S.,University of California at San Francisco
Journal of Cardiovascular Nursing | Year: 2017

BACKGROUND:: We conducted a secondary analysis to (1) compare changes in mood disorders and quality of life (QOL) among 4 groups of patients with heart failure in a home-based exercise program who had varying degrees of change in their exercise capacity and (2) determine whether there was an association between exercise capacity, mood disorders, and QOL. METHODS:: Seventy-one patients were divided into 4 groups based on changes in exercise capacity from baseline to 6 months: group 1showed improvements of greater than 10% (n = 19), group 2 showed improvements of 10% or less (n = 16), group 3 showed reductions of 10% or less (n = 9), and group 4 showed reductions of greater than 10% (n = 27). RESULTS:: Over time, patients in all 4 groups demonstrated significantly lower levels of depression and hostility (P < .001) and higher levels of physical and overall quality of life (P = .046). Group differences over time were noted in anxiety (P = .009), depression (P = .015), physical quality of life (P < .001), and overall quality of life (P = .002). Greater improvement in exercise capacity was strongly associated with lower depression scores (r = −0.49, P = .01). CONCLUSIONS:: An improvement in exercise capacity with exercise training was associated with a decrease in depression and anxiety and an increase in QOL in patients with heart failure. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved

Chou C.L.,University of California at San Francisco
Academic Medicine | Year: 2017

Most medical students on clerkships currently experience lack of continuity of patient care, disjointed learning, and frequent changes in supervisors. Clerkship programs with continuity of care, curriculum, and supervisors appear to benefit student learning and patient-centeredness. A fourth form of continuity is proposed: continuity of peers, in which a stable cohort of students frequently meets to process their experiences on clerkships. This structure builds on benefits previously seen in peer-assisted learning, including enhanced knowledge, technical skills, and collegial peer relationships. Additional advantages of peer continuity in clerkships include facilitated integration into the workplace, social support, and enhanced clinical and professional learning. Practical components required for a successful peer continuity structure include intentional formation of peer cohorts; regular meetings that cover didactic or clinical skills learning; frequent opportunities for reflection on patient care, professional development, and well-being; and skilled facilitators without evaluative roles. Theoretical support for peer continuity comes from social cognitive theory, communities of clinical practice, and social comparison theory. Therefore, in conjunction with empirical programs that have shown benefits of developing these structures, peer continuity should become a formalized educational structure in clerkships. © 2017 by the Association of American Medical Colleges

Zhu W.,University of California at San Francisco
Stroke | Year: 2017

BACKGROUND AND PURPOSE—: Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current therapies are associated with high morbidities. Excessive vascular endothelial growth factor has been implicated in bAVM pathophysiology. Because soluble FLT1 binds to vascular endothelial growth factor with high affinity, we tested intravenous delivery of an adeno-associated viral vector serotype-9 expressing soluble FLT1 (AAV9-sFLT1) to alleviate the bAVM phenotype. METHODS—: Two mouse models were used. In model 1, bAVM was induced in R26CreER;Eng mice through global Eng gene deletion and brain focal angiogenic stimulation; AAV2-sFLT02 (an AAV expressing a shorter form of sFLT1) was injected into the brain at the time of model induction, and AAV9-sFLT1, intravenously injected 8 weeks after. In model 2, SM22αCre;Eng mice had a 90% occurrence of spontaneous bAVM at 5 weeks of age and 50% mortality at 6 weeks; AAV9-sFLT1 was intravenously delivered into 4- to 5-week-old mice. Tissue samples were collected 4 weeks after AAV9-sFLT1 delivery. RESULTS—: AAV2-sFLT02 inhibited bAVM formation, and AAV9-sFLT1 reduced abnormal vessels in model 1 (GFP versus sFLT1: 3.66±1.58/200 vessels versus 1.98±1.29, P<0.05). AAV9-sFLT1 reduced the occurrence of bAVM (GFP versus sFLT1: 100% versus 36%) and mortality (GFP versus sFLT1: 57% [12/22 mice] versus 24% [4/19 mice], P<0.05) in model 2. Kidney and liver function did not change significantly. Minor liver inflammation was found in 56% of AAV9-sFLT1–treated model 1 mice. CONCLUSIONS—: By applying a regulated mechanism to restrict sFLT1 expression to bAVM, AAV9-sFLT1 can potentially be developed into a safer therapy to reduce the bAVM severity. © 2017 American Heart Association, Inc.

Shin N.-M.,University of California at San Francisco
Journal of Cardiovascular Nursing | Year: 2017

BACKGROUND:: The prevalence of metabolic syndrome (MetS) has been increasing among Koreans, and middle-aged and older women are at risk of metabolic syndrome. Effective strategies to promote lifestyle modification need to be developed. OBJECTIVE:: We examined the effects of a self-management program on improving the cardiovascular health status and promoting healthy behaviors among overweight or obese Korean women at risk of metabolic syndrome. METHODS:: A pretest and posttest intervention design was used. Sixty women participated in a group teaching session. They also received a pedometer and a diary for self-monitoring. On the basis of blood test results, womenʼs metabolic syndrome status was identified. Thirty women with metabolic syndrome received additional tailored counseling and weekly follow-up calls for 4 weeks, whereas 30 women without metabolic syndrome did not receive any tailored counseling or follow-up calls. Twenty-three women in the MetS group and 22 women in the non-MetS group completed the posttest. RESULTS:: Overall, women significantly improved their cardiovascular health status including systolic blood pressure, diastolic blood pressure, body mass index, low-density lipoprotein, triglycerides, number of metabolic syndrome risk factors, and 10-year risk estimates from pretest to posttest. Seventy-eight percent of the MetS group (n = 18) no longer had metabolic syndrome, whereas 5% of the non-MetS group (n = 1) became to have metabolic syndrome. Women significantly increased frequency and duration of walking per week and significantly decreased the time spent sitting. CONCLUSIONS:: Promoting self-management for healthy behaviors might be effective for obese or overweight women to prevent metabolic syndrome and cardiovascular diseases, if it is tailored to their health needs. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved

News Article | May 8, 2017

UCSF survey finds 4 in 5 report discrimination, much of it based on motherhood Of the nearly 6,000 physician mothers in the survey, nearly 78 percent reported discrimination of any type. Forms of perceived discrimination ranged from disrespect and reduced pay to being overlooked for promotions or being held to higher performance standards. To combat gender-based discrimination while retaining high-quality physicians, the researchers recommend that employers implement policies such as longer paid maternity leaves, backup child care, lactation support, and schedule flexibility. The study will be published in JAMA Internal Medicine on May 8, 2017. "Physician mothers treat patients, raise children, teach students and care for sick relatives and friends. But who looks after them?," said corresponding author Eleni Linos, MD, DrPH, an assistant professor of medicine at UCSF. "We need to make sure these women get fair and unbiased treatment at the workplace. The role of physician mothers is essential and we can't afford to lose them to burnout," said Linos, a UCSF Health physician in the Department of Dermatology who is also a member of the UCSF Helen Diller Family Comprehensive Cancer Center. Previous research has shown that women physicians are typically paid lower salaries than male peers, are less likely to be promoted, and spend on average 8.5 more hours a week on household activities than male counterparts. The new research focused on how motherhood affects perceived discrimination among women physicians. The Physician Moms Group (PMG), launched in 2014, is an online community with more than 60,000 physician members in the United States. Members are highly active, filing on average 415 posts daily and more than 7,400 comments. The online, cross-sectional survey, conducted in 2016, queried PMG members about demographic and physical factors, perceived workplace maternal discrimination based on pregnancy, maternity leave, or breastfeeding, and desired workplace changes. Altogether, 5,782 physician mothers completed the survey and provided responses that could be analyzed for the study, which adjusted for race or ethnicity, medical specialty and practice setting. Of those, about 66 percent reported gender discrimination, while nearly 36 percent reported maternal discrimination. Approximately 32 percent reported discrimination based on pregnancy or maternity leave, and about 17 percent reported discrimination based on breastfeeding. Maternal discrimination was associated with higher burnout among the physician responders. Overall, nearly 39 percent of the physicians experienced disrespectful treatment by nursing or other support staff. Among the 2,070 physicians reporting maternal discrimination, the most common forms were disrespectful treatment, not being included in administrative decision-making, and pay or benefits not being equivalent to male peers. The physician mothers also listed numerous desired workplace changes including: Respondents included physicians in a variety of medical specialties, including anesthesia, dermatology, emergency medicine, family medicine, internal medicine, neurology, obstetrics-gynecology, ophthalmology, pathology, pediatrics, psychiatry, radiology and surgery. They worked in a variety of medical settings, among them academic medical centers, public hospitals, military and VA practices, and health maintenance organizations. Some 68 percent of the physicians in the survey were between 31 and 40 years old. Nearly 76 percent had one or two children, while almost 18 percent reported having three children. "It's just good business sense," said co-author Christina Mangurian, MD, MAS, vice chair for diversity in the UCSF Department of Psychiatry and associate professor of psychiatry at UCSF. "In corporate America, it has been shown that family-friendly policies increase productivity," she said. "It is so well known, in fact, that investors buy stocks when these policies are announced. We need to learn from our business colleagues. If we want to retain talented women physicians, we need more family-friendly policies." Co-authors are Taiwo Adesoye, MD, of the University of Texas at MD Anderson Cancer Center; Esther K. Choo, MD, MPH, of the Oregon Health & Science University; Christina Girgis of Loyola University Medical Center; and Hala Sabry-Elnaggar, DO, MBA, founder of the Physician Moms Group. Contributors to the article from UCSF are Adi Nosrati, MD, and Mary-Margaret Chren, MD. About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area. Please visit http://www. .

Gelfand A.A.,University of California at San Francisco
Current Opinion in Neurology | Year: 2013

Purpose of Review: This review covers recent advances in our understanding of migraine and childhood periodic syndromes in children and adolescents, as well as the treatment of these disorders. Recent Findings: The childhood periodic syndromes include benign paroxysmal torticollis, benign paroxysmal vertigo, abdominal migraine, and cyclic vomiting syndrome. Recent research suggests infant colic may also fit into this category. Migraine headache is common in children and adolescents, and chronic migraine effects 0.8-1.8% of adolescents and 0.6% of children. Two triptans are now FDA-approved for the acute treatment of migraine in pediatric patients. For preventive therapy, a number of medications have been studied and a major national trial is ongoing. Summary: Childhood periodic syndromes are thought to be early life expressions of those genes that later in life are expressed as migraine headache. Future research into mechanisms of identifying children with these disorders prior to extensive and often invasive testing would be of benefit to these families and children. Migraine-specific therapies are now approved for the acute treatment of migraine in pediatric patients. Preventive migraine therapy is indicated in appropriate patients, although which medications are most effective in children is an area of active research. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Verkman A.S.,University of California at San Francisco
Cold Spring Harbor Perspectives in Medicine | Year: 2013

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, a cAMP-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia. Nearly 2000 mutations in the CFTR gene have been identified that cause disease by impairing its translation, cellular processing, and/ or chloride channel gating. The fundamental premise of CFTR corrector and potentiator therapy for CF is that addressing the underlying defects in the cellular processing and chloride channel function of CF-causing mutant CFTR alleles will result in clinical benefit by addressing the basic defect underlying CF. Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface. This article reviews the discovery of CFTR potentiators and correctors, what is known regarding their mechanistic basis, and encouraging results achieved in clinical testing. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

Xu L.,University of California at Davis | Li S.,National University of Singapore | Stohr B.A.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2013

Telomere biology plays a critical and complex role in the initiation and progression of cancer. Although telomere dysfunction resulting from replicative attrition constrains tumor growth by engaging DNA-damage signaling pathways, it can also promote tumorigenesis by causing oncogenic chromosomal rearrangements. Expression of the telomerase enzyme enables telomere-length homeostasis and allows tumor cells to escape the antiproliferative barrier posed by short telomeres. Telomeres and telomerase also function independently of one another. Recent work has suggested that telomerase promotes cell growth through pathways unrelated to telomere maintenance, and a subset of tumors elongate telomeres through telomerase-independent mechanisms. In an effort to exploit the integral link between telomere biology and cancer growth, investigators have developed several telomerase-based therapeutic strategies, which are currently in clinical trials. Here, we broadly review the state of the field with a particular focus on recent developments of interest. © 2013 by Annual Reviews. All rights reserved.

Alavi M.V.,University of California at San Francisco | Fuhrmann N.,Institute For Medizinische Genetik Und Molekulare Medizin
Molecular Neurodegeneration | Year: 2013

Mitochondrial quality control is fundamental to all neurodegenerative diseases, including the most prominent ones, Alzheimer's Disease and Parkinsonism. It is accomplished by mitochondrial network dynamics - continuous fission and fusion of mitochondria. Mitochondrial fission is facilitated by DRP1, while MFN1 and MFN2 on the mitochondrial outer membrane and OPA1 on the mitochondrial inner membrane are essential for mitochondrial fusion. Mitochondrial network dynamics are regulated in highly sophisticated ways by various different posttranslational modifications, such as phosphorylation, ubiquitination, and proteolytic processing of their key-proteins. By this, mitochondria process a wide range of different intracellular and extracellular parameters in order to adapt mitochondrial function to actual energetic and metabolic demands of the host cell, attenuate mitochondrial damage, recycle dysfunctional mitochondria via the mitochondrial autophagy pathway, or arrange for the recycling of the complete host cell by apoptosis. Most of the genes coding for proteins involved in this process have been associated with neurodegenerative diseases. Mutations in one of these genes are associated with a neurodegenerative disease that originally was described to affect retinal ganglion cells only. Since more and more evidence shows that other cell types are affected as well, we would like to discuss the pathology of dominant optic atrophy, which is caused by heterozygous sequence variants in OPA1, in the light of the current view on OPA1 protein function in mitochondrial quality control, in particular on its function in mitochondrial fusion and cytochrome C release. We think OPA1 is a good example to understand the molecular basis for mitochondrial network dynamics. © 2013 Alavi and Fuhrmann; licensee BioMed Central Ltd.

Katsumoto T.R.,University of California at San Francisco | Connolly M.K.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2011

Systemic sclerosis (SSc), also known as scleroderma, is a rare connective tissue disease characterized by vascular and immune dysfunction, leading to fibrosis that can damage multiple organs. Its pathogenesis is complex and poorly understood. Two major clinical subtypes are the limited and diffuse forms. Research into SSc has been hampered by its rarity, its clinical heterogeneity, and the lack of mouse models that accurately recapitulate the disease. Clinical and basic studies have yielded some mechanistic clues regarding pathogenesis. Recent insights gained through the use of microarrays have revealed distinctive subsets of SSc within and beyond the limited and diffuse subsets. In this review, we discuss potential mechanisms underlying the vascular, autoimmune, and fibrotic points of dysregulation. Proper categorization of SSc patients for research studies by use of microarrays or other biomarkers is critical, as disease heterogeneity may explain some of the inconsistencies of prior studies. Copyright © 2011 by Annual Reviews. All rights reserved.

Bershteyn M.,University of California at San Francisco | Kriegstein A.R.,University of California at San Francisco
Cell | Year: 2013

A three-dimensional culture of cortical tissues derived from pluripotent stem cells offers an opportunity to model human brain development and disorders. In a recent issue of Nature, Lancaster et al. describe a new method for generating cerebral organoids in a dish and use it to model microcephaly. © 2013 Elsevier Inc.

Bush J.O.,University of California at San Francisco
Seminars in Cell and Developmental Biology | Year: 2012

The Eph receptor tyrosine kinases and their ephrin partners compose a large and complex family of signaling molecules involved in a wide variety of processes in development, homeostasis, and disease. The complexity inherent to Eph/ephrin signaling derives from several characteristics of the family. First, the large size and functional redundancy/compensation by family members presents a challenge in defining their in vivo roles. Second, the capacity for bidirectional signaling doubles the potential complexity, since every member has the ability to act both as a ligand and a receptor. Third, Ephs and ephrins can utilize a wide array of signal transduction pathways with a tremendous diversity of cell biological effect. The daunting complexity of Eph/ephrin signaling has increasingly prompted investigators to resort to multiple technological approaches to gain mechanistic insight. Here we review recent progress in the use of advanced mouse genetics in combination with proteomic and transcriptomic approaches to gain a more complete understanding of signaling mechanism in vivo. Integrating insights from such disparate approaches provides advantages in continuing to advance our understanding of how this multifarious group of signaling molecules functions in a diverse array of biological contexts. © 2011 Elsevier Ltd.

London M.J.,University of California at San Francisco | Hur K.,Center for Medication Safety | Schwartz G.G.,University of Colorado at Denver
JAMA - Journal of the American Medical Association | Year: 2013

Importance: The effectiveness of perioperative β-blockade in patients undergoing noncardiac surgery remains controversial. Objective: To determine the associations of early perioperative exposure to β-blockers with 30-day postoperative outcome in patients undergoing noncardiac surgery. Design, Setting, and Patients: A retrospective cohort analysis evaluating exposure to β-blockers on the day of or following major noncardiac surgery among a population-based sample of 136 745 patients who were 1:1 matched on propensity scores (37 805 matched pairs) treated at 104 VA medical centers from January 2005 through August 2010. Main Outcomes and Measures: All cause 30-day mortality and cardiac morbidity (cardiac arrest or Q-wave myocardial infarction). Results: Overall 55 138 patients (40.3%) were exposed to β-blockers. Exposure was higher in the 66.7% of 13 863 patients undergoing vascular surgery (95% CI, 65.9%-67.5%) than in the 37.4% of 122 882 patients undergoing nonvascular surgery (95% CI, 37.1%-37.6%; P < .001). Exposure increased as Revised Cardiac Risk Index factors increased, with 25.3% (95% CI, 24.9%-25.6%) of those with no risk vs 71.3% (95% CI, 69.5%-73.2%) of those with 4 risk factors or more exposed to β-blockers (P < .001). Death occurred among 1.1% (95% CI, 1.1%-1.2%) and cardiac morbidity occurred among 0.9% (95% CI, 0.8%-0.9%) of patients. In the propensity matched cohort, exposure was associated with lower mortality (relative risk [RR], 0.73; 95% CI, 0.65-0.83; P < .001; number need to treat [NNT], 241; 95% CI, 173-397). When stratified by cumulative numbers of Revised Cardiac Risk Index factors, β-blocker exposure was associated with significantly lower mortality among patients with 2 factors (RR, 0.63 [95% CI, 0.50-0.80]; P < .001; NNT, 105 [95% CI, 69-212]), 3 factors (RR, 0.54 [95% CI, 0.39-0.73]; P < .001; NNT, 41 [95% CI, 28-80]), or 4 factors or more (RR, 0.40 [95% CI, 0.25-0.73]; P < .001; NNT, 18 [95% CI, 12-34]). This association was limited to patients undergoing nonvascular surgery. β-Blocker exposure was also associated with a lower rate of nonfatal Q-wave infarction or cardiac arrest (RR, 0.67 [95% CI, 0.57-0.79]; P < .001; NNT, 339 [95% CI, 240-582]), again limited to patients undergoing nonvascular surgery. Conclusions and Relevance: Among propensity-matched patients undergoing noncardiac, nonvascular surgery, perioperative β-blocker exposure was associated with lower rates of 30-day all-cause mortality in patients with 2 or more Revised Cardiac Risk Index factors. Our findings support use of a cumulative number of Revised Cardiac Risk Index predictors in decision making regarding institution and continuation of perioperative β-blockade. A multicenter randomized trial involving patients at a low to intermediate risk by these factors would be of interest to validate these observational findings. ©2013 American Medical Association. All rights reserved.

Rowitch D.H.,Howard Hughes Medical Institute | Rowitch D.H.,University of California at San Francisco | Kriegstein A.R.,University of California at San Francisco
Nature | Year: 2010

Oligodendrocytes and astrocytes are macroglial cells of the vertebrate central nervous system. These cells have diverse roles in the maintenance of neurological function. In the embryo, the genetic mechanisms that underlie the specification of macroglial precursors in vivo appear strikingly similar to those that regulate the development of the diverse neuron types. The switch from producing neuronal to glial subtype-specific precursors can be modelled as an interplay between region-restricted components and temporal regulators that determine neurogenic or gliogenic phases of development, contributing to glial diversity. Gaining insight into the developmental genetics of macroglia has great potential to improve our understanding of a variety of neurological disorders in humans. © 2010 Macmillan Publishers Limited. All rights reserved.

Gandhi M.,University of California at San Francisco | Gandhi R.T.,MGH | Gandhi R.T.,Massachusetts Institute of Technology
New England Journal of Medicine | Year: 2014

A 52-year-old man with a history of homelessness, depression, and polysubstance use received a diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in 2005 but has declined antiretroviral therapy (ART) in the past. His CD4+ T-cell count is now 257 per cubic millimeter, and his plasma HIV-1 RNA level is 17,000 copies per milliliter. The patient was prescribed a multipill antiretroviral regimen 2 months ago but has not followed this regimen regularly because "taking out lots of pills in the shelter just announces to the world that I have AIDS [the acquired immunodeficiency syndrome]." The patient desires to keep his HIV status private and states that he would take medications regularly if he could take just "one pill once a day." The patient is not taking any other medications; his renal function is normal. How should he be evaluated and treated? Copyright © 2014 Massachusetts Medical Society.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 277.42K | Year: 2015

DESCRIPTION provided by applicant There is a significant need for novel HIV therapies given the emergence of viruses resistant to existing drug regimens The Rev RRE protein RNA interaction in HIV plays an essential role in the transport of viral mRNA from the nucleus to the cytoplasm where it can be translated or packaged Previously we identified the thienopyridine scaffold that inhibited HIV replication and by targeting HIV Rev We carried out extensive structure activity SAR studies producing patentable new analogs that are fold more potent than our original screening hits and with therapeutic indices andgt exceeding our original goals Having successfully completed key milestones towards submission of an Investigational New Drug IND we propose to carry out a detailed study of the mechanism of action of the inhibitors This study is a key scientific milestone that will open many corporate and venture opportunities as well as significantly strengthen our opportunity to access SBIR STTR Phase II funding The work described in this proposal has a high likelihood for success given that in preliminary studies we have shown that a mutant in the RRE confers resistance to the compound PUBLIC HEALTH RELEVANCE We previously carried out a structure activity study of a promising Rev inhibitor and identified the key structural elements necessary for activity We propose to carry out experiments to establish the molecular mechanism of the molecule

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2014

Project Summary: Intravenous dosing of drugs for applications ranging from cancer chemotherapy to anti-microbials to lytic (blood clot dissolving) agents is limited by systemic toxicity. Currently, the only ways to remove drugs from the blood are throughnatural metabolism or costly impractical measures such as dialysis. Despite intense focus on targeted drug delivery agents, these therapies are costly and rare, especially considering traditional older drugs are low-cost yet clinically effective, and can be used in a targeted manner with higher efficacy if they could be filtered out of the body after their effect in order to prevent toxicities. Intra-arterial chemotherapy (IAC) is performed in interventional radiology (IR), enabling direct delivery of chemotherapy to tumors by guiding micro-catheters into the arteries feeding these tumors. IAC with Doxorubicin (Dox) has proven to be a successful method demonstrating mortality benefit in randomized controlled trials (1, 2) for treating non- operative prima

BACKGROUND: Previous studies have characterized an increasing trend of double burden households, or households with individuals experiencing both undernutrition and obesity, in countries undergoing a nutrition transition. Although most prior studies indicate the prevalence of double burden households is highest in middle-income countries, there is some support for an increase in double burden households in sub-Saharan African countries as well.METHOD: Using data from the Demographic Health Surveys (DHS) and the World Health Organization (WHO), the prevalence of double burden households in sub-Saharan African countries was calculated and the associations between prevalence of overweight/obese adults and underweight, stunted and wasted children were evaluated at the country and household (DHS only) levels. Restricted analyses and frequencies were calculated using urban-only datasets. Surveys from 28 African countries were available using WHO data and 26 from the DHS surveys. Only surveys that were conducted after 2000 were included in analyses.RESULTS: Using the WHO datasets, there were inverse associations between the prevalence of overweight and obesity in adults and underweight, stunting and wasting in children. Correspondingly, there were positive associations between adult underweight and child underweight, stunting and wasting. These associations were not significant in a smaller sample size using urban-only surveys. The prevalence of double burden households in DHS datasets was low: under 5 percent for obese mothers and underweight, stunted or wasted child pairs with a slightly higher percentage for overweight mothers and children with undernutrition. Restricting the analysis to urban only populations did not increase the frequencies of double burden households significantly.CONCLUSION: There was a low prevalence of double burden households in recent data from sub-Saharan Africa. Countries that have a high prevalence of child undernutrition correspondingly have a high prevalence of adult underweight and low prevalence of adult overweight and obesity.

Kamimura Y.,University of California at San Francisco | Lanier L.L.,University of California at San Francisco
Cell Reports | Year: 2015

Recent studies have demonstrated that natural killer (NK) cells are able to undergo clonal expansion and contraction and to generate self-renewing memory cells after infection with mouse cytomegalovirus (MCMV). It is unclear whether all or only certain subsets preferentially contribute to the generation of memory NK cells. Here, we show that memory NK cells predominantly arise from killer cell lectin-like receptor G1 (KLRG1)-negative NK cell progenitors, whereas KLRG1-positive NK cells have limited capacity for expansion during infection with MCMV. Unexpectedly, the frequency of KLRG1-positive NK cells is significantly affected by the presence of Tcells in the host and potentially by the host microbiota. Our findings demonstrate that excessive availability of interleukin (IL)-15 may erode the pool of memory progenitors, resulting in the decreased efficiency of memory generation in the NK cell lineage. © 2015 The Authors.

Stannard D.,University of California at San Francisco
Pain Management Nursing | Year: 2012

For more than a century, acetaminophen has been recognized worldwide as a safe and effective agent for relieving pain and reducing fever in a wide range of patients. However, until recently, acetaminophen was available in the United States only in oral and rectal suppository formulations. In November 2010, the United States Food and Drug Administration granted approval for the use of a new intravenous (IV) formulation of acetaminophen for: 1) the management of mild to moderate pain; 2) the management of moderate to severe pain with adjunctive opioid analgesics; and 3) the reduction of fever in adults and children (age ≥2 years). This case-illustrated review of IV acetaminophen begins with a discussion of the rationale for the drug's development and proceeds to analyze the clinical pharmacology, efficacy, safety, and nursing implications of its use, both as monotherapy and in combination with other agents as part of a multimodal pain therapy strategy. © 2012 American Society for Pain Management Nursing.

Plesh O.,University of California at San Francisco
Journal of orofacial pain | Year: 2011

To compare prevalences of self-reported temporomandibular joint and muscle disorders (TMJMD)-type pain, headaches, and neck and back pains in the 2000 to 2005 US National Health Interview Survey (NHIS) by gender and age for non-Hispanic Whites (Whites), Hispanics, and non-Hispanic Blacks (Blacks). Data from the 2000 to 2005 NHIS included information on gender, age, race, ethnicity, and different common types of pain specifically: TMJMD-type pain, severe headaches/migraine, neck, and low back pains. A total of 189,992 people were included: 52% female and 48% male, 73% White, 12% Hispanic, 11% Black, and 4% "Other." The overall prevalence of TMJMD-type pain was 4.6%; severe headaches/migraine was 15.4%; neck, 14.9%; and low back, 28.0%. Survey logistic regression models estimating race-specific, age-adjusted curves revealed race by age pain differences. For TMJMD-type pain, White females presented the highest prevalence at younger ages, decreasing after age 40. Prevalences for Hispanic and Black females, although lower at younger ages, increased up to age 60 and remained higher than Whites. Males showed less racial/ethnic and age variation. Severe headaches/migraines presented an age pattern similar to TMJMD-type pain for White females and little overall variation for males, but without racial differences. Neck pain showed some similarities to TMJMD-type pain: higher in Whites at younger ages, lower at older ages, with Hispanics having the highest rates after their 60's. For low back pain, the rates peaked around the sixth decade for all racial/ethnic groups. The patterns of TMJMD-type pain varied greatly within and across racial/ethnic groups by gender and across the adult lifespan. Similarities and differences for the other pains were noted.

Sennino B.,University of California at San Francisco | McDonald D.M.,University of California at San Francisco
Nature Reviews Cancer | Year: 2012

Selective inhibition of vascular endothelial growth factor (VEGF) increases the efficacy of chemotherapy and has beneficial effects on multiple advanced cancers, but response is often limited and the disease eventually progresses. Changes in the tumour microenvironment - hypoxia among them - that result from vascular pruning, suppressed angiogenesis and other consequences of VEGF inhibition can promote escape and tumour progression. New therapeutic approaches that target pathways that are involved in the escape mechanisms add the benefits of blocking tumour progression to those of slowing tumour growth by inhibiting angiogenesis. © 2012 Macmillan Publishers Limited. All rights reserved.

Minami S.S.,University of California at San Francisco | Farese R.V.,Jr
Nature Medicine | Year: 2014

Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

Stephen Kaye H.,University of California at San Francisco
Health Affairs | Year: 2013

The aging of the baby-boom generation, as well as predicted growth in the number of people with disabilities, is expected to increase the demand for long-term services and supports dramatically. This study analyzed data from the Survey of Income and Program Participation from 1984 to 2010 to discern trends among noninstitutionalized working-age adults and the elderly who had some level of disability or need for help with activities of daily living. Some impairments among the elderly, such as in mobility and mental health, decreased. Meanwhile, some impairments among working-age adults, such as in cognitive ability, increased substantially. Of particular importance, the overall prevalence of disability for both age groups has largely stabilized since 2000. Among working-age adults, that stabilization is good news because it eases concern, fueled by prior research, that this population was becoming increasingly disabled and costly to public benefit programs such as Social Security Disability Insurance. However, the flattening of disability trends among the elderly is not good news, since it suggests that the number of elderly people with disabilities will continue to increase in direct proportion to the growing size of the elderly population. Among other implications, the need for both paid workers and unpaid caregivers to assist elderly people, especially those ages seventy-five and older, will continue to increase sharply. © 2013 Project HOPE-The People-to-People Health Foundation, Inc.

Shusterman D.,University of California at San Francisco
Current allergy and asthma reports | Year: 2014

The upper airway (extending from the nares to larynx) fulfills essential physiologic functions, including sensation, air conditioning, filtration, and communication. As the portal of entry for the respiratory tract, the upper airway's sentinel function is performed by the olfactory and trigeminal nerves. Sensory (eye, nose and throat) irritation figures prominently in symptom reporting in so-called "problem buildings," as well as in industrial exposures to irritant gases, vapors, and smokes. Both irritants and allergens can alter function in the upper airway, leading to loss of air conditioning and filtering due to airflow obstruction and hypersecretion. Increasing evidence points to a "unified airway" model of pathogenesis (in which rhinitis may precede the development of asthma). The spectrum of occupational irritant- and allergen-related upper airway health effects-including sensory irritation, olfactory dysfunction, rhinitis, sinusitis, nasal septal perforation, and sinonasal cancer-is reviewed in this article.

Fujimura K.E.,University of California at San Francisco | Lynch S.V.,University of California at San Francisco
Cell Host and Microbe | Year: 2015

Asthma and atopy, classically associated with hyper-activation of the T helper 2 (Th2) arm of adaptive immunity, are among the most common chronic illnesses worldwide. Emerging evidence relates atopy and asthma to the composition and function of the human microbiome, the collection of microbes that reside in and on and interact with the human body. The ability to interrogate microbial ecology of the human host is due in large part to recent technological developments that permit identification of microbes and their products using culture-independent molecular detection techniques. In this review we explore the roles of respiratory, gut, and environmental microbiomes in asthma and allergic disease development, manifestation, and attenuation. Though still a relatively nascent field of research, evidence to date suggests that the airway and/or gut microbiome may represent fertile targets for prevention or management of allergic asthma and other diseases in which adaptive immune dysfunction is a prominent feature. © 2015 Elsevier Inc.

Arron S.T.,University of California at San Francisco
Seminars in cutaneous medicine and surgery | Year: 2014

Targeted therapies for cutaneous squamous cell carcinoma (cSCC) remain limited. Extensive genetic heterogeneity complicates a robust molecular characterization of the evolution of cSCC. Nonetheless, potential targeted therapies for this cancer are under investigation, including the inhibition of epidermal growth factor receptor (EGFR), which may yield promising results. In addition, the emergence of immune checkpoint blockade therapy and vaccine-based methods may provide novel treatment strategies for cSCC that are tailored to the individual patient. Ultimately, a combination of such methods may yield a multi-pronged targeted approach to personalize the treatment of cSCC.

Huang Y.,University of California at San Francisco
Current Opinion in Lipidology | Year: 2010

PURPOSE OF REVIEW: The purpose of this review is to provide insights into recent advances in mechanisms linking apolipoprotein (apo) E isoforms to cardiovascular and neurological diseases. RECENT FINDINGS: Human apoE has three common isoforms (apoE2, apoE3, and apoE4) with different structural and biophysical properties and different effects on lipid and neuronal homeostasis. ApoE is a protein constituent of different plasma lipoproteins and serves as a high-affinity ligand for several receptors. By interacting with its receptors, apoE mediates the clearance of different lipoproteins from the circulation. Absence or structural mutations of apoE cause significant disorders in lipid metabolism and cardiovascular disease. ApoE also has significant roles in neurobiology. ApoE4 is the major known genetic risk factor for Alzheimer's disease. It increases the occurrence and lowers the age of onset of Alzheimer's disease. ApoE4 carriers account for 65-80% of all Alzheimer's disease cases, highlighting the importance of apoE4 in Alzheimer's disease pathogenesis. ApoE4 has both amyloid β-dependent and amyloid β-independent roles in Alzheimer's disease pathogenesis. SUMMARY: Emerging data suggest that apoE isoforms, with their multiple cellular origins and multiple structural and biophysical properties, contribute to cardiovascular and neurological diseases by interacting with different factors through various pathways. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Orr M.T.,University of California at San Francisco | Lanier L.L.,University of California at San Francisco
Cell | Year: 2010

Natural killer (NK) cells play a key role in the immune response to certain infections and malignancies by direct cytolysis of infected or transformed cells and by secretion of potent immune mediators. NK cells express an array of activating receptors that recognize self-molecules. If not restrained by inhibitory receptors recognizing major histocompatibility complex (MHC) class I proteins on the surface of self cells, NK cells are able to kill normal, healthy cells. Not all NK cells express inhibitory receptors for self-MHC class I; thus, other tolerance mechanisms are necessary to prevent NK cell-mediated autoimmunity. Here we review the major mechanisms of NK cell education and tolerance. © 2010 Elsevier Inc.

Bukata L.,University of California at San Francisco | Parker S.L.,University of California at San Francisco | D'Angelo M.A.,University of California at San Francisco
Current Opinion in Cell Biology | Year: 2013

Maintaining genome integrity is crucial for successful organismal propagation and for cell and tissue homeostasis. Several processes contribute to safeguarding the genomic information of cells. These include accurate replication of genetic information, detection and repair of DNA damage, efficient segregation of chromosomes, protection of chromosome ends, and proper organization of genome architecture. Interestingly, recent evidence shows that nuclear pore complexes, the channels connecting the nucleus with the cytoplasm, play important roles in these processes suggesting that these multiprotein platforms are key regulators of genome integrity. © 2013 Elsevier Ltd.

Shaw R.M.,University of California at San Francisco | Colecraft H.M.,Columbia University
Cardiovascular Research | Year: 2013

In the heart, Ca2+ influx via CaV1.2 L-type calcium channels (LTCCs) is a multi-functional signal that triggers muscle contraction, controls action potential duration, and regulates gene expression. The use of LTCC Ca2+ as a multi-dimensional signalling molecule in the heart is complicated by several aspects of cardiac physiology. Cytosolic Ca2+ continuously cycles between ∼100 nM and ∼1 μM with each heartbeat due to Ca2+ linked signalling from LTCCs to ryanodine receptors. This rapid cycling raises the question as to how cardiac myocytes distinguish the Ca2+ fluxes originating through L-type channels that are dedicated to contraction from Ca2+ fluxes originating from other L-type channels that are used for non-contraction-related signalling. In general, disparate Ca2+ sources in cardiac myocytes such as current through differently localized LTCCs as well as from IP3 receptors can signal selectively to Ca2+-dependent effectors in local microdomains that can be impervious to the cytoplasmic Ca2+ transients that drive contraction. A particular challenge for diversified signalling via cardiac LTCCs is that they are voltage-gated and, therefore, open and presumably flood their microdomains with Ca2+ with each action potential. Thus spatial localization of Cav1.2 channels to different types of microdomains of the ventricular cardiomyocyte membrane as well as the existence of particular macromolecular complexes in each Cav1.2 microdomain are important to effect different types of Cav1.2 signalling. In this review we examine aspects of Cav1.2 structure, targeting and signalling in two specialized membrane microdomains-transverse tubules and caveolae. © 2012 The Author.

Thiam A.R.,Yale University | Thiam A.R.,Ecole Normale Superieure de Paris | Farese Jr. R.V.,Gladstone | Farese Jr. R.V.,University of California at San Francisco | Walther T.C.,Yale University
Nature Reviews Molecular Cell Biology | Year: 2013

Lipid droplets are intracellular organelles that are found in most cells, where they have fundamental roles in metabolism. They function prominently in storing oil-based reserves of metabolic energy and components of membrane lipids. Lipid droplets are the dispersed phase of an oil-in-water emulsion in the aqueous cytosol of cells, and the importance of basic biophysical principles of emulsions for lipid droplet biology is now being appreciated. Because of their unique architecture, with an interface between the dispersed oil phase and the aqueous cytosol, specific mechanisms underlie their formation, growth and shrinkage. Such mechanisms enable cells to use emulsified oil when the demands for metabolic energy or membrane synthesis change. The regulation of the composition of the phospholipid surfactants at the surface of lipid droplets is crucial for lipid droplet homeostasis and protein targeting to their surfaces. © 2013 Macmillan Publishers Limited. All rights reserved.

Stachowiak J.C.,University of Texas at Austin | Brodsky F.M.,University of California at San Francisco | Miller E.A.,Columbia University
Nature Cell Biology | Year: 2013

Many cellular membrane-bound structures exhibit distinct curvature that is driven by the physical properties of their lipid and protein constituents. Here we review how cells manipulate and control this curvature in the context of dynamic events such as vesicle-mediated membrane traffic. Lipids and cargo proteins each contribute energy barriers that must be overcome during vesicle formation. In contrast, protein coats and their associated accessory proteins drive membrane bending using a variety of interdependent physical mechanisms. We survey the energy costs and drivers involved in membrane curvature, and draw a contrast between the stochastic contributions of molecular crowding and the deterministic assembly of protein coats. These basic principles also apply to other cellular examples of membrane bending events, including important disease-related problems such as viral egress. © 2013 Macmillan Publishers Limited. All rights reserved.

Prusiner S.B.,University of California at San Francisco
Annual Review of Genetics | Year: 2013

Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and Lou Gehrig's diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests. © 2013 by Annual Reviews. All rights reserved.

Choi J.Y.,Scripps Florida | Podust L.M.,University of California at San Francisco | Roush W.R.,Scripps Florida
Chemical Reviews | Year: 2014

CYP51 is considered one of the most ancient P450 protein families. structure guided lead development has proven to be a productive strategy for generating highly potent antiparasitic CYP51 inhibitors. Lead selectivity can also be assessed in silico at early stages of drug discovery via molecular docking and comparative modeling of newly designed inhibitors against the structures for human CYP enzymes. Drugs of the azole class have been developed as antifungal agents for human diseases. Substantial efforts have been made to repurpose approved antifungal azole drugs for treatment of Chagas disease. It is likely that parasite-specific inhibitors, optimized by structure-based drug-design criteria with close monitoring of PK parameters and inhibition of human drug-metabolizing CYPs, will be more effective in developing efficacious treatments of human T. cruzi and other protozoan infections than the antifungal agents. The long-term success of these efforts will depend on the ability to develop potent therapeutic agents ensuring parasitological cure with minimal or no harm to the human host.

Bhattacharya J.,Columbia University | Matthay M.A.,University of California at San Francisco
Annual Review of Physiology | Year: 2013

Considerable progress has been made in understanding the basic mechanisms that regulate fluid and protein exchange across the endothelial and epithelial barriers of the lung under both normal and pathological conditions. Clinically relevant lung injury occurs most commonly from severe viral and bacterial infections, aspiration syndromes, and severe shock. The mechanisms of lung injury have been identified in both experimental and clinical studies. Recovery from lung injury requires the reestablishment of an intact endothelial barrier and a functional alveolar epithelial barrier capable of secreting surfactant and removing alveolar edema fluid. Repair mechanisms include the participation of endogenous progenitor cells in strategically located niches in the lung. Novel treatment strategies include the possibility of cell-based therapy that may reduce the severity of lung injury and enhance lung repair. Copyright © 2013 by Annual Reviews. All rights reserved.

Hata A.,University of California at San Francisco
Annual Review of Physiology | Year: 2013

In 1993, lin-4 was discovered as a critical modulator of temporal development in Caenorhabditis elegans and, most notably, as the first in the class of small, single-stranded noncoding RNAs now defined as microRNAs (miRNAs). Another eight years elapsed before miRNA expression was detected in mammalian cells. Since then, explosive advancements in the field of miRNA biology have elucidated the basic mechanism of miRNA biogenesis, regulation, and gene-regulatory function. The discovery of this new class of small RNAs has augmented the complexity of gene-regulatory programs as well as the understanding of developmental and pathological processes in the cardiovascular system. Indeed, the contributions of miRNAs in cardiovascular development and function have been widely explored, revealing the extensive role of these small regulatory RNAs in cardiovascular physiology. Copyright © 2013 by Annual Reviews. All rights reserved.

Itoh K.,Johns Hopkins University | Nakamura K.,University of California at San Francisco | Iijima M.,Johns Hopkins University | Sesaki H.,Johns Hopkins University
Trends in Cell Biology | Year: 2013

It has been only 15 years since studies began on the molecular mechanisms underlying mitochondrial fission and fusion using simple model organisms such as Drosophila, yeast, and Caenorhabditis elegans. Beyond the primary functions of mitochondrial fission and fusion in controlling organelle shape, size, and number, it became clear that these dynamic processes are also critical to regulating cell death, mitophagy, and organelle distribution. Now, studies suggest that prominent changes occur in mitochondrial dynamics in a broad array of neurodegenerative diseases, and there is substantial evidence suggesting a key role in disease pathogenesis because neurons are among the most energy-consuming cell types and have a highly developed cell shape. Here, we review the recent findings on mitochondrial dynamics in neurodegeneration. © 2012 Elsevier Ltd.

Katsuno Y.,University of California at San Francisco | Lamouille S.,University of California at San Francisco | Derynck R.,University of California at San Francisco
Current Opinion in Oncology | Year: 2013

PURPOSE OF REVIEW: TGF-β acts as a potent driver of cancer progression through the induction of epithelial-mesenchymal transition (EMT), in which epithelial cells acquire mesenchymal phenotype, leading to enhanced motility and invasion. Recent reports highlight the fundamental roles of TGF-β-induced EMT in multiple aspects of cancer progression. In this review, we focus on the novel insights into the roles of TGF-β-induced EMT in cancer progression and the underlying mechanisms that enable TGF-β to activate this epithelial plasticity response at transcription, translation, and posttranslational levels. RECENT FINDINGS: Smad-mediated transcription regulation is known to activate TGF-β-induced EMT. More recently, novel mechanisms of epigenetic control, alternative splicing, miRNAs, translation control, and posttranslational modifications have been shown to play key roles in the control of EMT. In addition to initiating carcinoma cell invasion, TGF-β-induced EMT can guide cancer cells to de-differentiate and gain cancer stem-cell-like properties. EMT also allows the generation of stromal cells that support and instruct cancer progression. SUMMARY: The differentiation plasticity of epithelial cells that mediates TGF-β-induced EMT and reversion from mesenchymal to epithelial phenotype are increasingly seen as integral aspects of cancer progression that contribute to survival and dissemination of cancer cells. Further mechanistic insights under physiological conditions may lead to new therapeutic or prognostic strategies in cancer treatment. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Krahmer N.,Yale University | Farese Jr. R.V.,University of California at San Francisco | Walther T.C.,Yale University
EMBO Molecular Medicine | Year: 2013

Lipid droplets (LDs) are dynamic, cytosolic lipid-storage organelles found in nearly all cell types. Too many or too few LDs during excess or deficient fat storage lead to many different human diseases. Recent insights into LD biology and LD protein functions shed new light on mechanisms underlying those metabolic pathologies. These findings will likely provide opportunities for treatment of diseases associated with too much or too little fat. Too many or too few lipid droplets during excess or deficient fat storage lead to many different human diseases. Recent insights into lipid droplet biology and functions shed new light on mechanisms underlying those metabolic pathologies. © 2013 The Authors.

Rauen K.A.,University of California at San Francisco
Annual Review of Genomics and Human Genetics | Year: 2013

The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration. Copyright © 2013 by Annual Reviews. All rights reserved.

Huang Y.,University of California at San Francisco
Biochemical Society Transactions | Year: 2011

ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65-80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Aβ (amyloid β-peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoEmouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects. ©The Authors Journal compilation ©2011 Biochemical Society.

Zhu L.,Georgia Institute of Technology | Zhang W.,University of California at San Francisco | Elnatan D.,University of California at San Francisco | Huang B.,University of California at San Francisco
Nature Methods | Year: 2012

In super-resolution microscopy methods based on single-molecule switching, the rate of accumulating single-molecule activation events often limits the time resolution. Here we developed a sparse-signal recovery technique using compressed sensing to analyze images with highly overlapping fluorescent spots. This method allows an activated fluorophore density an order of magnitude higher than what conventional single-molecule fitting methods can handle. Using this method, we demonstrated imaging microtubule dynamics in living cells with a time resolution of 3 s. © 2012 Nature America, Inc. All rights reserved.

Schachter J.,University of California at San Francisco
Expert Review of Molecular Diagnostics | Year: 2013

Evaluation of: Roberts CH, Last A, Molina-Gonzalez S et al. Development and evaluation of a next-generation digital PCR diagnostic assay for ocular chlamydia trachomatis infections. J. Clin. Microbiol. 51(7), 2195-2203 (2013). Trachoma is the leading infectious cause of blindness in developing countries. Currently, there is no program to eliminate blinding trachoma as a public health problem. We need better diagnostic tests for research and to assess progress in control programs. Roberts et al. adapted droplet digital PCR (ddPCR), an emulsion PCR process that performs absolute quantitation of nucleic acids, to detect and quantify Chlamydia trachomatis infections. They compared the results with ddPCR on conjunctival swab specimens collected in trachoma-endemic area to results using Roche's Amplicor® C. trachomatis/Neisseria gonorrhoeae (CT/NG) PCR and found that ddPCR sensitivity was 73.3%. The authors concluded that 'ddPCR is an effective diagnostic technology suitable for both research and clinical use in diagnosing ocular C. trachomatis infections'. This reviewer disagrees, feeling that if the stated sensitivity is accurate, it is too low, and suggests there may be good reasons to adapt commercially available tests for this purpose. © 2013 Informa UK Ltd.

Sakoda L.C.,Kaiser Permanente | Sakoda L.C.,Fred Hutchinson Cancer Research Center | Jorgenson E.,Kaiser Permanente | Witte J.S.,University of California at San Francisco
Nature Genetics | Year: 2013

The large-scale Collaborative Oncological Gene-environment Study (COGS) presents new findings that further characterize the genetic bases of breast, ovarian and prostate cancers. We summarize and provide insights into this collection of papers from COGS and discuss the implications of the results and future directions for such efforts.

Hesslein D.G.T.,University of California at San Francisco | Lanier L.L.,University of California at San Francisco
Advances in Immunology | Year: 2011

Natural killer (NK) cells play an important role in host defense against tumors and viruses and other infectious diseases. NK cell development is regulated by mechanisms that are both shared with and separate from other hematopoietic cell lineages. Functionally, NK cells use activating and inhibitory receptors to recognize both healthy and altered cells such as transformed or infected cells. Upon activation, NK cells produce cytokines and cytotoxic granules using mechanisms similar to other hematopoietic cell lineages especially cytotoxic T cells. Here we review the transcription factors that control NK cell development and function. Although many of these transcription factors are shared with other hematopoietic cell lineages, they control unexpected and unique aspects of NK cell biology. We review the mechanisms and target genes by which these transcriptional regulators control NK cell development and functional activity. © 2011 Elsevier Inc.

Minematsu T.,University of California at San Francisco | Giacomini K.M.,University of California at San Francisco
Molecular Cancer Therapeutics | Year: 2011

The drug-drug interaction (DDI) potential of tyrosine kinase inhibitors (TKI) as interacting drugs via transporter inhibition has not been fully assessed. Here, we estimated the half maximal inhibitory concentration (IC 50) values for 8 small-molecule TKIs (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib) on [ 14C]metformin transport by human organic cation transporters (OCT), OCT1, OCT2, and OCT3, and multidrug and toxic compound extrusion (MATE) proteins, MATE1 and MATE2-K, using human embryonic kidney cells stably expressing these transporters. We then compared the estimated IC 50 values to the maximum clinical concentrations of unbound TKIs in plasma (unbound C max,sys,p). Results showed that imatinib, nilotinib, gefitinib, and erlotinib exerted selectively potent inhibitory effects, with unbound C max,sys,p/IC 50 values >0.1, on MATE1, OCT3, MATE2-K, and OCT1, respectively. In comparison to the common form of OCT1, the OCT1 polymorphism, M420del, was more sensitive to drug inhibition by erlotinib. Major metabolites of several TKIs showed IC 50 values similar to those for unchanged TKIs. Taken together, these findings suggest the potential of clinical transporter-mediated DDIs between specific TKIs and OCTs and MATEs, which may affect the disposition, efficacy, and toxicity of metformin and other drugs that are substrates of these transporters. The study provides the basis for further clinical DDI studies with TKIs. ©2011 AACR.

Venook A.P.,University of California at San Francisco
The oncologist | Year: 2010

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the burden of this devastating cancer is expected to increase further in coming years. The collection and analysis of epidemiologic HCC data will play a critical role in guiding future disease prevention strategies and optimizing patient management. Previous epidemiologic studies have highlighted striking global variations in the incidence of HCC, which is particularly high in much of east Asia and sub-Saharan Africa, and lower, but on the increase, in North America and most of Europe. This variation appears to be related to the complex etiology of HCC, with different risk factors, primarily infection with hepatitis B or hepatitis C virus, responsible for driving HCC incidence rates in different regions. Although previous studies have contributed considerably to the knowledge of HCC epidemiology, there are limitations associated with the currently available data, which arise from studies performed at different times in the past, using varying methodologies, and with diverse patient populations. A new and global approach to the study of HCC epidemiology is required if HCC disease prevention and treatment strategies are to be adequately directed and supported in coming years.

Link T.M.,University of California at San Francisco
Radiology | Year: 2012

Osteoporosis is becoming an increasingly important public health issue, and effective treatments to prevent fragility fractures are available. Osteoporosis imaging is of critical importance in identifying individuals at risk for fractures who would require pharmacotherapy to reduce fracture risk and also in monitoring response to treatment. Dual x-ray absorptiometry is currently the state-of-the-art technique to measure bone mineral density and to diagnose osteoporosis according to the World Health Organization guidelines. Motivated by a 2000 National Institutes of Health consensus conference, substantial research efforts have focused on assessing bone quality by using advanced imaging techniques. Among these techniques aimed at better characterizing fracture risk and treatment effects, high-resolution peripheral quantitative computed tomography (CT) currently plays a central role, and a large number of recent studies have used this technique to study trabecular and cortical bone architecture. Other techniques to analyze bone quality include multidetector CT, magnetic resonance imaging, and quantitative ultrasonography. In addition to quantitative imaging techniques measuring bone density and quality, imaging needs to be used to diagnose prevalent osteoporotic fractures, such as spine fractures on chest radiographs and sagittal multidetector CT reconstructions. Radiologists need to be sensitized to the fact that the presence of fragility fractures will alter patient care, and these fractures need to be described in the report. This review article covers state-of-the-art imaging techniques to measure bone mineral density, describes novel techniques to study bone quality, and focuses on how standard imaging techniques should be used to diagnose prevalent osteoporotic fractures. © RSNA, 2012.

Bain-Brickley D.,University of California at San Francisco
Cochrane database of systematic reviews (Online) | Year: 2011

Achieving and maintaining high levels of medication adherence are required to achieve the full benefits of antiretroviral therapy (ART), yet suboptimal adherence among children is common in both developed and developing countries. To conduct a systematic review of the literature of evaluations of interventions for improving paediatric ART adherence. We created a comprehensive search strategy in order to identify all studies relevant to this topic. In July 2010, we searched the following electronic databases: EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, LILACS, Web of Science, Web of Social Science, NLM Gateway (supplemented by a manual search of the most recent abstracts not included in the Gateway database). We searched abstracts from the International AIDS Conference from 2002 to 2010, the International AIDS Society Conference on Pathogenesis, Treatment and Prevention from 2003 to 2009, and from the Conference on Retroviruses and Opportunistic Infections from 1997 to 2010. We used search strategies determined by the Cochrane Review Group on HIV/AIDS. We also contacted researchers who work in this field and checked reference lists of related systematic reviews and of all included studies. Randomised and non-randomised controlled trials of interventions to improve adherence to ART among children and adolescents (age ≤18 years) were included. Studies had to report adherence to ART as an outcome. After one author performed an initial screening to exclude citations that did not meet the inclusion criteria, two authors did a second screening of those citations that likely met the criteria. For all articles that passed the second screening, full articles were pulled in order to make a final determination. Two authors then extracted data and graded methodological quality independently. Differences were resolved through discussion. Four studies met the inclusion criteria. No single intervention was evaluated by more than one trial. Two studies were conducted in low-income countries. Two studies were randomised controlled trials (RCT), and two were non-randomised trials. An RCT of a home-based nursing programme showed a positive effect of the intervention on knowledge and medication refills (p=.002), but no effect on CD4 count and viral load. A second RCT of caregiver medication diaries showed that the intervention group had fewer participants reporting no missed doses compared to the control group (85% vs. 92%, respectively), although this difference was not statistically significant (p=.08). The intervention had no effect on CD4 percentage or viral load. A non-randomised trial of peer support group therapy for adolescents demonstrated no change in self-reported adherence, yet the percentage of participants with suppressed viral load increased from 30% to 80% (p=.06). The second non-randomised trial found that the percentage of children achieving >80% adherence was no different between children on a lopinavir-ritonavir (LPV/r) regimen compared to children on a non-nucleoside reverse transcriptase regimen (p=.781). However, the proportion of children achieving virological suppression was significantly greater for children on the LPV/r regimen than for children on the NNRTI-containing regimen (p=.002). A home-based nursing intervention has the potential to improve ART adherence, but more evidence is needed. Medication diaries do not appear to have an effect on adherence or disease outcomes. Two interventions, an LPV/r-containing regimen and peer support therapy for adolescents, did not demonstrate improvements in adherence, yet demonstrated greater viral load suppression compared to control groups, suggesting a different mechanism for improved health outcomes. Well-designed evaluations of interventions to improve paediatric adherence to ART are needed.

Thakur N.,University of California at San Francisco
International journal of chronic obstructive pulmonary disease | Year: 2010

several studies have shown an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment. These studies have been limited by methodological issues such as diagnostic uncertainty, cross-sectional design, small sample size, or lack of appropriate referent group. This study aimed to elucidate the association between COPD and the risk of cognitive impairment compared to referent subjects without COPD. In patients with established COPD, we evaluated the impact of disease severity and impairment of respiratory physiology on cognitive impairment and the potential mitigating role of oxygen therapy. we used the Function, Living, Outcomes and Work (FLOW) cohort study of adults with COPD (n = 1202) and referent subjects matched by age, sex, and race (n = 302) to study the potential risk factors for cognitive impairment among subjects with COPD. Cognitive impairment was defined as a Mini-Mental State Exam score of <24 points. Disease severity was using Forced Expiratory Volume in one second (FEV(1)); the validated COPD Severity Score; and the BMI (Body Mass Index), Obstruction, Dyspnea, Exercise Capacity (BODE) Index. Multivariable analysis was used to control for confounding by age, sex, race, educational attainment, and cigarette smoking. COPD was associated with a substantive risk of cognitive impairment compared to referent subjects (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.043-6.64). Among COPD patients, none of the COPD severity measures were associated with the risk of cognitive impairment (P > 0.20 in all cases). Low baseline oxygen saturation was related to increased risk of cognitive impairment (OR for oxygen saturation ≤88% (OR 5.45; 95% CI 1.014-29.2; P = 0.048). Conversely, regular use of supplemental oxygen therapy decreased the risk for cognitive impairment (OR 0.14; 95% CI 0.07-0.27; P < 0.0001). COPD is a major risk factor for cognitive impairment. Among patients with COPD, hypoxemia is a major contributor and regular use of home oxygen is protective. Health care providers should consider screening their COPD patients for cognitive impairment.

Baker C.R.,University of California at San Francisco | Booth L.N.,University of California at San Francisco | Sorrells T.R.,University of California at San Francisco | Johnson A.D.,University of California at San Francisco
Cell | Year: 2012

We examine how different transcriptional network structures can evolve from an ancestral network. By characterizing how the ancestral mode of gene regulation for genes specific to a-type cells in yeast species evolved from an activating paradigm to a repressing one, we show that regulatory protein modularity, conversion of one cis-regulatory sequence to another, distribution of binding energy among protein-protein and protein-DNA interactions, and exploitation of ancestral network features all contribute to the evolution of a novel regulatory mode. The formation of this derived mode of regulation did not disrupt the ancestral mode and thereby created a hybrid regulatory state where both means of transcription regulation (ancestral and derived) contribute to the conserved expression pattern of the network. Finally, we show how this hybrid regulatory state has resolved in different ways in different lineages to generate the diversity of regulatory network structures observed in modern species. © 2012 Elsevier Inc.

King Jr. T.E.,University of California at San Francisco | Pardo A.,National Autonomous University of Mexico | Selman M.,Instituto Nacional Of Enfermedades Respiratorias
The Lancet | Year: 2011

Idiopathic pulmonary fibrosis is a devastating, age-related lung disease of unknown cause that has few treatment options. This disease was once thought to be a chronic inflammatory process, but current evidence indicates that the fibrotic response is driven by abnormally activated alveolar epithelial cells (AECs). These cells produce mediators that induce the formation of fibroblast and myofibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of the epithelial to mesenchymal transition. The fibroblast and myofibroblast foci secrete excessive amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture. The mechanisms that link idiopathic pulmonary fibrosis with ageing and aberrant epithelial activation are unknown; evidence suggests that the abnormal recapitulation of developmental pathways and epigenetic changes have a role. In this Seminar, we review recent data on the clinical course, therapeutic options, and underlying mechanisms thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis. © 2011 Elsevier Ltd.

Nagalingam N.A.,University of California at San Francisco | Lynch S.V.,University of California at San Francisco
Inflammatory Bowel Diseases | Year: 2012

Studying the role of the human microbiome as it relates to human health status has revolutionized our view of microbial community contributions to a large number of diseases, particularly chronic inflammatory disorders. The lower gastrointestinal (GI) tract houses trillions of microbial cells representing a large diversity of species in relatively well-defined phylogenetic ratios that are associated with maintenance of key aspects of host physiology and immune homeostasis. It is not surprising, therefore, that many GI inflammatory diseases, including inflammatory bowel disease (IBD), are associated with substantial changes in the composition of these microbial assemblages, either as a cause or consequence of host inflammatory response. Here we review current knowledge in the emerging field of human microbiome research as it relates to IBD, specifically focusing on Crohn's disease (CD) and ulcerative colitis (UC). We discuss bacteriotherapeutic efforts to restore GI microbial assemblage integrity via probiotic supplementation of IBD patients, and speculate on future directions for the field. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

Miller W.L.,University of California at San Francisco | Auchus R.J.,University of Texas Southwestern Medical Center
Endocrine Reviews | Year: 2011

Steroidogenesis entails processes by which cholesterol is converted to biologically active steroid hormones. Whereas most endocrine texts discuss adrenal, ovarian, testicular, placental, and other steroidogenic processes in a gland-specific fashion, steroidogenesis is better understood as a single process that is repeated in each gland with cell-type-specific variations on a single theme. Thus, understanding steroidogenesis is rooted in an understanding of the biochemistry of the various steroidogenic enzymes and cofactors and the genes that encode them. The first and rate-limiting step in steroidogenesis is the conversion of cholesterol to pregnenolone by a single enzyme, P450scc (CYP11A1), but this enzymatically complex step is subject to multiple regulatory mechanisms, yielding finely tuned quantitative regulation. Qualitative regulation determining the type of steroid to be produced is mediated by many enzymes and cofactors. Steroidogenic enzymes fall into two groups: cytochrome P450 enzymes and hydroxysteroid dehydrogenases. A cytochrome P450 may be either type 1 (in mitochondria) or type 2 (in endoplasmic reticulum), and a hydroxysteroid dehydrogenase may belong to either the aldo-keto reductase or short-chain dehydrogenase/reductase families. The activities of these enzymes are modulated by posttranslational modifications and by cofactors, especially electron-donating redox partners. The elucidation of the precise roles of these various enzymes and cofactors has been greatly facilitated by identifying the genetic bases of rare disorders of steroidogenesis. Some enzymes not principally involved in steroidogenesis may also catalyze extraglandular steroidogenesis, modulating the phenotype expected to result from some mutations. Understanding steroidogenesis is of fundamental importance to understanding disorders of sexual differentiation, reproduction, fertility, hypertension, obesity, and physiological homeostasis. Copyright © 2011 by The Endocrine Society.

DeLuca S.Z.,University of California at San Francisco | O'Farrell P.H.,University of California at San Francisco
Developmental Cell | Year: 2012

Across the eukaryotic phylogeny, offspring usually inherit their mitochondrial genome from only one of two parents: in animals, the female. Although mechanisms that eliminate paternally derived mitochondria from the zygote have been sought, the developmental stage at which paternal transmission of mitochondrial DNA is restricted is unknown in most animals. Here, we show that the mitochondria of mature Drosophila sperm lack DNA, and we uncover two processes that eliminate mitochondrial DNA during spermatogenesis. Visualization of mitochondrial DNA nucleoids revealed their abrupt disappearance from developing spermatids in a process requiring the mitochondrial nuclease, Endonuclease G. In Endonuclease G mutants, persisting nucleoids are swept out of spermatids by a cellular remodeling process that trims and shapes spermatid tails. Our results show that mitochondrial DNA is eliminated during spermatogenesis, thereby removing the capacity of sperm to transmit the mitochondrial genome to the next generation. Unlike the nuclear genome, the mitochondrial genome is only inherited from the mother. DeLuca et al. show that mature Drosophila sperm lack mitochondrial DNA (mtDNA). They uncover two developmental processes-including mtDNA degradation by Endonuclease G-that remove the mitochondrial genome from developing sperm to ensure its uniparental inheritance. © 2012 Elsevier Inc.

Oksenberg N.,University of California at San Francisco | Ahituv N.,University of California at San Francisco
Trends in Genetics | Year: 2013

The autism susceptibility candidate 2 ( AUTS2) gene is associated with multiple neurological diseases, including autism, and has been implicated as an important gene in human-specific evolution. Recent functional analysis of this gene has revealed a potential role in neuronal development. Here, we review the literature regarding AUTS2, including its discovery, expression, association with autism and other neurological and non-neurological traits, implication in human evolution, function, regulation, and genetic pathways. Through progress in clinical genomic analysis, the medical importance of this gene is becoming more apparent, as highlighted in this review, but more work needs to be done to discover the precise function and the genetic pathways associated with AUTS2. © 2013 Elsevier Ltd.

Barte H.,University of California at San Francisco
The Cochrane database of systematic reviews | Year: 2014

Yellow fever (YF) is an acute viral haemorrhagic disease prevalent in tropical Africa and Latin America. The World Health Organization (WHO) estimates that there are 200,000 cases of YF and 30,000 deaths worldwide annually. Treatment for YF is supportive, but a live attenuated virus vaccine is effective for preventing infection. WHO recommends immunisation for all individuals > 9 months living in countries or areas at risk. However, the United States Advisory Committee on Immunization Practices (ACIP) advises that YF vaccine is contraindicated in individuals with HIV. Given the large populations of HIV-infected individuals living in tropical areas where YF is endemic, YF vaccine may be an important intervention for preventing YF in immunocompromised populations. To assess the risk and benefits of YF immunisation for people infected with HIV. We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language. Randomised controlled trials and cohort studies of individuals with HIV infection who received YF vaccine (17DD or 17D-204). Two authors screened abstracts of references identified by electronic or bibliographic searches according to inclusion and exclusion criteria as detailed in the protocol. We identified 199 references and examined 19 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form. Three cohort studies were included in the review. They examined 484 patients with HIV infection who received YF immunisation. Patients with HIV infection developed significantly lower concentrations of neutralising antibodies in the first year post immunisation compared to uninfected patients, though decay patterns were similar for recipients regardless of HIV infection. No study patient with HIV infection suffered serious adverse events as a result of YF vaccination. YF vaccination can produce protective levels of neutralising antibodies in HIV patients. Immunogenicity of YF vaccine is slightly less in HIV-infected patients compared to HIV-uninfected patients. No serious adverse events related to YF vaccine were observed in HIV-infected study participants. At time of immunisation, higher CD4 cell counts and lower HIV RNA levels in patients with HIV infection seem to be key determinants for development of protective titres of neutralising antibodies. The quality of the evidence for all outcomes was low to very low. YF vaccine may potentially be used safely in HIV-infected patients, although our conclusions are limited by small numbers of patients who have been reported. To assure maximum effectiveness YF vaccine should be given to HIV-infected patients after HIV replication has been suppressed.

Warne J.P.,University of California at San Francisco | Xu A.W.,University of California at San Francisco
Trends in Endocrinology and Metabolism | Year: 2013

The central melanocortin system plays an essential role in the regulation of energy metabolism. Key to this regulation are the responses of neurons expressing proopiomelanocortin (POMC) and agouti-related protein (AgRP) to blood-borne metabolic signals. Recent evidence has demonstrated that POMC and AgRP neurons are not simply mirror opposites of each other in function and responsiveness to metabolic signals, nor are they exclusively first-order neurons. These neurons act as central transceivers, integrating both hormonal and neural signals, and then transmitting this information to peripheral tissues via the autonomic nervous system to coordinate whole-body energy metabolism. This review focuses on most recent developments obtained from rodent studies on the function, metabolic regulation, and circuitry of the central melanocortin system. © 2012 Elsevier Ltd.

Zhang H.,University of California at San Francisco | Verkman A.S.,University of California at San Francisco
Experimental Neurology | Year: 2015

Dorsal root ganglion (DRG) neurons transduce peripheral pain signals through small-diameter, non-myelinated C-fibers, which, when injured, can regenerate to restore pain sensation. Water channel aquaporin-1 (AQP1) is expressed at the plasma membrane of cell bodies and axons of DRG neurons, where it modulates the sensing of certain types of pain. Here, we found that AQP1 is also involved in DRG axonal growth and regeneration by a mechanism that may involve water transport-facilitated extension of axonal outgrowths. Spontaneous and nerve growth factor-stimulated axonal extension was reduced in cultures of AQP1-deficient DRG neurons and DRG explants compared to the wildtype. Axonal growth in AQP1-deficient DRG cultures was rescued by transfection with AQP1 or a different water-transporting AQP (AQP4), but not by a non-water-transporting AQP1 mutant. Following sciatic nerve compression injury AQP1 expression was increased in DRG neurons in wildtype mice, and DRG axonal growth was impaired in AQP1-deficient mice. Our results indicate AQP1 as a novel determinant of DRG axonal regeneration and hence a potential therapeutic target to accelerate neuronal regeneration. © 2015 Elsevier Inc.

Westhoff G.,University of California at San Francisco
The Cochrane database of systematic reviews | Year: 2013

Active management of the third stage of labour has been shown to reduce the risk of postpartum haemorrhage (PPH) greater than 1000 mL. One aspect of the active management protocol is the administration of prophylactic uterotonics, however, the type of uterotonic, dose, and and discharge from the labour ward (RR 0.18; 95% CI 0.06 to 0.53; three trials, 1091 women; T2 = 0.41, I2 = 41%) and vomiting between delivery of the baby and discharge from the labour ward (RR 0.07; 95% CI 0.02 to 0.25; three trials, 1091 women; T2 = 0.45, I2 = 30%). Prophylactic oxytocin + ergometrine versus ergot alkaloids: There was no benefit seen in the combination of oxytocin and ergometrine versus ergometrine alone in preventing PPH greater than 500 mL (RR 0.90; 95% CI 0.34 to 2.41; five trials, 2891 women; T2 = 0.89, I2 = 80%). The use of oxytocin and ergometrine was associated with increased mean blood loss (MD 61.0 mL; 95% CI 6.00 to 116.00 mL; fixed-effect analysis; one trial, 34 women; heterogeneity not applicable).In all three comparisons, there was no difference in mean length of the third stage or need for manual removal of the placenta between treatment arms. Prophylactic oxytocin at any dose decreases both PPH greater than 500 mL and the need for therapeutic uterotonics compared to placebo alone. Taking into account the subgroup analyses from both primary outcomes, to achieve maximal benefit providers may opt to implement a practice of giving prophylactic oxytocin as part of the active management of the third stage of labour at a dose of 10 IU given as an IV bolus. If IV delivery is not possible, IM delivery may be used as this route of delivery did show a benefit to prevent PPH greater than 500 mL and there was a trend to decrease the need for therapeutic uterotonics, albeit not statistically significant.Prophylactic oxytocin was superior to ergot alkaloids in preventing PPH greater than 500 mL; however, in subgroup analysis this benefit did not persist when only randomised trials with low risk of methodologic bias were analysed. Based on this, there is limited high-quality evidence supporting a benefit of prophylactic oxytocin over ergot alkaloids. However, the use of prophylactic oxytocin was associated with fewer side effects, specifically nausea and vomiting, making oxytocin the more desirable option for routine use to prevent PPH.There is no evidence of benefit when adding oxytocin to ergometrine compared to ergot alkaloids alone, and there may even be increased harm as one study showed evidence that using the combination was associated with increased mean blood loss compared to ergot alkaloids alone.Importantly, there is no evidence to suggest that prophylactic oxytocin increases the risk of retained placenta when compared to placebo or ergot alkaloids.More placebo-controlled, randomised, and double-blinded trials are needed to improve the quality of data used to evaluate the effective dose, timing, and route of administration of prophylactic oxytocin to prevent PPH. In addition, more trials are needed especially, but not only, in low- and middle-income countries to evaluate these interventions in the birth centres that shoulder the majority of the burden of PPH in order to improve maternal morbidity and mortality worldwide.

Smith C.C.,University of California at San Francisco
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2011

The 21st century ushered in the dawn of a new era of targeted therapeutics and a dramatic shift in the management of chronic-phase chronic myeloid leukemia (CP-CML) patients. Groundbreaking scientific and translational studies have led to the rapid development and approval of several effective BCR-ABL tyrosine kinase inhibitors (TKIs). In the United States, there are currently 3 approved BCR-ABL TKIs for newly diagnosed CP-CML patients. It is anticipated that clinical outcomes will continue to improve as more TKIs that address unmet medical needs are approved. However, to achieve this goal, it is critical to carefully monitor and optimally manage patients. To this end, the latest seminal clinical trial results of approved and investigational BCR-ABL TKIs and some of the salient unique features of each of these agents are summarized herein.

Cammas L.,University of California at San Francisco
Investigative ophthalmology & visual science | Year: 2012

The lens is a powerful model system to study integrin-mediated cell-matrix interaction in an in vivo context, as it is surrounded by a true basement membrane, the lens capsule. To characterize better the function of integrin-linked kinase (ILK), we examined the phenotypic consequences of its deletion in the developing mouse lens. ILK was deleted from the embryonic lens either at the time of placode invagination using the Le-Cre line or after initial lens formation using the Nestin-Cre line. Early deletion of ILK leads to defects in extracellular matrix deposition that result in lens capsule rupture at the lens vesicle stage (E13.5). If ILK was deleted at a later time-point after initial establishment of the lens capsule, rupture was prevented. Instead, ILK deletion resulted in secondary fiber migration defects and, most notably, in cell death of the anterior epithelium (E18.5-P0). Remarkably, dying cells did not stain positively for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or activated-caspase 3, suggesting that they were dying from a non-apoptotic mechanism. Moreover, cross to a Bax(fl/fl)/Bak-/- mouse line that is resistant to most forms of apoptosis failed to promote cell survival in the ILK-deleted lens epithelium. Electron microscopy revealed the presence of numerous membranous vacuoles containing degrading cellular material. CONCLUSIONS. Our study reveals a role for ILK in extracellular matrix organization, fiber migration, and cell survival. Furthermore, to our knowledge we show for the first time that ILK disruption results in non-apoptotic cell death in vivo.

Bikle D.D.,University of California at San Francisco
Trends in Endocrinology and Metabolism | Year: 2010

Vitamin D is not just for preventing rickets and osteomalacia. Recent findings in animal experiments, epidemiologic studies and clinical trials indicate that adequate vitamin D levels are important for cancer prevention, controlling hormone levels and regulating the immune response. Although 25 hydroxyvitamin D (25OHD) levels >10 ng/ml can prevent rickets and osteomalacia, these levels are not sufficient to provide these more recently discovered clinical benefits. Rather, levels of 25OHD >30 ng/ml are generally recommended. Determining optimal levels of 25OHD and the amount of vitamin D supplementation required to achieve those levels for the numerous actions of vitamin D will only be established with additional trials. In this review, these newer applications are summarized and therapeutic considerations are provided. © 2010.

DeNardo D.G.,University of California at San Francisco | Andreu P.,University of California at San Francisco | Coussens L.M.,University of California at San Francisco
Cancer and Metastasis Reviews | Year: 2010

Tumor-associated myeloid cells have been implicated in regulating many of the "hallmarks of cancer" and thus fostering solid tumor development and metastasis. However, the same innate leukocytes also participate in anti-tumor immunity and restraint of malignant disease. While many factors regulate the propensity of myeloid cells to promote or repress cancerous growths, polarized adaptive immune responses by B and T lymphocytes have been identified as regulators of many aspects of myeloid cell biology by specifically regulating their functional capabilities. Here, we detail the diversity of heterogeneous B and T lymphocyte populations and their impacts on solid tumor development through their abilities to regulate myeloid cell function in solid tumors. © The Author(s) 2010.

Murray J.F.,University of California at San Francisco
American Journal of Respiratory and Critical Care Medicine | Year: 2012

U.S. taxpayers and scientists throughout the world are profiting enormously from the Human Genome Project and will continue to profit in the foreseeable future. Sensational technical advances, which show no signs of slowing, are constantly depressing the price of genomic profiling, and it looks like the NIH's goal of $1000 per analysis might be met before its projected appearance in 2014. Initial efforts to translate the immense cache of fundamental genomic information into improvements in the practice of medicine were both natural and obligatory according to the precedents of science. Though the accomplishments of the more than a decade of all-out research have been disappointing, they were accompanied by an indisputable message: getting from where we are today to where preconceived visions are leading us is going to be immensely more complicated, more time consuming, and more costly than imagined at the outset. My chief complaint is directed at the efforts to co-opt the term "personalized medicine," which doctors have been consistently practicing for centuries. While contemplating this criticism, the powers-that-be should also reappraise where the benefits of hoped-for clinical applications of genomic analysis stand in competition with the need for continued funding in support of traditional basic science and clinical research, which have so greatly enriched the current practice of personalized medicine. Copyright © 2012 by the American Thoracic Society.

Huysentruyt L.C.,University of California at San Francisco
Cancer and Metastasis Reviews | Year: 2010

Emerging evidence suggests that many metastatic cancers arise from cells of the myeloid/macrophage lineage regardless of the primary tissue of origin. A myeloid origin of metastatic cancer stands apart from origins involving clonal evolution or epithelial-mesenchymal transitions. Evidence is reviewed demonstrating that numerous human cancers express multiple properties of macrophages including phagocytosis, fusogenicity, and gene/protein expression. It is unlikely that the macrophage properties expressed in metastatic cancers arise from sporadic random mutations in epithelial cells, but rather from damage to an already existing mesenchymal cell, e.g., a myeloid/macrophage-type cell. Such cells would naturally embody the capacity to express the multiple behaviors of metastatic cells. The view of metastasis as a myeloid/macrophage disease will impact future cancer research and anti-metastatic therapies. © 2010 The Author(s).

Wolters P.J.,University of California at San Francisco | Collard H.R.,University of California at San Francisco | Jones K.D.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2014

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated. © 2014 by Annual Reviews. All rights reserved.

Papa F.R.,University of California at San Francisco
Cold Spring Harbor Perspectives in Medicine | Year: 2012

Overwhelming of protein folding in the endoplasmic reticulum (ER)-referred to as "ER stress"-activates a set of intracellular signaling pathways termed the unfolded protein response (UPR). Beneficial outputs of the UPR promote adaptation in cells experiencing manageably low levels of ER stress. However, if ER stress reaches critically high levels, the UPR uses destructive outputs to trigger programmed cell death. Genetic mutations in various UPR components cause inherited syndromes of diabetes mellitus in both rodents and humans, implicating the UPR in the proper functioning and survival of pancreatic islet β cells. Markers of chronically elevated ER stress, terminal UPR signaling, and apoptosis are evident in β cells in these rare disorders; these markers are similarly present in islets of human patients with common forms of diabetes. These findings promise to enhance our molecular understanding of human diabetes significantly and may lead to new and effective therapies. © 2012 Cold Spring Harbor Laboratory Press.

Ma H.,University of California at San Francisco | Xu H.,University of California at San Francisco | O'Farrell P.H.,University of California at San Francisco
Nature Genetics | Year: 2014

It is not known how selection affects mutations in the multiple copies of the mitochondrial genome. We transferred cytoplasm between D. melanogaster embryos carrying mitochondrial mutations to create heteroplasmic lines transmitting two mitochondrial genotypes. Increased temperature imposed selection against a temperature-sensitive mutation affecting cytochrome oxidase, driving decreases in the abundance of the mutant genome over successive generations. Selection did not influence the health or fertility of the flies but acted during midoogenesis to influence competition between the genomes. Mitochondria might incur an advantage through selective localization, survival or proliferation, yet timing and insensitivity to park mutation suggest that preferential proliferation underlies selection. Selection drove complete replacement of the temperature-sensitive mitochondrial genome by a wild-type genome but also stabilized the multigenerational transmission of two genomes carrying complementing detrimental mutations. While they are so balanced, these stably transmitted mutations have no detrimental phenotype, but their segregation could contribute to disease phenotypes and somatic aging. © 2014 Nature America, Inc.

Julian L.J.,University of California at San Francisco
Arthritis care & research | Year: 2011

Depression and cardiovascular disease are common and debilitating comorbidities associated with systemic lupus erythematosus (SLE). In this study, history of cardiovascular events, cardiovascular risk factors, and SLE disease-related factors were evaluated as longitudinal predictors of depression in a large cohort of patients with SLE. Data were derived from 663 adult participants in the 2004-2008 Lupus Outcomes Study, who were followed for up to 5 annual interviews. Multivariate logistic regression analyses using generalized estimating equations were used to determine predictors of the development of increased depressive symptom severity over a 12-month period (Center for Epidemiologic Studies Depression Scale [CES-D] score of 23 or greater), yielding 2,224 paired observations. Predictors included sociodemographics, traditional cardiovascular risk factors (reported presence of heart disease, history of stroke or myocardial infarction, hypertension, hypercholesterolemia, diabetes mellitus, obesity, smoking status, and family history), and SLE-specific risk factors (glucocorticoid use, renal involvement, disease duration, and disease activity). The annual incidence of depression was 12% in this cohort. Multivariate predictors of new-onset depression included younger age (ages 20-39 years: odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.3-3.9; ages 40-59 years: OR 1.8, 95% CI 1.1-2.7), Hispanic/Latino ethnicity (OR 1.8, 95% CI 1.2-2.8), having some college education (OR 1.8, 95% CI 1.1-3.0), baseline CES-D score (OR per point 1.1, 95% CI 1.1-1.2), presence of diabetes mellitus (OR 1.8, 95% CI 1.1-2.8), and baseline SLE disease activity (OR 1.2, 95% CI 1.1-1.4). These results suggest that, in addition to known sociodemographic factors, the presence of diabetes mellitus and SLE disease activity may play a role in the development of depression in SLE. Copyright © 2011 by the American College of Rheumatology.

Lowell C.A.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2011

The response of innate immune cells to growth factors, immune complexes, extracellular matrix proteins, cytokines, pathogens, cellular damage, and many other stimuli is regulated by a complex net of intracellular signal transduction pathways. The majority of these pathways are either initiated or modulated by Src-family or Syk tyrosine kinases present in innate cells. The Src-family kinases modulate the broadest range of signaling responses, including regulating immunoreceptors, C-type lectins, integrins, G-protein-coupled receptors, and many others. Src-family kinases also modulate the activity of other kinases, including the Tec-family members as well as FAK and Pyk2. Syk kinase is required for initiation of signaling involving receptors that utilize immunoreceptor tyrosine activation (ITAM) domains. This article reviews the major activating and inhibitory signaling pathways regulated by these cytoplasmic tyrosine kinases, illuminating the many examples of signaling cross talk between pathways. © 2011 Cold Spring Harbor Laboratory Press.

Bastian B.C.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2014

Melanomas comprise multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ-line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain-of-function mutations in one of several primary oncogenes, which typically lead to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor-suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about the pathogenesis and clinical, histologic, and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. © 2014 by Annual Reviews. All rights reserved.

Reeves S.,University of California at San Francisco
The Cochrane database of systematic reviews | Year: 2013

The delivery of effective, high-quality patient care is a complex activity. It demands health and social care professionals collaborate in an effective manner. Research continues to suggest that collaboration between these professionals can be problematic. Interprofessional education (IPE) offers a possible way to improve interprofessional collaboration and patient care. To assess the effectiveness of IPE interventions compared to separate, profession-specific education interventions; and to assess the effectiveness of IPE interventions compared to no education intervention. For this update we searched the Cochrane Effective Practice and Organisation of Care Group specialised register, MEDLINE and CINAHL, for the years 2006 to 2011. We also handsearched the Journal of Interprofessional Care (2006 to 2011), reference lists of all included studies, the proceedings of leading IPE conferences, and websites of IPE organisations. Randomised controlled trials (RCTs), controlled before and after (CBA) studies and interrupted time series (ITS) studies of IPE interventions that reported objectively measured or self reported (validated instrument) patient/client or healthcare process outcomes. At least two review authors independently assessed the eligibility of potentially relevant studies. For included studies, at least two review authors extracted data and assessed study quality. A meta-analysis of study outcomes was not possible due to heterogeneity in study designs and outcome measures. Consequently, the results are presented in a narrative format. This update located nine new studies, which were added to the six studies from our last update in 2008. This review now includes 15 studies (eight RCTs, five CBA and two ITS studies). All of these studies measured the effectiveness of IPE interventions compared to no educational intervention. Seven studies indicated that IPE produced positive outcomes in the following areas: diabetes care, emergency department culture and patient satisfaction; collaborative team behaviour and reduction of clinical error rates for emergency department teams; collaborative team behaviour in operating rooms; management of care delivered in cases of domestic violence; and mental health practitioner competencies related to the delivery of patient care. In addition, four of the studies reported mixed outcomes (positive and neutral) and four studies reported that the IPE interventions had no impact on either professional practice or patient care. This updated review reports on 15 studies that met the inclusion criteria (nine studies from this update and six studies from the 2008 update). Although these studies reported some positive outcomes, due to the small number of studies and the heterogeneity of interventions and outcome measures, it is not possible to draw generalisable inferences about the key elements of IPE and its effectiveness. To improve the quality of evidence relating to IPE and patient outcomes or healthcare process outcomes, the following three gaps will need to be filled: first, studies that assess the effectiveness of IPE interventions compared to separate, profession-specific interventions; second, RCT, CBA or ITS studies with qualitative strands examining processes relating to the IPE and practice changes; third, cost-benefit analyses.

Fujimura K.E.,University of California at San Francisco
Nature Medicine | Year: 2016

Gut microbiota bacterial depletions and altered metabolic activity at 3 months are implicated in childhood atopy and asthma. We hypothesized that compositionally distinct human neonatal gut microbiota (NGM) exist, and are differentially related to relative risk (RR) of childhood atopy and asthma. Using stool samples (n = 298; aged 1–11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age, 35 d) were divisible into three microbiota composition states (NGM1–3). Each incurred a substantially different RR for multisensitized atopy at age 2 years and doctor-diagnosed asthma at age 4 years. The highest risk group, labeled NGM3, showed lower relative abundance of certain bacteria (for example, Bifidobacterium, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi (Candida and Rhodotorula) and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of human adult peripheral T cells with sterile fecal water from NGM3 subjects increased the proportion of CD4+ cells producing interleukin (IL)-4 and reduced the relative abundance of CD4+CD25+FOXP3+ cells. 12,13-DiHOME, enriched in NGM3 versus lower-risk NGM states, recapitulated the effect of NGM3 fecal water on relative CD4+CD25+FOXP3+ cell abundance. These findings suggest that neonatal gut microbiome dysbiosis might promote CD4+ T cell dysfunction associated with childhood atopy. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Witte J.S.,University of California at San Francisco | Visscher P.M.,University of Queensland | Wray N.R.,University of Queensland
Nature Reviews Genetics | Year: 2014

Our understanding of the genetic basis of disease has evolved from descriptions of overall heritability or familiality to the identification of large numbers of risk loci. One can quantify the impact of such loci on disease using a plethora of measures, which can guide future research decisions. However, different measures can attribute varying degrees of importance to a variant. In this Analysis, we consider and contrast the most commonly used measures-specifically, the heritability of disease liability, approximate heritability, sibling recurrence risk, overall genetic variance using a logarithmic relative risk scale, the area under the receiver-operating curve for risk prediction and the population attributable fraction-and give guidelines for their use that should be explicitly considered when assessing the contribution of genetic variants to disease. © 2014 Macmillan Publishers Limited. All rights reserved.

Nicholls R.A.,University of Cambridge | Fischer M.,University of California at San Francisco | Mcnicholas S.,University of York | Murshudov G.N.,University of Cambridge
Acta Crystallographica Section D: Biological Crystallography | Year: 2014

The identification and exploration of (dis)similarities between macromolecular structures can help to gain biological insight, for instance when visualizing or quantifying the response of a protein to ligand binding. Obtaining a residue alignment between compared structures is often a prerequisite for such comparative analysis. If the conformational change of the protein is dramatic, conventional alignment methods may struggle to provide an intuitive solution for straightforward analysis. To make such analyses more accessible, the Procrustes Structural Matching Alignment and Restraints Tool (ProSMART) has been developed, which achieves a conformation-independent structural alignment, as well as providing such additional functionalities as the generation of restraints for use in the refinement of macromolecular models. Sensible comparison of protein (or DNA/RNA) structures in the presence of conformational changes is achieved by enforcing neither chain nor domain rigidity. The visualization of results is facilitated by popular molecular-graphics software such as CCP4mg and PyMOL, providing intuitive feedback regarding structural conservation and subtle dissimilarities between close homologues that can otherwise be hard to identify. Automatically generated colour schemes corresponding to various residue-based scores are provided, which allow the assessment of the conservation of backbone and side-chain conformations relative to the local coordinate frame. Structural comparison tools such as ProSMART can help to break the complexity that accompanies the constantly growing pool of structural data into a more readily accessible form, potentially offering biological insight or influencing subsequent experiments. © 2014 International Union of Crystallography.

Verkman A.S.,University of California at San Francisco
Physical Biology | Year: 2013

Diffusion of solutes and macromolecules in the extracellular space (ECS) in brain is important for non-synaptic intercellular communication, extracellular ionic buffering, and delivery of drugs and metabolites. Diffusion in tumor ECS is important for delivery of anti-tumor drugs. The ECS in brain comprises ∼20% of brain parenchymal volume and contains cell-cell gaps down to ∼50 nm. We have developed fluorescence methods to quantify solute diffusion in the ECS, allowing measurements deep in solid tissues using microfiberoptics with micron tip size. Diffusion through the tortuous ECS in brain is generally slowed by ∼3-5-fold compared with that in water, with approximately half of the slowing due to tortuous ECS geometry and half due to the mildly viscous extracellular matrix (ECM). Mathematical modeling of slowed diffusion in an ECS with reasonable anatomical accuracy is in good agreement with experiment. In tumor tissue, diffusion of small macromolecules is only mildly slowed (<3-fold slower than in water) in superficial tumor, but is greatly slowed (>10-fold) at a depth of few millimeters as the tumor tissue becomes more compact. Slowing by ECM components such as collagen contribute to the slowed diffusion. Therefore, as found within cells, cellular crowding and highly tortuous transport can produce only minor slowing of diffusion in the ECS. © 2013 IOP Publishing Ltd.

Minzenberg M.J.,University of California at San Francisco
Neuropsychopharmacology | Year: 2014

Control-related cognitive processes such as rule selection are associated with cortical oscillations in the theta, alpha and, beta ranges, and modulated by catecholamine neurotransmission. Thus, a potential strategy for improving cognitive control deficits in schizophrenia would be to use pro-catecholamine pharmacological agents to augment these control-related oscillations. In a double-blind, placebo-controlled (within-subjects) study, we tested the effects of adjunctive single-dose modafinil 200 mg on rule-related 4-30 Hz oscillations in 23 stable schizophrenia patients, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine the power of 4-30 Hz oscillations. Modafinil (relative to placebo) enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with modest effects during rule maintenance. Modafinil treatment in schizophrenia augments middle-frequency cortical oscillatory power associated with rule selection, and may subserve diverse subcomponent processes in proactive cognitive control.Neuropsychopharmacology advance online publication, 23 July 2014; doi:10.1038/npp.2014.155.

Shin S.Y.,University of California at San Francisco
Arthritis care & research | Year: 2013

Research shows a gap between perceived cognitive dysfunction and objective neuropsychological performance in persons with chronic diseases. We explored this relationship in persons with rheumatoid arthritis (RA). Individuals from a longitudinal cohort study of RA participated in a study visit that included physical, psychosocial, cognitive, and biologic metrics. Subjective cognitive dysfunction was assessed using the Perceived Deficits Questionnaire (PDQ; range 0-20, where higher scores = greater perceived impairment). Objective cognitive impairment was assessed using a battery of 12 standardized neuropsychological measures yielding 16 indices. On each test, subjects were classified as impaired if they performed 1 SD below the age-based population norms. Total cognitive function scores were calculated by summing the transformed scores (range 0-16, where higher scores = greater impairment). Multiple linear regression analyses determined the relationship of the total cognitive function score with the PDQ score, controlling for sex, race, marital status, income, education, disease duration, disease severity, depression, and fatigue. One hundred twenty subjects (mean ± SD age 58.5 ± 11.0 years) were included. Mean ± SD scores of total cognitive function and the PDQ were 2.5 ± 2.2 (range 0-10) and 5.8 ± 3.8 (range 0-16), respectively. In multivariate analysis, there was no significant relationship between the total cognitive function score and the PDQ score. However, depression and fatigue (β = 0.32, P < 0.001 and β = 0.31, P = 0.001, respectively) were significantly associated with the PDQ score. The findings emphasize the gap between subjective and objective measures of cognitive impairment and the importance of considering psychological factors within the context of cognitive symptoms in clinical settings. Copyright © 2013 by the American College of Rheumatology.

Potter M.B.,University of California at San Francisco
Annual Review of Public Health | Year: 2013

Colorectal cancer is a significant cause of mortality in the United States and globally. In the United States, increased access to screening and effective treatment has contributed to a reduction in colorectal cancer incidence and mortality for the general population, though significant disparities persist. Worldwide, the disparities are even more pronounced, with vastly different colorectal cancer mortality rates and trends among nations. Newly organized colorectal cancer screening programs in economically developed countries with a high burden of colorectal cancer may provide pathways to reduce these disparities over time. This article provides an overview of colorectal cancer incidence, mortality, screening, and disparities in the United States and other world populations. Promising strategies and resources are identified to address colorectal cancer screening rates and disparities in the United States and worldwide. © 2013 by Annual Reviews. All rights reserved.

Shewan A.,University of California at San Francisco | Eastburn D.J.,University of California at San Francisco | Mostov K.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2011

Inositol phospholipids have been implicated in almost all aspects of cellular physiology including spatiotemporal regulation of cellular signaling, acquisition of cellular polarity, specification of membrane identity, cytoskeletal dynamics, and regulation of cellular adhesion, motility, and cytokinesis. In this review, we examine the critical role phosphoinositides play in these processes to execute the establishment and maintenance of cellular architecture. Epithelial tissues perform essential barrier and transport functions in almost all major organs. Key to their development and function is the establishment of epithelial cell polarity.We place a special emphasis on highlighting recent studies demonstrating phosphoinositide regulation of epithelial cell polarity and how individual cells use phosphoinositides to further organize into epithelial tissues. © 2011 Cold Spring Harbor Laboratory Press.

Kornberg T.B.,University of California at San Francisco
Science Signaling | Year: 2011

Hedgehog, an essential protein for the development of many vertebrate and invertebrate organs, signals at both short and long distances to control growth and patterning. The mechanism by which it moves between source and target cells is not known, but characterization of the covalent modification of its N terminus with palmitate and of its C terminus with cholesterol has led to the suggestion that the lipophilic properties of the modified protein serve to regulate movement after its secretion into the extracellular space. Another interpretation and model is that the C-terminal cholesterol acts to target Hedgehog to an intracellular trafficking pathway that prepares Hedgehog for release in an encapsulated form.

Fox E.P.,University of California at San Francisco
Transcription | Year: 2012

Candida albicans is a commensal microorganism of the human microbiome; it is also the most prevalent fungal pathogen of humans. Many infections caused by C. albicans are a direct consequence of its proclivity to form biofilms--resilient, surface-associated communities of cells where individual cells acquire specialized properties that are distinct from those observed in suspension cultures. We recently identified the transcriptional network that orchestrates the formation of biofilms in C. albicans. These results set the stage for understanding how biofilms are formed and, once formed, how the specialized properties of biofilms are elaborated. This information will provide new insight for understanding biofilms in more detail and may lead to improvements in preventing and treating biofilm-based infections in the future.

Bainbridge K.E.,U.S. National Institutes of Health | Wallhagen M.I.,University of California at San Francisco
Annual Review of Public Health | Year: 2014

Despite contributing substantially to disability in the United States, age-related hearing loss is an underappreciated public health concern. Loss of hearing sensitivity has been documented in two-thirds of adults aged 70 years and older and has been associated with communication difficulties, lower health-related quality of life, and decreased physical and cognitive function. Management strategies for age-related hearing loss are costly, yet the indirect costs due to lost productivity among people with communication difficulties are also substantial and likely to grow. Hearing aids can improve health-related quality of life, but the majority of people with documented hearing loss do not report using them. Uncovering effective means to improve the utilization of hearing health care services is essential for meeting the hearing health care demands of our aging population. The importance of hearing for general well-being warrants an effort to enhance awareness among the general population of the indications of hearing loss and options for assistance. ©2014 by Annual Reviews. All rights reserved.

Gray D.C.,University of California at San Francisco | Mahrus S.,University of California at San Francisco | Wells J.A.,University of California at San Francisco
Cell | Year: 2010

Apoptosis is a conserved cellular pathway that results in the activation of cysteine- aspartyl proteases, or caspases. To dissect the nonredundant roles of the executioner caspase-3, -6, and -7 in orchestrating apoptosis, we have developed an orthogonal protease to selectively activate each isoform in human cells. Our approach uses a split-tobacco etch virus (TEV) protease under small-molecule control, which we call the SNIPer, with caspase alleles containing genetically encoded TEV cleavage sites. These studies reveal that all three caspases are transiently activated but only activation of caspase-3 or -7 is sufficient to induce apoptosis. Proteomic analysis shown here and from others reveals that 20 of the 33 subunits of the 26S proteasome can be cut by caspases, and we demonstrate synergy between proteasome inhibition and dose-dependent caspase activation. We propose a model of proteolytic reciprocal negative regulation with mechanistic implications for the combined clinical use of proteasome inhibitors and proapoptotic drugs. PaperClip: © 2010 Elsevier Inc.

Dadarlat M.C.,University of California at San Francisco | O'Doherty J.E.,University of California at San Francisco | Sabes P.N.,University of California at San Francisco
Nature Neuroscience | Year: 2015

Proprioception-the sense of the body's position in space-is important to natural movement planning and execution and will likewise be necessary for successful motor prostheses and brain-machine interfaces (BMIs). Here we demonstrate that monkeys were able to learn to use an initially unfamiliar multichannel intracortical microstimulation signal, which provided continuous information about hand position relative to an unseen target, to complete accurate reaches. Furthermore, monkeys combined this artificial signal with vision to form an optimal, minimum-variance estimate of relative hand position. These results demonstrate that a learning-based approach can be used to provide a rich artificial sensory feedback signal, suggesting a new strategy for restoring proprioception to patients using BMIs, as well as a powerful new tool for studying the adaptive mechanisms of sensory integration. © 2015 Nature America, Inc. All rights reserved.

Shore G.C.,McGill University | Papa F.R.,University of California at San Francisco | Oakes S.A.,University of California at San Francisco
Current Opinion in Cell Biology | Year: 2011

Inability to meet protein folding demands within the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), a signaling pathway with both adaptive and apoptotic outputs. While some secretory cell types have a remarkable ability to increase protein folding capacity, their upper limits can be reached when pathological conditions overwhelm the fidelity and/or output of the secretory pathway. Irremediable 'ER stress' induces apoptosis and contributes to cell loss in several common human diseases, including type 2 diabetes and neurodegeneration. Researchers have begun to elucidate the molecular switches that determine when ER stress is too great to repair and the signals that are then sent from the UPR to execute the cell. © 2010 Elsevier Ltd.

Bhakta N.R.,University of California at San Francisco | Woodruff P.G.,University of California at San Francisco
Immunological Reviews | Year: 2011

A large body of experimental evidence supports the hypothesis that T-helper 2 (Th2) cytokines orchestrate allergic airway inflammation in animal models. However, human asthma is heterogeneous with respect to clinical features, cellular sources of inflammation, and response to common therapies. This disease heterogeneity has been investigated using sputum cytology as well as unbiased clustering approaches using cellular and clinical data. Important differences in cytokine-driven inflammation may underlie this heterogeneity, and studies in human subjects with asthma have begun to elucidate these molecular differences. This molecular heterogeneity may be assessed by existing biomarkers (induced sputum evaluation or exhaled nitric oxide testing) or may require novel biomarkers. Effective testing and application of emerging therapies that target Th2 cytokines will depend on accurate and easily obtained biomarkers of this molecular heterogeneity in asthma. Furthermore, whether other non-Th2 cytokine pathways underlie airway inflammation in specific subsets of patients with asthma is an unresolved question and an important goal of future research using both mouse models and human studies. © 2011 John Wiley & Sons A/S.

Cheng Y.W.,University of California at San Francisco
Obstetrics and Gynecology | Year: 2010

Objective: To estimate whether length of the first stage of labor is associated with adverse maternal and neonatal outcomes. Methods: This is a retrospective cohort study of nulliparous women with term, singleton gestations delivered in one academic center between 1990 and 2008. The length of the first stage was stratified into three subgroups: less than the 5th percentile, 5th to 95th percentile, and greater than the 95th percentile. Maternal and neonatal outcomes were compared using the χ test. Multivariable logistic regression models were used to control for confounders. Results: Of the 10,661 nulliparous women meeting study criteria, the median (50th percentile) length of the first stage was 10.5 hours. Compared with women with a first stage between 2.8 and 30 hours (5th to 95th percentile thresholds), the risk of cesarean delivery was higher (6.1% compared with 13.5%; adjusted odds ratio [OR], 2.28, 95% confidence interval [CI], 1.92-2.72) in women with a first stage longer than 30 hours (greater than the 95th percentile). These women also had higher odds of chorioamnionitis (12.5% compared with 23.5%; adjusted OR, 1.58; 95% CI, 1.25-1.98) and neonatal admission to the neonatal intensive care unit (4.7% compared with 9.8%; adjusted OR, 1.53; 95% CI, 1.18-1.97) but no other associated adverse neonatal outcomes. Conclusion: Women with a prolonged first stage of labor have higher odds of cesarean delivery and chorioamnionitis, but their neonates are not at risk of increased morbidity. © 2010 by The American College of Obstetricians and Gynecologists.

Jiang N.,University of California at San Francisco | Ling P.M.,University of California at San Francisco
American Journal of Public Health | Year: 2013

Objectives. We examined cigarette smoking and quit attempts in the context of alcohol use and bar attendance among young adult bar patrons with different smoking patterns. Methods. We used randomized time location sampling to collect data among adult bar patrons aged 21 to 26 years in San Diego, California (n = 1235; response rate = 73%). We used multinomial and multivariate logistic regression models to analyze the association between smoking and quit attempts and both drinking and binge drinking among occasional, regular, very light, and heavier smokers, controlling for age, gender, race/ethnicity, and education. Results. Young adult bar patrons reported high rates of smoking and co-use of cigarettes and alcohol. Binge drinking predicted smoking status, especially occasional and very light smoking. All types of smokers reported alcohol use, and bar attendance made it harder to quit. Alcohol use was negatively associated with quit attempts for very light smokers, but positively associated with quitting among heavier smokers. Conclusions. Smoking and co-use of cigarettes and alcohol are common among young adult bar patrons, but there are important differences by smoking patterns. Tobacco interventions for young adults should prioritize bars and address alcohol use.

Murnane J.P.,University of California at San Francisco
Cancer Research | Year: 2010

Cancer cells commonly have a high rate of telomere loss, even when expressing telomerase, contributing to chromosome instability and tumor cell progression. This review addresses the hypothesis that this high rate of telomere loss results from a combination of four factors. The first factor is an increase in the frequency of double-strand breaks (dsb) at fragile sites in cancer cells due to replication stress. The second factor is that telomeres are fragile sites. The third factor is that subtelomeric regions are highly sensitive to dsbs, so that dsbs near telomeres have an increased probability of resulting in chromosome instability. The fourth factor is that cancer cells may be deficient in chromosome healing, the de novo addition of telomeres to the sites of dsbs, a mechanism that prevents chromosome instability resulting from dsbs near telomeres. Understanding these factors and how they influence telomere loss will provide important insights into the mechanisms of chromosome instability and the development of novel approaches for anti-cancer therapy. ©2010 AACR.

Lauring A.S.,University of California at San Francisco | Andino R.,University of California at San Francisco
PLoS Pathogens | Year: 2010

A large number of medically important viruses, including HIV, hepatitis C virus, and influenza, have RNA genomes. These viruses replicate with extremely high mutation rates and exhibit significant genetic diversity. This diversity allows a viral population to rapidly adapt to dynamic environments and evolve resistance to vaccines and antiviral drugs. For the last 30 years, quasispecies theory has provided a population-based framework for understanding RNA viral evolution. A quasispecies is a cloud of diverse variants that are genetically linked through mutation, interact cooperatively on a functional level, and collectively contribute to the characteristics of the population. Many predictions of quasispecies theory run counter to traditional views of microbial behavior and evolution and have profound implications for our understanding of viral disease. Here, we discuss basic principles of quasispecies theory and describe its relevance for our understanding of viral fitness, virulence, and antiviral therapeutic strategy. © 2010 Lauring, Andino.

Kenyon C.,University of California at San Francisco
Annals of the New York Academy of Sciences | Year: 2010

In the nematode Caenorhabditis elegans and the fruit fly Drosophila, loss of the germline stem cells activates lifespan-extending FOXO-family transcription factors in somatic tissues and extends lifespan, suggesting the existence of an evolutionarily conserved pathway that links reproductive state and aging. Consistent with this idea, reproductive tissues have been shown to influence the lifespans of mice and humans as well. In C. elegans, loss of the germ cells activates a pathway that triggers nuclear localization of the FOXO transcription factor DAF-16 in endodermal tissue. DAF-16 then acts in the endoderm to activate downstream lifespan-extending genes. DAF-16 is also required for inhibition of insulin/insulin-like growth factor 1 (IGF-1) signaling to extend lifespan. However, the mechanisms by which inhibition of insulin/IGF-1 signaling and germline loss activate DAF-16/FOXO are distinct. As loss of the germ cells further doubles the already-long lifespan of insulin/IGF-1 pathway mutants, a better understanding of this reproductive longevity pathway could potentially suggest powerful ways to increase healthy lifespan in humans. © 2010 New York Academy of Sciences.

Whooley M.A.,University of California at San Francisco | Wong J.M.,University of California at Irvine
Annual Review of Clinical Psychology | Year: 2013

During the past two decades, research in the field of depression and cardiovascular disorders has exploded. Multiple studies have demonstrated that depression is more prevalent in populations with cardiovascular disease, is a robust risk factor for the development of cardiovascular disease in healthy populations, and is predictive of adverse outcomes (such as myocardial infarction and death) among populations with preexisting cardiovascular disease. Mechanistic studies have shown that poor health behaviors, such as physical inactivity, medication nonadherence, and smoking, strongly contribute to this association. Small randomized trials have found that antidepressant therapies may improve cardiac outcomes. Based on this accumulating evidence, the American Heart Association has recommended routine screening for depression in all patients with coronary heart disease. This review examines the key epidemiological literature on depression and cardiovascular disorders and discusses our current understanding of the mechanisms responsible for this association. We also examine current recommendations for screening, diagnosis, and management of depression. We conclude by highlighting new research areas and discussing therapeutic management of depression in patients with cardiovascular disorders. Copyright © 2013 by Annual Reviews.

Anderson M.S.,University of California at San Francisco | Su M.A.,University of North Carolina at Chapel Hill
Current Opinion in Immunology | Year: 2011

In the thymus, developing T cells that react against self-antigens with high affinity are deleted in the process of negative selection. An essential component of this process is the display of self-antigens, including those whose expression are usually restricted to specific tissues, to developing T cells within the thymus. The Autoimmune Regulator (Aire) gene plays a crucial role in the expression of tissue specific self-antigens within the thymus, and disruption of Aire function results in spontaneous autoimmunity in both humans and mice. Recent advances have been made in our understanding of how Aire influences the expression of thousands of tissue-specific antigens in the thymus. Additional roles of Aire, including roles in chemokine and cytokine expression, have also been revealed. Factors important in the differentiation of Aire-expressing medullary thymic epithelial cells have been defined. Finally, the identity of antigen presenting cells in negative selection, including the role of medullary thymic epithelial cells in displaying tissue specific antigens to T cells, has also been clarified. © 2010 Elsevier Ltd.

Colby D.W.,University of California at San Francisco
Cold Spring Harbor perspectives in biology | Year: 2011

The discovery of infectious proteins, denoted prions, was unexpected. After much debate over the chemical basis of heredity, resolution of this issue began with the discovery that DNA, not protein, from pneumococcus was capable of genetically transforming bacteria (Avery et al. 1944). Four decades later, the discovery that a protein could mimic viral and bacterial pathogens with respect to the transmission of some nervous system diseases (Prusiner 1982) met with great resistance. Overwhelming evidence now shows that Creutzfeldt-Jakob disease (CJD) and related disorders are caused by prions. The prion diseases are characterized by neurodegeneration and lethality. In mammals, prions reproduce by recruiting the normal, cellular isoform of the prion protein (PrP(C)) and stimulating its conversion into the disease-causing isoform (PrP(Sc)). PrP(C) and PrP(Sc) have distinct conformations: PrP(C) is rich in α-helical content and has little β-sheet structure, whereas PrP(Sc) has less α-helical content and is rich in β-sheet structure (Pan et al. 1993). The conformational conversion of PrP(C) to PrP(Sc) is the fundamental event underlying prion diseases. In this article, we provide an introduction to prions and the diseases they cause.

Bindman A.B.,University of California at San Francisco
Journal of the American College of Radiology | Year: 2014

CMS is testing a range of payment policy options, including pay for performance, bundled payments, and shared savings through accountable care organizations. Radiologists can anticipate that the basis for how they are paid by Medicare will change and that they will need to play a greater role than has been required of them in the traditional fee-for-service payment system to demonstrate that imaging studies are used safely and efficiently. © 2014 Published by Elsevier on behalf of American College of Radiology.

Chen N.,University of California at San Francisco | Debnath J.,University of California at San Francisco
FEBS Letters | Year: 2010

Autophagy, or cellular self-digestion, is activated in cancer cells in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance. Nonetheless, genetic evidence supports that autophagy functions as a tumor suppressor mechanism. Hence, the precise role of autophagy during cancer progression and treatment is both tissue and context dependent. Here, we discuss our current understanding of the biological functions of autophagy during cancer development, overview how autophagy is regulated by cancer-associated signaling pathways, and review how autophagy inhibition is being exploited to improve clinical outcomes. © 2009 Federation of European Biochemical Societies.

Berger A.C.,University of California at San Francisco | Whistler J.L.,University of California at San Francisco
Annals of Neurology | Year: 2010

Mu opioid receptor (MOR) agonists such as morphine are extremely effective treatments for acute pain. In the setting of chronic pain, however, their long-term utility is limited by the development of tolerance and physical dependence. Drug companies have tried to overcome these problems by simply "dialing up" signal transduction at the receptor, designing more potent and efficacious agonists and more long-lasting formulations. Neither of these strategies has proven to be successful, however, because the net amount of signal transduction, particularly over extended periods of drug use, is a product of much more than the pharmacokinetic properties of potency, efficacy, half-life, and bioavailability, the mainstays of traditional pharmaceutical screening. Both the quantity and quality of signal transduction are influenced by many regulated processes, including receptor desensitization, trafficking, and oligomerization. Importantly, the efficiency with which an agonist first stimulates signal transduction is not necessarily related to the efficiency with which it stimulates these other processes. Here we describe recent findings that suggest MOR agonists with diminished propensity to cause tolerance and dependence can be identified by screening drugs for the ability to induce MOR desensitization, endocytosis, and recycling. We also discuss preliminary evidence that heteromers of the delta opioid receptor and the MOR are pronociceptive, and that drugs that spare such heteromers may also induce reduced tolerance. © 2010 American Neurological Association.

Bikle D.D.,University of California at San Francisco
Journal of Bone and Mineral Metabolism | Year: 2010

The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but also possessing the enzymatic machinery to metabolize vitamin D to active metabolites [in particular, 1,25 dihydroxyvitamin D (1,25(OH)2D)] and the vitamin D receptor (VDR) that enables the keratinocytes to respond to the 1,25(OH)2D they produce. Numerous functions of the skin are regulated by vitamin D and/or its receptor: these include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, regulation of the hair follicle cycle, and suppression of tumor formation. Regulation of these actions is exerted by a number of different coregulators including the coactivators DRIP and SRC, a less well known inhibitor, hairless, and β-catenin. Different coregulators appear to be involved in different VDR-reg-ulated functions. This review examines the various functions of vitamin D and its receptor, and to the extent known explores the mechanisms by which these functions are regulated. © The Japanese Society for Bone and Mineral Research and Springer 2010.

Schwartz A.V.,University of California at San Francisco
Frontiers in Endocrinology | Year: 2015

With growing interest in the connection between fat and bone, there has been increased investigation of the relationship with marrow fat in particular. Clinical research has been facilitated by the development of non-invasive methods to measure bone marrow fat content and composition. Studies in different populations using different measurement techniques have established that higher marrow fat is associated with lower bone density and prevalent vertebral fracture. The degree of unsaturation in marrow fat may also affect bone health. Although other fat depots tend to be strongly correlated, marrow fat has a distinct pattern, suggesting separate mechanisms of control. Longitudinal studies are limited, but are crucial to understand the direct and indirect roles of marrow fat as an influence on skeletal health. With greater appreciation of the links between bone and energy metabolism, there has been growing interest in understanding the relationship between marrow fat and bone. It is well established that levels of marrow fat are higher in older adults with osteoporosis, defined by either low bone density or vertebral fracture. However, the reasons for and implications of this association are not clear. This review focuses on clinical studies of marrow fat and its relationship to bone. © 2015 Schwartz.

Zorn J.A.,University of California at San Francisco | Wells J.A.,University of California at San Francisco
Nature Chemical Biology | Year: 2010

Drug discovery and chemical genetic efforts typically focus on the identification and design of inhibitors or loss-of-function probes as a means to perturb enzyme function. These tools are effective in determining the physiological consequence of ablating the activity of a specific enzyme. Remarkably, nearly a dozen examples of non-natural small molecules that activate enzyme catalysis have been identified within the past decade. In aggregate, these studies delineate four unique activation mechanisms that the small molecules exploit. These complementary gain-of-function probes offer a way to address the sufficiency of an enzyme to drive a particular cellular phenotype, and they also provide new opportunities for drug discovery. This review covers the identification and characterization of these unique small-molecule activators. © 2010 Nature America, Inc. All rights reserved.

Bruneau B.G.,Gladstone | Bruneau B.G.,University of California at San Francisco
Current Opinion in Genetics and Development | Year: 2010

Heart development is a complex process that relies on networks of interacting transcription factors. Mutations in genes encoding some of these transcription factors result in many inherited congenital heart defects and point to the importance of these networks. Chromatin remodeling complexes are intimately associated with these transcriptional networks, adding an additional layer of complexity and fine-tuning to the regulation of heart development. Understanding these relationships will be crucial to understand fundamental concepts in tissue-specific gene regulation in organogenesis, in unraveling the mechanisms of congenital heart disease, as well as providing new avenues for reprogramming new cardiomyocytes for heart repair. © 2010 Elsevier Ltd.

Hsieh A.C.,University of California at San Francisco | Ruggero D.,University of California at San Francisco
Clinical Cancer Research | Year: 2010

Recent advances in understanding the role of eukaryotic translation initiator factor 4E (eIF4E) in tumorigenesis and cancer progression have generated significant interest in therapeutic agents that indirectly or directly target aberrant activation of eIF4E in cancer. Here, we address the general function of eIF4E in translation initiation and cancer, present evidence supporting its role in cancer initiation and progression, and highlight emerging therapeutics that efficiently target hyperactivated eIF4E. In doing so, we also highlight the major differences between these therapeutics that may influence their mechanism of action. ©2010 AACR.

Huang Y.J.,University of California at San Francisco
Current Opinion in Pulmonary Medicine | Year: 2015

Purpose of review The purpose of this study is to summarize recent studies of the lower respiratory microbiome in asthma, the role of innate immunity in asthma and strategies to understand complex microbiome-immune interactions in asthma.Recent findings Recent evidence indicates that the composition of lower respiratory microbiota in asthmatic individuals, across a spectrum of disease severity, is altered compared with healthy individuals. Attributes of this altered airway microbiome have been linked to clinical and inflammatory features of asthma. The importance of innate immune cells and mucosal defense systems in asthma is increasingly appreciated and may be dysregulated in the disease.Summary Interactions between the respiratory microbiome and innate mucosal immunity in asthma are complex and a challenge to dissect. Multiple avenues of investigation, leveraging a variety of methodologies, will need to be pursued to understand functional relationships to clinical and inflammatory phenotypes seen in asthma. © 2014 Wolters Kluwer Health.

Kenific C.M.,University of California at San Francisco | Thorburn A.,University of Colorado at Denver | Debnath J.,University of California at San Francisco
Current Opinion in Cell Biology | Year: 2010

In order to metastasize, tumor cells must adapt to untoward, stressful microenvironments as they disseminate into the systemic circulation and colonize distant organ sites. Autophagy, a tightly regulated lysosomal self-digestion process that is upregulated during cellular stress, has been demonstrated to suppress primary tumor formation, but how autophagy influences metastasis remains unknown. Autophagy may inhibit metastasis by promoting antitumor inflammatory responses or by restricting the expansion of dormant tumor cells into macrometastases. Conversely, self-eating may promote metastasis by enhancing tumor cell fitness in response to environmental stresses, such as anoikis, during metastatic progression. Because autophagy is titratable, it may serve both prometastatic and antimetastatic functions depending on the contextual demands placed on tumor cells throughout the metastatic process. © 2009 Elsevier Ltd.

Dallman M.F.,University of California at San Francisco
Trends in Endocrinology and Metabolism | Year: 2010

Stress and emotional brain networks foster eating behaviors that can lead to obesity. The neural networks underlying the complex interactions among stressors, body, brain and food intake are now better understood. Stressors, by activating a neural stress-response network, bias cognition toward increased emotional activity and degraded executive function. This causes formed habits to be used rather than a cognitive appraisal of responses. Stress also induces secretion of glucocorticoids, which increases motivation for food, and insulin, which promotes food intake and obesity. Pleasurable feeding then reduces activity in the stress-response network, reinforcing the feeding habit. These effects of stressors emphasize the importance of teaching mental reappraisal techniques to restore responses from habitual to thoughtful, thus battling stress-induced obesity. © 2009 Elsevier Ltd.

Korennykh A.,Princeton University | Walter P.,Howard Hughes Medical Institute | Walter P.,University of California at San Francisco
Annual Review of Cell and Developmental Biology | Year: 2012

The unfolded protein response (UPR) is a network of intracellular signaling pathways that maintain the protein-folding capacity of the endoplasmic reticulum (ER) in eukaryotic cells. Dedicated molecular sensors embedded in the ER membrane detect incompletely folded or unfolded proteins in the ER lumen and activate a transcriptional program that increases the abundance of the ER according to need. In metazoans the UPR additionally regulates translation and thus relieves unfolded protein load by globally reducing protein synthesis. If homeostasis in the ER cannot be reestablished, the metazoan UPR switches from the prosurvival to the apoptotic mode. The UPR involves a complex, coordinated action of many genes that is controlled by one ER-embedded sensor, Ire1, in yeasts, and three sensors, Ire1, PERK, and ATF6, in higher eukaryotes, including human. We discuss the emerging molecular understanding of the UPR and focus on the structural biology of Ire1 and PERK, the two recently crystallized UPR sensors. Copyright © 2012 by Annual Reviews. All rights reserved.

Egeblad M.,Cold Spring Harbor Laboratory | Nakasone E.S.,Cold Spring Harbor Laboratory | Werb Z.,University of California at San Francisco
Developmental Cell | Year: 2010

Solid tumors are not simply clones of cancer cells. Instead, they are abnormal organs composed of multiple cell types and extracellular matrix. Some aspects of tumor development resemble processes seen in developing organs, whereas others are more akin to tissue remodeling. Some microenvironments, particularly those associated with tissue injury, are favorable for progression of mutant cells, whereas others restrict it. Cancer cells can also instruct surrounding tissues to undergo changes that promote malignancy. Understanding the complex ways in which cancer cells interact with their surroundings, both locally in the tumor organ and systemically in the body as a whole, has implications for effective cancer prevention and therapy. © 2010 Elsevier Inc.

Yang J.,University of Queensland | Zaitlen N.A.,University of California at San Francisco | Goddard M.E.,University of Melbourne | Visscher P.M.,University of Queensland | And 2 more authors.
Nature Genetics | Year: 2014

Mixed linear models are emerging as a method of choice for conducting genetic association studies in humans and other organisms. The advantages of the mixed-linear-model association (MLMA) method include the prevention of false positive associations due to population or relatedness structure and an increase in power obtained through the application of a correction that is specific to this structure. An underappreciated point is that MLMA can also increase power in studies without sample structure by implicitly conditioning on associated loci other than the candidate locus. Numerous variations on the standard MLMA approach have recently been published, with a focus on reducing computational cost. These advances provide researchers applying MLMA methods with many options to choose from, but we caution that MLMA methods are still subject to potential pitfalls. Here we describe and quantify the advantages and pitfalls of MLMA methods as a function of study design and provide recommendations for the application of these methods in practical settings. © 2014 Nature America, Inc.

Luce J.M.,University of California at San Francisco | Luce J.M.,San Francisco General Hospital
Chest | Year: 2015

A 13-year-old patient named Jahi McMath was determined to be dead by neurologic criteria following cardiopulmonary arrest and resuscitation at a hospital in Oakland, California. Her family did not agree that she was dead and refused to allow her ventilator to be removed. The family's attorney stated in the media that families, rather than physicians, should decide whether patients are dead and argued in the courts that the families' constitutional rights of religion and privacy would be violated otherwise. Ultimately, a judge agreed that the patient was dead in keeping with California law, but the constitutional issue was undecided. The patient was then transferred to a hospital in New Jersey, a state whose laws allow families to require on religious grounds that death be determined by cardiopulmonary criteria. Although cases such as this are uncommon, they demonstrate public confusion about the concept of neurologic death and the rejection of this concept by some families. The confusion may be caused in part by a lack of uniformity in state laws regarding the legal basis of death, as reflected in the differences between New Jersey and California statutes. Families who reject the determination of death by neurologic criteria on religious grounds should be given reasonable accommodation in all states, but society should not pay for costly treatments for patients who meet these criteria unless the state requires it, as only New Jersey does. Laws that give physicians the right to determine death by neurologic criteria in other states probably can survive a constitutional challenge. Physicians and hospitals faced with similar cases in the future should follow state laws and work through the courts if necessary. © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS.

Mouw J.K.,University of California at San Francisco
Nature Reviews Molecular Cell Biology | Year: 2014

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Beemiller P.,University of California at San Francisco
Cold Spring Harbor perspectives in biology | Year: 2010

Although the actin cytoskeleton and T-cell receptor (TCR) signaling complexes are seemingly distinct molecular structures, they are tightly integrated in T cells. The signaling pathways initiated by TCRs binding to peptide MHC complexes are extensively influenced by the actin cytoskeletal activities of the motile phase before TCR signaling, the signalosome scaffolding function of the cytoskeleton, and the translocation of signaling clusters that precedes the termination of signaling at these complexes. As these three successive phases constitute essentially all the steps consequent to immune synapse formation, it has become clear that the substantial physical forces and signaling interactions generated by the actin cytoskeleton dominate the signaling life cycle of TCR signalosomes. We discuss the contributions of the actin cytoskeleton to TCR signaling phases and model some remaining questions about how specific cytoskeletal factors regulate TCR signaling outcomes.

Lohela M.,University of California at San Francisco | Werb Z.,University of California at San Francisco
Current Opinion in Genetics and Development | Year: 2010

Tumor stroma, consisting of the extracellular matrix and multiple cell types such as immune cells, fibroblasts and vascular cells, contributes to the malignancy of solid tumors by a variety of mechanisms. Intravital imaging by different microscopy techniques, especially by confocal and multi-photon microscopy, has proven to be a powerful method for analyzing the cell-cell and cell-matrix interactions in the dynamic tumor microenvironments. Intravital imaging has fostered the acquisition of data on parameters such as motility of different cell types in distinct tumor regions or manipulated with defined challenges, kinetics of tumor cell killing by T cells or macrophage-assisted tumor cell extravasation, functionality of the vasculature, protease activity and metabolic state. Achieving the direct observation of intact tumors offered by intavital imaging provides unique insights into tumor biology that will continue to deepen our understanding of the processes leading to malignancy and of the ways they can be targeted. © 2009 Elsevier Ltd. All rights reserved.

Collins C.A.,University of California at San Francisco | Brown E.J.,Genentech
Trends in Cell Biology | Year: 2010

Ubiquitin was first described as a tag allowing cells to degrade and recycle their own proteins. Recent research has shown ubiquitin to be central for immune system recognition of invading bacteria. This review describes a set of complex host-pathogen interactions that are dependent on ubiquitination. From the host perspective, ubiquitin-dependent activation of inflammation and degradation of bacterial effectors is protective. Several pathogens become ubiquitinated in the host cell cytosol, and recent research suggests that this could trigger a form of autophagy, increasingly recognized as an important mechanism for the control of infection by a variety of human pathogens. Meanwhile, bacteria have developed mechanisms to evade or exploit the fundamental processes activated by ubiquitination, producing both ubiquitin ligases and deubiquitinases that modulate host responses. © 2010 Elsevier Ltd.

Soucek L.,University of California at San Francisco | Evan G.I.,University of California at San Francisco
Current Opinion in Genetics and Development | Year: 2010

The basic helix-loop-helix protein Myc is a renowned transcription factor controlling disparate aspects of cell physiology that, together, allow efficient proliferation of somatic cells. This ability, together with the observation that its deregulated expression occurs in the majority of human cancers, suggests that Myc could be a good therapeutic target. However, several aspects of Myc biology remain elusive: what is the major difference between oncogenic and physiological Myc? How does oncogenic Myc evade the intrinsic tumor surveillance pathways provided by evolution? If Myc inhibition were even possible, what would be the consequences for the homeostasis of normal proliferating tissues versus the fate of cancer cells? Here we summarize the latest works addressing these issues. © 2009 Elsevier Ltd. All rights reserved.

Ho T.C.,University of California at San Francisco
Channels (Austin, Tex.) | Year: 2012

We recorded the activity of single mechanosensitive (MS) ion channels from membrane patches on single muscle fibers isolated from mice. We investigated the actions of various TRP (transient receptor potential) channel blockers on MS channel activity. 2-aminoethoxydiphenyl borate (2-APB) neither inhibited nor facilitated single channel activity at submillimolar concentrations. The absence of an effect of 2-APB indicates MS channels are not composed purely of TRPC or TRPV1, 2 or 3 proteins. Exposing patches to 1-oleolyl-2-acetyl-sn-glycerol (OAG), a potent activator of TRPC channels, also had no effect on MS channel activity. In addition, flufenamic acid and spermidine had no effect on the activity of single MS channels. By contrast, SKF-96365 and ruthenium red blocked single-channel currents at micromolar concentrations. SKF-96365 produced a rapid block of the open channel current. The blocking rate depended linearly on blocker concentration, while the unblocking rate was independent of concentration, consistent with a simple model of open channel block. A fit to the concentration-dependence of block gave k(on) = 13 x 10 ( 6) M (-1) s (-1) and k(off) = 1609 sec (-1) with K(D) = ~124 μM. Block by ruthenium red was complex, involving both reduction of the amplitude of the single-channel current and increased occupancy of subconductance levels. The reduction in current amplitude with increasing concentration of ruthenium red gave a K(D) = ~49 μM. The high sensitivity of MS channels to block by ruthenium red suggests MS channels in skeletal muscle contain TRPV subunits. Recordings from skeletal muscle isolated from TRPV4 knockout mice failed to show MS channel activity, consistent with a contribution of TRPV4. In addition, exposure to hypo-osmotic solutions increases opening of MS channels in muscle. Our results provide evidence TRPV4 contributes to MS channels in skeletal muscle.

Plesh O.,University of California at San Francisco
Journal of orofacial pain | Year: 2011

To compare prevalences of self-reported comorbid headache, neck, back, and joint pains in respondents with temporomandibular joint and muscle disorder (TMJMD)-type pain in the 2000-2005 US National Health Interview Survey (NHIS), and to analyze these self-reported pains by gender and age for Non-Hispanic (NH) Whites (Caucasians), Hispanics, and NH Blacks (African Americans). Data from the 2000-2005 NHIS included information on gender, age, race, ethnicity, education, different common types of pain (specifically TMJMD-type, severe headache/migraine, neck, and low back pains), changes in health status, and health care utilization. Estimates and test statistics (ie, Pearson correlations, regressions, and logistic models) were conducted using SAS survey analysis and SUDAAN software that take into account the complex sample design. A total of 189,977 people (52% female and 48% males, 73% NH Whites, 12% Hispanic, 11% NH Blacks, and 4% "Other") were included. A total of 4.6% reported TMJMD-type pain, and only 0.77% overall reported it without any comorbid headache/migraine, neck, or low back pains; also 59% of the TMJMD-type pain (n = 8,964) reported two comorbid pains. Females reported more comorbid pain than males (odds ratio [OR] = 1.41, P < .001); Hispanic and NH Blacks reported more than NH Whites (OR = 1.56, P <.001; OR= 1.38, P <.001, respectively). In addition, 53% of those with TMJMD-type pain had severe headache/migraines, 54% had neck pain, 64% low back pain, and 62% joint pain. Differences in gender and race by age patterns were detected. For females, headache/migraine pain with TMJMD-type pain peaked around age 40 and decreased thereafter regardless of race/ethnicity. Neck pain continued to increase up to about age 60, with a higher prevalence for Hispanic women at younger ages, and more pronounced in males, being the highest in the non-Whites. Low back pain was higher in Black and Hispanic females across the age span, and higher among non-White males after age 60. Joint pain demonstrated similar patterns by race/ethnicity, with higher rates for Black females, and increased with age regardless of gender. TMJMD-type pain was most often associated with other common pains, and seldom existed alone. Two or more comorbid pains were common. Gender, race, and age patterns for pains with TMJMD-type pain resembled the specific underlying comorbid pain.

Keshari K.R.,Sloan Kettering Cancer Center | Wilson D.M.,University of California at San Francisco
Chemical Society Reviews | Year: 2014

The study of transient chemical phenomena by conventional NMR has proved elusive, particularly for non-1H nuclei. For 13C, hyperpolarization using the dynamic nuclear polarization (DNP) technique has emerged as a powerful means to improve SNR. The recent development of rapid dissolution DNP methods has facilitated previously impossible in vitro and in vivo study of small molecules. This review presents the basics of the DNP technique, identification of appropriate DNP substrates, and approaches to increase hyperpolarized signal lifetimes. Also addressed are the biochemical events to which DNP-NMR has been applied, with descriptions of several probes that have met with in vivo success. © 2014 The Royal Society of Chemistry.

Granger A.J.,University of California at San Francisco | Nicoll R.A.,University of California at San Francisco
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors. © 2013 The Author(s) Published by the Royal Society. All rights reserved.

Daniels N.A.,University of California at San Francisco
Urology | Year: 2010

Objective: To assess whether sex hormone levels are associated with subsequent development of prostate cancer. Methods: A case-cohort study was conducted within the ongoing Osteoporotic Fractures in Men cohort study of community-dwelling men <65 years old recruited at 6 US clinical sites. After a mean follow-up of 4.7 years, all men with incident-confirmed prostate cancer and a random sample of the full cohort (subcohort) were selected for analysis: after excluding men with a history of prostate cancer and those who reported androgen or antiandrogen therapy at baseline, the resulting analytic sample comprised 275 cases and 1652 noncases with complete sex hormone measurements. Serum testosterone, estradiol, estrone, and sex hormonebinding globulin were assayed at baseline (prediagnosis) by gas chromatography combined with mass spectrometry. Associations between incident prostate cancer and each sex hormone were evaluated using Cox proportional hazards regression models adjusted for age, race, study site, body mass index, and person-time. Results: In the subcohort, the mean age was 73 years. Higher serum estrone was strongly related to an increased risk of prostate cancer: compared with men in the lower quartile, the risk of prostate cancer among those in the highest 3 quartiles (>24.9 pg/dL) was nearly 4-fold higher (adjusted heart rate = 3.93, CI: 1.61-9.57). Other sex hormones were not associated with the risk of prostate cancer. Conclusions: In this cohort of older men, higher estrone levels were strongly associated with an increased risk of incident prostate cancer. This association between estrone and prostate cancer risk needs to be clarified by further study. © 2010 Elsevier Inc. All Rights Reserved.

Guo M.S.,University of California at San Francisco | Gross C.A.,University of California at San Francisco
Current Biology | Year: 2014

Microorganisms live in fluctuating environments, requiring stress response pathways to resist environmental insults and stress. These pathways dynamically monitor cellular status, and mediate adaptive changes by remodeling the proteome, largely accomplished by remodeling transcriptional networks and protein degradation. The complementarity of fast, specific proteolytic degradation and slower, broad transcriptomic changes gives cells the mechanistic repertoire to dynamically adjust cellular processes and optimize response behavior. Together, this enables cells to minimize the 'cost' of the response while maximizing the ability to survive environmental stress. Here we highlight recent progress in our understanding of transcriptional networks and proteolysis that illustrates the design principles used by bacteria to generate the complex behaviors required to resist stress. © 2014 Elsevier Ltd.

Napoles A.M.,University of California at San Francisco
Preventing chronic disease | Year: 2013

Populations composed of racial/ethnic minorities, disabled persons, and people with low socioeconomic status have worse health than their counterparts. Implementing evidence-based behavioral interventions (EBIs) to prevent and manage chronic disease and disability in community settings could help ameliorate disparities. Although numerous models of implementation processes are available, they are broad in scope, few offer specific methodological guidance, and few address the special issues in reaching vulnerable populations. Drawing from 2 existing models, we describe 7 methodological phases in the process of translating and implementing EBIs in communities to reach these vulnerable groups: establish infrastructure for translation partnership, identify multiple inputs (information gathering), review and distill information (synthesis), adapt and integrate program components (translation), build general and specific capacity (support system), implement intervention (delivery system), and develop appropriate designs and measures (evaluation). For each phase, we describe specific methodological steps and resources and provide examples from research on racial/ethnic minorities, disabled persons, and those with low socioeconomic status. Our methods focus on how to incorporate adaptations so that programs fit new community contexts, meet the needs of individuals in health-disparity populations, capitalize on scientific evidence, and use and build community assets and resources. A key tenet of our approach is to integrate EBIs with community best practices to the extent possible while building local capacity. We discuss tradeoffs between maintaining fidelity to the EBIs while maximizing fit to the new context. These methods could advance our ability to implement potentially effective interventions to reduce health disparities.

Loh M.L.,University of California at San Francisco | Mullighan C.G.,St Jude Childrens Research Hospital
Clinical Cancer Research | Year: 2012

Hematologic malignancies of childhood comprise the most common childhood cancers. These neoplasms derive from the pathologic clonal expansion of an abnormal cancer-initiating cell and span a diverse spectrum of phenotypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). Expansion of immature lymphoid or myeloid blasts with suppression of normal hematopoiesis is the hallmark of ALL and AML, whereasMPNis associated with proliferation of 1 or more lineages that retain the ability to differentiate, and MDS is characterized by abnormal hematopoiesis and cytopenias. The outcomes for children with the most common childhood cancer, B-progenitor ALL (B-ALL), in general, is quite favorable, in contrast to children affected by myeloid malignancies. The advent of highly sensitive genomic technologies reveals the remarkable genetic complexity of multiple subsets of high-risk B-progenitor ALL, in contrast to a somewhat simpler model of myeloid neoplasms, although a number of recently discovered alterations displayed by both types of malignancies may lead to common therapeutic approaches. This review outlines recent advances in our understanding of the genetic underpinnings of high-risk B-ALL and juvenile myelomonocytic leukemia, an overlapMPN/MDSfound exclusively in children, and we also discuss novel therapeutic approaches that are currently being tested in clinical trials. Recent insights into the clonal heterogeneity of leukemic samples and the implications for diagnostic and therapeutic approaches are also discussed. ©2012 AACR.

Kamiyama D.,University of California at San Francisco | Huang B.,University of California at San Francisco
Developmental Cell | Year: 2012

The recent invention of superresolution microscopy has brought up much excitement in the biological research community. Here, we focus on stochastic optical reconstruction microscopy/photoactivated localization microscopy (STORM/PALM) to discuss the challenges in applying superresolution microscopy to the study of developmental biology, including tissue imaging, sample preparation artifacts, and image interpretation. We also summarize new opportunities that superresolution microscopy could bring to the field of developmental biology. © 2012 Elsevier Inc.

Cinar P.,University of California at San Francisco | Tempero M.A.,University of California at San Francisco
Cancer Journal (United States) | Year: 2012

Pancreatic cancer continues to be a challenging disease to treat because of its aggressive nature, advanced stage at the time of diagnosis, and limited treatment options that are available. Traditional cytotoxic chemotherapy provides modest benefit to patients with pancreatic adenocarcinoma. Recently, a FOLFIRINOX regimen revealed improved response in overall and progression-free survival over single-agent gemcitabine in metastatic pancreatic cancer, but there is still much needed advancement in the systemic treatment of pancreatic cancer. There is a growing interest in the development of novel agents, while our understanding of molecular pathogenesis of pancreatic adenocarcinoma continues to expand. With identification of various molecular pathways in pancreatic cancer tumorigenesis, potential targets for drug development have been pursued with the use of monoclonal antibodies and small-molecule inhibitors. Although preclinical studies with multiple targeted therapies demonstrated encouraging results in pancreatic cancer, only erlotinib, an epidermal growth factor receptor inhibitor, showed a marginal survival benefit in a phase III clinical trial, when combined with gemcitabine. As further signaling pathways and their importance in pancreatic cancer tumorigenesis are better understood, further clinical trials will need to be designed to study these targeted agents as single agents, in combination with other novel agents or in combination with cytotoxic chemotherapy. In this review, we present the current knowledge on targeted therapy in pancreatic adenocarcinoma and its application in clinical practice. Copyright © 2012 by Lippincott Williams &Wilkins.

Hong M.,Iowa State University | DeGrado W.F.,University of California at San Francisco
Protein Science | Year: 2012

The influenza M2 protein forms an acid-activated and drug-sensitive proton channel in the virus envelope that is important for the virus lifecycle. The functional properties and high-resolution structures of this proton channel have been extensively studied to understand the mechanisms of proton conduction and drug inhibition. We review biochemical and electrophysiological studies of M2 and discuss how high-resolution structures have transformed our understanding of this proton channel. Comparison of structures obtained in different membrane-mimetic solvents and under different pH using X-ray crystallography, solution NMR, and solid-state NMR spectroscopy revealed how the M2 structure depends on the environment and showed that the pharmacologically relevant drug-binding site lies in the transmembrane (TM) pore. Competing models of proton conduction have been evaluated using biochemical experiments, high-resolution structural methods, and computational modeling. These results are converging to a model in which a histidine residue in the TM domain mediates proton relay with water, aided by microsecond conformational dynamics of the imidazole ring. These mechanistic insights are guiding the design of new inhibitors that target drug-resistant M2 variants and may be relevant for other proton channels. © 2012 The Protein Society.

Li L.-C.,University of California at San Francisco
Epigenetics | Year: 2014

Chromatin states, quite different from changes in DNA sequence, can impact fundamental cellular processes such as determination of cell identity and development of disease. However, how chromatin states are established and regulated remain to be fully elucidated. In several lower eukaryotes, the small RNA machinery comprised of small RNA and its partners, the Argonaute proteins, is known to play important roles in the establishment of heterochromatin and silencing of repetitive sequences. In mammalian cells, however, the nuclear function of the small RNA machinery is largely unknown. Emerging evidence suggests that components of the small RNA pathway interact with chromatin to regulate nuclear events, including gene transcription and alternative splicing. In addition, these endogenous mechanisms are being exploited to target specific genomic loci for manipulation of gene expression and splicing events. In this review, I summarize current understanding of chromatin remodeling by small RNAs in mammalian cells and highlight recent efforts to map genome-wide interactions between RNAi-related factors and chromatin. © 2014 Landes Bioscience.

Liu J.,University of California at San Francisco | Stainier D.Y.R.,University of California at San Francisco
Circulation Research | Year: 2012

Heart development is a complex process that involves cell specification and differentiation, as well as elaborate tissue morphogenesis and remodeling, to generate a functional organ. The zebrafish has emerged as a powerful model system to unravel the basic genetic, molecular, and cellular mechanisms of cardiac development and function. We summarize and discuss recent discoveries on early cardiac specification and the identification of the second heart field in zebrafish. In addition to the inductive signals regulating cardiac specification, these studies have shown that heart development also requires a repressive mechanism imposed by retinoic acid signaling to select cardiac progenitors from a multipotent population. Another recent advance in the study of early zebrafish cardiac development is the identification of the second heart field. These studies suggest that the molecular mechanisms that regulate the second heart field development are conserved between zebrafish and other vertebrates including mammals and provide insight into the evolution of the second heart field and its derivatives. © 2012 American Heart Association, Inc.

Akhurst R.J.,University of California at San Francisco
Nature Genetics | Year: 2012

Two new studies show that haploinsufficiency for TGFB2 causes a familial syndrome of thoracic aortic aneurysms and dissections with other clinical features that overlap the Marfan, Loeys-Dietz spectrum of syndromes. Their finding of loss-of-function mutations in yet another transforming growth factor (TGF)-β pathway gene reinforces the seeming paradox of observed increases in the downstream TGF-β signaling pathway. © 2012 Nature America, Inc. All rights reserved.

Charles M.A.,University of California at San Francisco | Kane J.P.,University of California at San Francisco
Journal of Lipid Research | Year: 2012

Cholesteryl ester transfer protein (CETP) is important clinically and is the current target for new drug development. Its structure and mechanism of action has not been well understood. We have combined current new structural and functional methods to compare with relevant prior data. These analyses have led us to propose several steps in CETP's function at the molecular level, in the context of its interactions with lipoproteins, e.g., sensing, penetration, docking, selectivity, ternary complex formation, lipid transfer, and HDL dissociation. These new molecular insights improve our understanding of CETP's mechanisms of action. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.

Kumar P.,University of California at San Francisco | Wittmann T.,University of California at San Francisco
Trends in Cell Biology | Year: 2012

+TIPs are a heterogeneous class of proteins that specifically bind to growing microtubule ends. Because dynamic microtubules are essential for many intracellular processes, +TIPs play important roles in regulating microtubule dynamics and microtubule interactions with other intracellular structures. End-binding proteins (EBs) recognize a structural cap at growing microtubule ends, and have emerged as central adaptors that mediate microtubule plus-end tracking of potentially all other +TIPs. The majority of these +TIPs bind to EBs through a short hydrophobic (S/T)x(I/L)P sequence motif (SxIP) and surrounding electrostatic interactions. These recent discoveries have resulted in a rapid expansion of the number of possible +TIPs. In this review, we outline our current understanding of the molecular mechanism of plus-end tracking and provide an overview of SxIP-recruited +TIPs. © 2012 Elsevier Ltd.

Ratelade J.,University of California at San Francisco | Verkman A.S.,University of California at San Francisco
International Journal of Biochemistry and Cell Biology | Year: 2012

Neuromyelitis optica (NMO) is an autoimmune 'aquaporinopathy' of the central nervous system that causes inflammatory demyelinating lesions primarily in spinal cord and optic nerve, leading to paralysis and blindness. NMO lesions show loss of aquaporin-4 (AQP4), GFAP and myelin, infiltration of granulocytes and macrophages, and perivascular deposition of activated complement. Most patients with NMO are seropositive for immunoglobulin autoantibodies (AQP4-IgG) against AQP4, the principal water channel of astrocytes. There is strong evidence that AQP4-IgG is pathogenic in NMO, probably by a mechanism involving complement-dependent astrocyte cytotoxicity, causing leukocyte infiltration, cytokine release and blood-brain barrier disruption, which leads to oligodendrocyte death, myelin loss and neuron death. Here, we review the evidence for this and alternative proposed NMO pathogenesis mechanisms, such as AQP4-IgG-induced internalization of AQP4 and glutamate transporters, complement-independent cell-mediated cytotoxicity, and AQP4-IgG inhibition of AQP4 water transport function. Based on the initiating pathogenic role of AQP4-IgG binding to astrocyte AQP4 in NMO, selective blocker therapies are under development in which AQP4-targeted monoclonal antibodies or small molecules block binding of AQP4-IgG to astrocytes and consequent downstream pathology. © 2012 Elsevier Ltd.

Ford J.M.,University of California at San Francisco
Nature protocols | Year: 2010

In this paper, we present a vocal production protocol for studying the neurophysiological action of the corollary discharge, a mechanism that allows animals to ignore sensations resulting from their own actions, and tag them as 'self'. Electroencephalograms are recorded while subjects say 'ah' about 100 times with minimal throat, jaw and tongue movements (Talk condition). This sequence of sounds is recorded and played back during the Listen condition. Event-related potentials are synchronized to the onset of speech sounds during the Talk and Listen conditions. Neural responses from the auditory cortex to the spoken sound as it is being spoken during the Talk condition are compared with neural responses to the same sounds when played back during the Listen condition. The successful action of the corollary discharge is seen when the response of the auditory cortex is suppressed during the Talk compared with the Listen condition. The protocol takes about 5 min to complete.

Bluestone J.A.,University of California at San Francisco | Bour-Jordan H.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2012

Autoimmune diseases reflect a breakdown in self-tolerance that results from defects in thymic deletion of potentially autoreactive T cells (central tolerance) and in T-cell intrinsic and extrinsic mechanisms that normally control potentially autoreactive T cells in the periphery (peripheral tolerance). The mechanisms leading to autoimmune diseases are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in pathogenic inflammatory responses in peripheral tissues driven by self-antigen-specific T cells. In this article, we describe the different checkpoints of tolerance that are defective in autoimmune diseases as well as specific events in the autoimmune response which represent therapeutic opportunities to restore long-term tolerance in autoimmune diseases. We present evidence for the role of different pathways in animal models and the therapeutic strategies targeting these pathways in clinical trials in autoimmune diseases. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Kenific C.M.,University of California at San Francisco | Debnath J.,University of California at San Francisco
Trends in Cell Biology | Year: 2015

Autophagy is a lysosomal degradation pathway that acts as a dynamic regulator of tumorigenesis. Specifically, autophagy has been shown to impede early cancer development while facilitating advanced tumor progression. Recent studies have uncovered several tumor-promoting functions for autophagy; these include the maintenance of multiple metabolic pathways critical for aggressive tumor growth and the promotion of tumor cell survival downstream of the unfolded protein response. Furthermore, autophagy supports anoikis resistance and cancer cell invasion. At the same time, because autophagy cargo receptors, which are essential for selective autophagy, lie upstream of diverse cancer-promoting signaling pathways, they may profoundly influence how alterations in autophagy affect tumor development. This review focuses on how these tumor cell autonomous functions of autophagy broadly impact tumorigenesis. © 2014 Elsevier Ltd.

Young A.,University of California at San Francisco
Cancer discovery | Year: 2013

H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and nonredundant roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, whereas wild-type Ras mediates signaling downstream of activated receptor tyrosine kinases (RTK). We show that both are necessary for exponential growth of Ras-mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes signaling from EGF receptor (EGFR). Depletion of oncogenic Ras with siRNA oligonucleotides relieves this negative feedback, leading to the hyperactivation of EGFR and wild-type Ras signaling. Consistent with this model, combining oncogenic Ras depletion with EGFR inhibition potently increases cell death. The results of this study highlight a novel role for wild-type Ras signaling in cancer cells harboring oncogenic RAS mutations. Furthermore, these findings reveal that therapeutically targeting oncogenic Ras signaling alone may be ineffective owing to feedback activation of RTKs, and suggest that blocking upstream RTKs in combination with downstream effector pathways may be beneficial in the treatment of Ras-mutant tumors.

Greninger A.L.,University of California at San Francisco
Progress in Molecular Biology and Translational Science | Year: 2015

Picornaviruses are positive-stranded RNA viruses of significant disease burden and ubiquitous global reach. Microscopic examination of picornavirus-infected cells has long revealed a drastic reordering of intracellular membranes. Through a confluence of candidate-based approaches and genomic and proteomic screens, the past decade has seen great leaps in understanding how picornaviruses usurp intracellular membranes for their own replication. The growing cast of assembled characters allows for a rich plot in the upcoming years. With their widespread genomic divergence, the number of potential mechanisms for RNA virus vesicogenesis for driving membrane formation and lipid synthesis required for viral replication is broad, but the overall story arch remains surprisingly recognizable. This chapter reviews the major discoveries associating picornavirus pathogenic interactions with the secretory system and highlights important questions and opportunities for future study. © 2015 Elsevier Inc. All rights reserved.

Kaur J.,University of California at San Francisco | Debnath J.,University of California at San Francisco
Nature Reviews Molecular Cell Biology | Year: 2015

Autophagy is a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome. Starvation-induced protein degradation is a salient feature of autophagy but recent progress has illuminated how autophagy, during both starvation and nutrient-replete conditions, can mobilize diverse cellular energy and nutrient stores such as lipids, carbohydrates and iron. Processes such as lipophagy, glycophagy and ferritinophagy enable cells to salvage key metabolites to sustain and facilitate core anabolic functions. Here, we discuss the established and emerging roles of autophagy in fuelling biosynthetic capacity and in promoting metabolic and nutrient homeostasis. © 2015 Macmillan Publishers Limited.

Odegaard J.I.,University of California at San Francisco | Chawla A.,University of California at San Francisco
Current Opinion in Immunology | Year: 2015

Adipose tissue resident leukocytes are often cast solely as the effectors of obesity and its attendant pathologies; however, recent observations have demonstrated that these cells support and effect 'healthy' physiologic function as well as pathologic dysfunction. Importantly, these two disparate outcomes are underpinned by similarly disparate immune programs; type 2 responses instruct and promote metabolic normalcy, while type 1 responses drive tissue dysfunction. In this Review, we summarize the literature regarding type 2 immunity's role in adipose tissue physiology and allude to its potential therapeutic implications. © 2015 Elsevier Ltd.

Farrell J.A.,University of California at San Francisco | O'Farrell P.H.,University of California at San Francisco
Current Biology | Year: 2013

Background: In Drosophila embryos, the midblastula transition (MBT) dramatically remodels the cell cycle during the 14th interphase. Before the MBT, each cycle is composed of only a short S phase and mitosis. At the MBT, S phase is dramatically lengthened by the onset of late replication, and a G2 phase is introduced. Both changes set the stage for gastrulation and require downregulation of Cdc25 phosphatase, which was previously attributed to the elimination of its transcripts at the MBT. Results: Premature removal of cdc25 transcripts by RNAi did not affect progression to the MBT. Instead, an antibody against the Cdc25 isoform Twine showed that Twine protein was abundant and stable until the MBT, when it was destabilized and rapidly eliminated. Persistence of pre-MBT levels of Twine was sufficient to prevent cell-cycle slowing. Twine protein destruction was timed by the nucleocytoplasmic ratio and depended on the activation of zygotic transcription at the MBT, including expression of the gene tribbles, whose activity was sufficient to trigger Twine destruction and was required for prompt Twine disappearance. Conclusions: We propose that the developmentally regulated destruction of Twine protein is a critical switch that contributes to the cell-cycle change at the MBT, including the addition of a G2 phase and onset of late replication. Moreover, we show that this destruction is triggered by the nucleocytoplasmic ratio-dependent onset of zygotic transcription of tribbles and other unknown genes. © 2013 Elsevier Ltd All rights reserved.

Huang Y.J.,University of Michigan | Boushey H.A.,University of California at San Francisco
Journal of Allergy and Clinical Immunology | Year: 2015

The application of recently developed sensitive, specific, culture-independent tools for identification of microbes is transforming concepts of microbial ecology, including concepts of the relationships between the vast complex populations of microbes associated with ourselves and with states of health and disease. Although most work initially focused on the community of microbes (microbiome) in the gastrointestinal tract and its relationship to gastrointestinal disease, interest has expanded to include study of the relationships of the airway microbiome to asthma and its phenotypes and to the relationships between the gastrointestinal microbiome, development of immune function, and predisposition to allergic sensitization and asthma. Here we provide our perspective on the findings of studies of differences in the airway microbiome between asthmatic patients and healthy subjects and of studies of relationships between environmental microbiota, gut microbiota, immune function, and asthma development. In addition, we provide our perspective on how these findings suggest the broad outline of a rationale for approaches involving directed manipulation of the gut and airway microbiome for the treatment and prevention of allergic asthma. © 2014 American Academy of Allergy, Asthma & Immunology.

Tasian G.E.,University of California at San Francisco | Copp H.L.,University of California at San Francisco
Pediatrics | Year: 2011

CONTEXT: Ultrasound is frequently obtained during the presurgical evaluation of boys with nonpalpable undescended testes, but its clinical utility is uncertain. OBJECTIVE: To determine the diagnostic performance of ultrasound in localizing nonpalpable testes in pediatric patients. METHODS: English-language articles were identified by searching Medline, Embase, and the Cochrane Library. We included studies of subjects younger than 18 years who had preoperative ultrasound evaluation for nonpalpable testes and whose testis position was determined by surgery. Data on testis location determined by ultrasound and surgery were extracted by 2 independent reviewers, from which ultrasound performance characteristics (true-positives, falsepositives, false-negatives, and true-negatives) were derived. Metaanalysis of 12 studies (591 testes) was performed by using a randomeffects regression model; composite estimates of sensitivity, specificity, and likelihood ratios were calculated. RESULTS: Ultrasound has a sensitivity of 45% (95% confidence interval [CI]: 29-61) and a specificity of 78% (95% CI: 43-94). The positive and negative likelihood ratios are 1.48 (95% CI: 0.54-4.03) and 0.79 (95% CI: 0.46-1.35), respectively. A positive ultrasound result increases and negative ultrasound result decreases the probability that a nonpalpable testis is located within the abdomen from 55% to 64% and 49%, respectively. Significant heterogeneity limited the precision of these estimates, which was attributable to variability in the reporting of selection criteria, ultrasound methodology, and differences in the proportion of intraabdominal testes. CONCLUSIONS: Ultrasound does not reliably localize nonpalpable testes and does not rule out an intraabdominal testis. Eliminating the use of ultrasound will not change management of nonpalpable cryptorchidism but will decrease health care expenditures. Copyright © 2011 by the American Academy of Pediatrics.

Bacchetti P.,University of California at San Francisco
BMC Medicine | Year: 2010

Background: The belief remains widespread that medical research studies must have statistical power of at least 80% in order to be scientifically sound, and peer reviewers often question whether power is high enough.Discussion: This requirement and the methods for meeting it have severe flaws. Notably, the true nature of how sample size influences a study's projected scientific or practical value precludes any meaningful blanket designation of <80% power as "inadequate". In addition, standard calculations are inherently unreliable, and focusing only on power neglects a completed study's most important results: estimates and confidence intervals. Current conventions harm the research process in many ways: promoting misinterpretation of completed studies, eroding scientific integrity, giving reviewers arbitrary power, inhibiting innovation, perverting ethical standards, wasting effort, and wasting money. Medical research would benefit from alternative approaches, including established value of information methods, simple choices based on cost or feasibility that have recently been justified, sensitivity analyses that examine a meaningful array of possible findings, and following previous analogous studies. To promote more rational approaches, research training should cover the issues presented here, peer reviewers should be extremely careful before raising issues of "inadequate" sample size, and reports of completed studies should not discuss power.Summary: Common conventions and expectations concerning sample size are deeply flawed, cause serious harm to the research process, and should be replaced by more rational alternatives. © 2010 Bacchetti; licensee BioMed Central Ltd.

Lustig R.H.,University of California at San Francisco
Advances in Nutrition | Year: 2013

What do the Atkins Diet and the traditional Japanese diet have in common? The Atkins Diet is low in carbohydrate and usually high in fat; the Japanese diet is high in carbohydrate and usually low in fat. Yet both work to promote weight loss. One commonality of both diets is that they both eliminate the monosaccharide fructose. Sucrose (table sugar) and its synthetic sister high fructose corn syrup consist of 2 molecules, glucose and fructose. Glucose is the molecule that when polymerized forms starch, which has a high glycemic index, generates an insulin response, and is not particularly sweet. Fructose is found in fruit, does not generate an insulin response, and is very sweet. Fructose consumption has increased worldwide, paralleling the obesity and chronic metabolic disease pandemic. Sugar (i.e., fructose-containing mixtures) has been vilified by nutritionists for ages as a source of "empty calories," no different from any other empty calorie. However, fructose is unlike glucose. In the hypercaloric glycogen-replete state, intermediary metabolites from fructose metabolism overwhelm hepatic mitochondrial capacity, which promotes de novo lipogenesis and leads to hepatic insulin resistance, which drives chronic metabolic disease. Fructose also promotes reactive oxygen species formation, which leads to cellular dysfunction and aging, and promotes changes in the brain's reward system, which drives excessive consumption. Thus, fructose can exert detrimental health effects beyond its calories and in ways that mimic those of ethanol, its metabolic cousin. Indeed, the only distinction is that because fructose is not metabolized in the central nervous system, it does not exert the acute neuronal depression experienced by those imbibing ethanol. These metabolic and hedonic analogies argue that fructose should be thought of as "alcohol without the buzz ". © 2013 American Society for Nutrition.

Hilton J.F.,University of California at San Francisco
Statistics in Medicine | Year: 2010

This study presents constrained maximum likelihood derivations of the design parameters of noninferiority trials for binary outcomes with the margin defined on the odds ratio (ψ) or risk-difference (δ) scale. The derivations show that, for trials in which the group-specific response rates are equal under the point-alternative hypothesis, the common response rate, Π N, is a fixed design parameter whose value lies between the control and experimental rates hypothesized at the point-null, {π C,π E}. We show that setting π N equal to the value of π C that holds under H 0 underestimates the overall sample size requirement. Given {π C,ψ} or {π C,δ} and the type I and II error rates, or algorithm finds clinically meaningful design values of π N, and the corresponding minimum asymptotic sample size, N=n E+n C, and optimal allocation ratio, γ=n E/n C. We find that optimal allocations are increasingly imbalanced as ψ increases, with γψ<1 and γδ≈1/γψ, and that ranges of allocation ratios map to the minimum sample size. The latter characteristic allows trialists to consider trade-offs between optimal allocation at a smaller N and a preferred allocation at a larger N. For designs with relatively large margins (e.g. ψ>2.5), trial results that are presented on both scales will differ in power, with more power lost if the study is designed on the risk-difference scale and reported on the odds ratio scale than vice versa. Copyright © 2010 John Wiley & Sons, Ltd.

Tompa P.,Vrije Universiteit Brussel | Tompa P.,Hungarian Academy of Sciences | Davey N.E.,University of California at San Francisco | Gibson T.J.,Structural and Computational Biology Unit | Babu M.M.,University of Cambridge
Molecular Cell | Year: 2014

A molecular description of functional modules in the cell is the focus of many high-throughput studies in the postgenomic era. A large portion of biomolecular interactions in virtually all cellular processes is mediated by compact interaction modules, referred to as peptide motifs. Such motifs are typically less than ten residues in length, occur within intrinsically disordered regions, and are recognized and/or posttranslationally modified by structured domains of the interacting partner. In this review, we suggest that there might be over a million instances of peptide motifs in the human proteome. While this staggering number suggests that peptide motifs are numerous and the most understudied functional module in the cell, it also holds great opportunities for new discoveries. © 2014 Elsevier Inc.

Hunt P.W.,University of California at San Francisco
Current HIV/AIDS Reports | Year: 2012

Persistent immune activation and inflammation despite sustained antiretroviral therapy (ART)-mediated viral suppression has emerged as a major challenge of the modern HIV treatment era. While immune activation, inflammatory, and coagulation markers typically decline during suppressive ART, they remain abnormally elevated in many HIV-infected individuals and predict subsequent mortality and non-AIDS morbidities including cardiovascular disease. The goal of this review is to summarize the current state of our knowledge regarding the underlying causes of persistent immune activation during ART-mediated viral suppression as well as the link between persistent immune activation and morbidity and mortality in this setting. Several recent studies have linked surrogate markers of this persistent inflammatory state to clinical outcomes, validating persistent immune activation as a viable therapeutic target. Other recent studies have helped clarify the roles of persistent HIV expression and/or replication, microbial trans-location, and co-infections in driving this persistent inflammatory state, identifying targets for novel interventions. © Springer Science+Business Media, LLC 2012.

Kaye H.S.,University of California at San Francisco
Health Affairs | Year: 2012

States are shifting Medicaid spending on long-term services and supports from institutional to home and community-based services, a process known as rebalancing. Using fifteen years of state expenditure data, a statistical model was developed to assess the effect of rebalancing on overall spending for long-term services and supports. The model indicates that spending is affected by the way rebalancing is implemented: Gradual rebalancing, by roughly two percentage points annually, can reduce spending by about 15 percent over ten years. More rapid rebalancing can save money, break even, or increase spending, depending on the pace and program specifics. Cuts to home and community-based services that hinder rebalancing are likely to increase, not decrease, overall spending on long-term services and supports as people who were receiving these services shift into nursing homes. Because many states continue to experience budget crises, policy makers must think carefully before altering spending patterns for long-term services and supports and adopt strategies that particular states have used to successfully reduce overall spending, such as gradually shifting expenditures toward home and community-based waiver programs. © 2012 by Project HOPE The People-to-People Health Foundation, Inc.

Phillips J.J.,University of California at San Francisco
Oncotarget | Year: 2012

Glioblastoma (GBM), a highly malignant brain tumor of adults and children, diffusely invades within the non-neoplastic brain. Despite aggressive current therapeutic interventions, improved therapeutic strategies are greatly needed. Interactions between the tumor and constituents of its microenvironment are known to regulate malignancy, and heparan sulfate proteoglycans (HSPGs) are important as they bind diverse extracellular proteins, including growth factors and cell adhesion molecules, regulating the activity of several ligand-mediated signaling pathways. Recent work from our group described a mechanism by which GBM regulates PDGFR-alpha signaling via enzymatic alteration of heparan sulfate proteoglycans (HSPGs) in the extracellular microenvironment. Blocking tumor-induced alterations of HSPGs, which can be achieved by pharmacological strategies, would potentially inhibit multiple oncogenic signaling pathways in tumor cells and disrupt critical tumormicroenvironment interactions. Here we examine HSPGs and the enzymes that modify them in GBM. We compare their expression across tumor subtypes, their potential roles in oncogenesis, and their potential as novel therapeutic targets in GBM. © Phillips et al.

Goodin D.S.,University of California at San Francisco
PLoS ONE | Year: 2012

Making only the assumption that twins are representative of the population from which they are drawn, we here develop a simple mathematical model (using widely available epidemiological information) that sheds considerable light on the pathogenesis of complex human diseases. Specifically, for the case of multiple sclerosis (MS), we demonstrate that the vast majority of patients (≥94%), possibly all, require genetic susceptibility in order to get MS. Nevertheless, only a tiny fraction of the population (≤2.2%) is actually susceptible to getting this disease; a finding which is highly consistent in all of the studied populations across both North America and Europe. Men are more likely to be susceptible than women although susceptible women are more than twice as likely to actually develop MS compared to susceptible men (i.e., they have a greater disease penetrance). This is because women are more responsive to the environmental factors involved in MS pathogenesis than men. These differences account for the current gender-ratio (3:1, favoring women) and also for the increasing incidence of MS in women around the world. By contrast, the most important genetic marker for MS susceptibility (DRB1*1501) influences the likelihood of susceptibility but not the penetrance of the disease. Nevertheless, even for this major susceptibility allele, only a very small fraction of DRB1*1501carriers (<5%) are susceptible to getting MS and for only a minority of MS patients (~41%) does this allele contribute to their susceptibility. Moreover, each copy of this allele seems to make an independent contribution to susceptibility. Finally, at least three environmental events are necessary for MS pathogenesis and, during the course of their lives, the large majority of the population (≥69%) experiences an environmental exposure, which is sufficient to produce MS in, at least, some susceptible genotypes. Also, susceptible men (compared to susceptible women) have a lower threshold, a greater hazard-rate, or both in response to the environmental factors involved in MS pathogenesis.

Ford K.J.,University of California at San Francisco | Davis G.W.,University of California at San Francisco
Journal of Neuroscience | Year: 2014

The strength and dynamics of synaptic transmission are determined, in part, by the presynaptic action potential (AP) waveform at the nerve terminal. The ion channels that shape the synaptic AP waveform remain essentially unknown for all but a few large synapses amenable to electrophysiological interrogation. The Drosophila neuromuscular junction (NMJ) is a powerful system for studying synaptic biology, but it is not amenable to presynaptic electrophysiology. Here, we demonstrate that Archaerhodopsin can be used to quantitatively image AP waveforms at the Drosophila NMJ without disrupting baseline synaptic transmission or neuromuscular development. It is established that Shaker mutations cause a dramatic increase in neurotransmitter release, suggesting that Shaker is predominantly responsible for AP repolarization. Here we demonstrate that this effect is caused by a concomitant loss of both Shaker and slowpoke (slo) channel activity because of the low extracellular calcium concentrations (0.2-0.5 mM) used typically to assess synaptic transmission in Shaker. In contrast, at physiological extracellular calcium (1.5 mM), the role of Shaker during AP repolarization is limited. We then provide evidence that calcium influx through synaptic CaV2.1 channels and subsequent recruitment of Slo channel activity is important, in concert with Shaker, to ensure proper AP repolarization. Finally, we show that Slo assumes a dominant repolarizing role during repetitive nerve stimulation. During repetitive stimulation, Slo effectively compensates for Shaker channel inactivation, stabilizing AP repolarization and limiting neurotransmitter release. Thus, we have defined an essential role for Slo channels during synaptic AP repolarization and have revised our understanding of Shaker channels at this model synapse. © 2014 the authors.

Lynch S.V.,University of California at San Francisco
Annals of the American Thoracic Society | Year: 2014

Viral infection represents a common and problematic health care issue, particularly in younger and senior populations. The respiratory tract is a major portal for microbial exposure, where viral infection can result in nonsymptomatic, mild, and self-limiting or severe and sometimes fatal infection. Although it is well established that virus-specific properties, such as longevity and replication kinetics, impact clinical manifestations, it is less well understood why distinct infectious outcomes may occur across a population of individuals infected with the same strain of virus. Emerging evidence points to interpersonal variation in pulmonary and gastrointestinal microbiome composition, and specifically tomembers of the Lactobacillus genus, as key components in defining respiratory viral infection outcomes. Moreover, human studies of airway microbiota after pH1N1 demonstrate that the composition of the respiratory microbiome can be modified by viral infection in amanner that enriches for pathogens associated with secondary bacterial infection. In this article, current knowledge in the field of human microbiome research, particularly as it pertains to respiratory viral infection, is reviewed. Copyright © 2014 by the American Thoracic Society.

Fox A.N.,University of California at San Francisco | Terrault N.A.,University of California at San Francisco
Journal of Hepatology | Year: 2012

Since the early 1990's, hepatitis B immune globulin (HBIG) has been central to the prevention of hepatitis B virus (HBV) recurrence after liver transplantation. When used in combination with oral nucleos(t)ide analogues, HBIG prevents reinfection with HBV in ≥90% of transplant recipients. While HBIG is highly efficacious, its use is undermined by its high cost. Because of this limitation, there have been many studies of alternative regimens seeking to minimize the dose or duration of HBIG without sacrificing low HBV recurrence rates. Toward that goal, lower dose intramuscular HBIG in combination with oral nucleos(t)ide analogues has been shown to be highly efficacious in preventing disease recurrence and represents a significant cost savings when compared with high dose intravenous administration. The withdrawal of HBIG after a defined course of combination HBIG and oral antivirals has also been shown to be effective, particularly if combination antiviral therapy is used. The ability to achieve undetectable HBV DNA levels pre-transplantation in the majority of patients may contribute to the high efficacy of these HBIG "light" regimens. Additionally, the success of antiviral rescue therapy for those patients who fail prophylaxis and develop recurrent HBV infection post-transplant has provided the impetus to move increasingly towards HBIG-free approaches. New techniques to detect occult HBV in hepatic and extrahepatic sites may allow clinicians to define a subgroup of patients in whom withdrawal of HBIG or all prophylaxis may be applicable. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Razooky B.S.,University of California at San Francisco | Pai A.,University of California at San Francisco | Aull K.,University of California at San Francisco | Rouzine I.M.,University of California at San Francisco | Weinberger L.S.,University of California at San Francisco
Cell | Year: 2015

Biological circuits can be controlled by two general schemes: environmental sensing or autonomous programs. For viruses such as HIV, the prevailing hypothesis is that latent infection is controlled by cellular state (i.e., environment), with latency simply an epiphenomenon of infected cells transitioning from an activated to resting state. However, we find that HIV expression persists despite the activated-to-resting cellular transition. Mathematical modeling indicates that HIV's Tat positive-feedback circuitry enables this persistence and strongly controls latency. To overcome the inherent crosstalk between viral circuitry and cellular activation and to directly test this hypothesis, we synthetically decouple viral dependence on cellular environment from viral transcription. These circuits enable control of viral transcription without cellular activation and show that Tat feedback is sufficient to regulate latency independent of cellular activation. Overall, synthetic reconstruction demonstrates that a largely autonomous, viral-encoded program underlies HIV latency - potentially explaining why cell-targeted latency-reversing agents exhibit incomplete penetrance. © 2015 Elsevier Inc.

Rouzine I.M.,Gladstone | Weinberger A.D.,Wyss Institute for Biologically Inspired Engineering | Weinberger L.S.,Gladstone | Weinberger L.S.,University of California at San Francisco
Cell | Year: 2015

HIV latency is the chief obstacle to eradicating HIV but is widely believed to be an evolutionary accident providing no lentiviral fitness advantage. However, findings of latency being "hardwired" into HIV's gene-regulatory circuitry appear inconsistent with latency being an evolutionary accident, given HIV's rapid mutation rate. Here, we propose that latency is an evolutionary "bet-hedging" strategy whose frequency has been optimized to maximize lentiviral transmission by reducing viral extinction during mucosal infections. The model quantitatively fits the available patient data, matches observations of high-frequency latency establishment in cell culture and primates, and generates two counterintuitive but testable predictions. The first prediction is that conventional CD8-depletion experiments in SIV-infected macaques increase latent cells more than viremia. The second prediction is that strains engineered to have higher replicative fitness - via reduced latency - will exhibit lower infectivity in animal-model mucosal inoculations. Therapeutically, the theory predicts treatment approaches that may substantially enhance "activate-and-kill" HIV-cure strategies. © 2015 Elsevier Inc.

Slorach E.M.,University of California at San Francisco | Chou J.,University of California at San Francisco | Werb Z.,University of California at San Francisco
Genes and Development | Year: 2011

Amplification of 8p11-12 in human breast cancers is associated with increased proliferation and tumor grade and reduced metastasis-free patient survival. We identified Zeppo1 (zinc finger elbow-related proline domain protein 1) (FLJ14299/ZNF703) within this amplicon as a regulator of cell adhesion, migration, and proliferation in mammary epithelial cells. Overexpression of Zeppo1 reduces cell-cell adhesion and stimulates migration and proliferation. Knockdown of Zeppo1 induces adhesion and lumen formation. Zeppo1 regulates transcription, complexing with Groucho and repressing E-cadherin expression and Wnt and TGFβ reporter expression. Zeppo1 promotes expression of metastasis-associated p120-catenin isoform 1 and alters p120-catenin localization upon cell contact with the extracellular matrix. Significantly, Zeppo1 overexpression in a mouse breast cancer model increases lung metastases, while reducing Zeppo1 expression reduces both tumor size and the number of lung metastases. These results indicate that Zeppo1 is a key regulator of breast cancer progression. © 2011 by Cold Spring Harbor Laboratory Press.

Whitfield-Gabrieli S.,Massachusetts Institute of Technology | Ford J.M.,University of California at San Francisco
Annual Review of Clinical Psychology | Year: 2012

Neuropsychiatric disorders are associated with abnormal function of the default mode network (DMN), a distributed network of brain regions more active during rest than during performance of many attention-demanding tasks and characterized by a high degree of functional connectivity (i.e., temporal correlations between brain regions). Functional magnetic resonance imaging studies have revealed that the DMN in the healthy brain is associated with stimulus-independent thought and self-reflection and that greater suppression of the DMN is associated with better performance on attention-demanding tasks. In schizophrenia and depression, the DMN is often found to be hyperactivated and hyperconnected. In schizophrenia this may relate to overly intensive self-reference and impairments in attention and working memory. In depression, DMN hyperactivity may be related to negative rumination. These findings are considered in terms of what is known about psychological functions supported by the DMN, and alteration of the DMN in other neuropsychiatric disorders. © Copyright ©2012 by Annual Reviews. All rights reserved.

Young A.,University of California at San Francisco | Lou D.,University of California at San Francisco | McCormick F.,University of California at San Francisco
Cancer Discovery | Year: 2013

H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often acti-vated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and nonredundant roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, whereas wild-type Ras mediates signaling downstream of activated receptor tyrosine kinases (RTK). We show that both are necessary for exponential growth of Ras-mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes signaling from EGF receptor (EGFR). Depletion of oncogenic Ras with siRNA oligonucleotides relieves this negative feedback, leading to the hyperactivation of EGFR and wild-type Ras signaling. Consistent with this model, combining oncogenic Ras depletion with EGFR inhibition potently increases cell death. © 2012 American Association for Cancer Research.

Kraus M.W.,University of California at San Francisco
Psychological science : a journal of the American Psychological Society / APS | Year: 2010

Recent research suggests that lower-class individuals favor explanations of personal and political outcomes that are oriented to features of the external environment. We extended this work by testing the hypothesis that, as a result, individuals of a lower social class are more empathically accurate in judging the emotions of other people. In three studies, lower-class individuals (compared with upper-class individuals) received higher scores on a test of empathic accuracy (Study 1), judged the emotions of an interaction partner more accurately (Study 2), and made more accurate inferences about emotion from static images of muscle movements in the eyes (Study 3). Moreover, the association between social class and empathic accuracy was explained by the tendency for lower-class individuals to explain social events in terms of features of the external environment. The implications of class-based patterns in empathic accuracy for well-being and relationship outcomes are discussed.

Collisson E.A.,University of California at San Francisco
Clinical Cancer Research | Year: 2015

The treatment of resected lung adenocarcinoma has ample room for improvement. Can genomic characterization aid us in deciding how and when to apply adjuvant therapy in the smallest resected tumors? © 2015 AACR.

Loh M.L.,University of California at San Francisco
British Journal of Haematology | Year: 2011

Myeloid neoplasms derive from the pathological clonal expansion of an abnormal stem cell and span a diverse spectrum of phenotypes including acute myeloid leukaemia (AML), myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). Expansion of myeloid blasts with suppression of normal haematopoiesis is the hallmark of AML, whereas MPN is associated with over-proliferation of one or more lineages that retain the capacity to differentiate, and MDS is characterized by cytopenias and aberrant differentiation. MPD and MDS can progress to AML, which is likely due to the acquisition of cooperative mutations. Juvenile myelomonocytic leukaemia (JMML) is an aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap MPN/MDS by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukaemia, a similar disease in adults. While the current standard of care for patients with JMML relies on allogeneic haematopoietic stem cell transplant (HSCT), relapse is the most frequent cause of treatment failure. This review outlines our understanding of the genetic underpinnings of JMML with a recent update on the discovery of novel CBL mutations, as well as a brief review on current therapeutic approaches. © 2011 Blackwell Publishing Ltd.

Podust L.M.,University of California at San Francisco | Sherman D.H.,University of Michigan
Natural Product Reports | Year: 2012

Covering: 1985 to 2012 Diverse oxygenation patterns of natural products generated by secondary metabolic pathways in microorganisms and plants are largely achieved through the tailoring reactions catalysed by cytochrome P450 enzymes (P450s). P450s are a large family of oxidative hemoproteins found in all life forms from prokaryotes to humans. Understanding the reactivity and selectivity of these fascinating C-H bond-activating catalysts will advance their use in generating valuable pharmaceuticals and products for medicine, agriculture and industry. A major strength of this P450 group is its set of established enzyme-substrate relationships, the source of the most detailed knowledge on how P450 enzymes work. Engineering microbial-derived P450 enzymes to accommodate alternative substrates and add new functions continues to be an important near- and long-term practical goal driving the structural characterization of these molecules. Understanding the natural evolution of P450 structure-function should accelerate metabolic engineering and directed evolutionary approaches to enhance diversification of natural product structures and other biosynthetic applications. This journal is © The Royal Society of Chemistry 2012.

Rabban J.T.,University of California at San Francisco | Zaloudek C.J.,University of California at San Francisco
Histopathology | Year: 2013

Immunohistochemistry can be useful in the diagnosis of ovarian germ cell tumours and sex cord-stromal tumours. A wide variety of markers are available, including many that are novel. The aim of this review is to provide a practical approach to the selection and interpretation of these markers, emphasizing an understanding of their sensitivity and specificity in the particular differential diagnosis in question. The main markers discussed include those for malignant germ cell differentiation (SALL4 and placental alkaline phosphatase), dysgerminoma (OCT4, CD117, and D2-40), yolk sac tumour (α-fetoprotein and glypican-3), embryonal carcinoma (OCT4, CD30, and SOX2), sex cord-stromal differentiation (calretinin, inhibin, SF-1, FOXL2) and steroid cell tumours (melan-A). In addition, the limited role of immunohistochemistry in determining the primary site of origin of an ovarian carcinoid tumour is discussed. © 2012 Blackwell Publishing Limited.

Yao T.,University of California at San Francisco
Cancer causes & control : CCC | Year: 2012

This study estimated secondhand smoke (SHS) exposure at home among nonsmoking children (age 0-18) and adults (age ≥ 19) in rural China, and examined associated socio-demographic factors. A total of 5,442 nonsmokers (including 1,456 children and 3,986 adults) living in six rural areas in China were interviewed in person. The standardized questionnaire obtained information on their demographic characteristics and SHS exposure at home. Differences in SHS exposure were assessed by use of the chi-squared test. Logistic regression analysis was used to examine the associated factors. Occurrence of SHS exposure at home among nonsmoking children and adults was 68.0 and 59.3%, respectively. Logistic regression analysis found that children living in households with married, low-education, and low-income heads of household, and those who resided in the Qinghai province of China were more likely to be exposed to SHS. Among adults, those who were female, aged 19-34, single, low-education, and low-income, and those who lived in Qinghai province were more likely to be exposed to SHS at home. Our findings of substantial SHS exposure at home in rural China emphasize the importance of implementing interventions to reduce SHS exposure among this population.

Marques S.C.,University of California at San Francisco
Human genomics | Year: 2010

Over the past decade, the number of pharmacogenetic tests has increased considerably, allowing for the development of our knowledge of their clinical application. The uridine diphosphate glucuronosyltransferase 1A1 gene ( UGT1A1 ) assay is an example of a pharmacogenetic test. Numerous variants have been found in UGT1A1 , the main conjugating enzyme of bilirubin and drugs such as the anticancer drug irinotecan. Recently, the US Food and Drug Administration (FDA) recommended testing for the presence of UGT1A1*28 , an allele correlated with decreased transcriptional activity, to predict patients at risk of irinotecan toxicity. The administration of other drugs - such as inhibitors of the UGT1A1 enzyme - can clinically mimic the *28 phenotype, whereas inducers of UGT1A1 can increase the glucuronidation rate of the enzyme. The *28 polymorphism is not present in all ethnicities at a similar frequency, which suggests that it is important to study different populations to determine the clinical relevance of testing for UGT1A1*28 and to identify other clinically relevant UGT1A1 variants. Environmental factors such as lifestyle can also affect UGT1A1 activity. This review is a critical analysis of studies on drugs that can be affected by the presence of UGT1A1*28 , the distribution of this polymorphism around the globe, distinct variants that may be clinically significant in African and Asian populations and how lifestyle can affect treatment outcomes that depend on UGT1A1 activity.

Cedars M.I.,University of California at San Francisco
Fertility and Sterility | Year: 2015

Men and women are increasingly delaying childbearing to the late 30s, the 40s and beyond. The implications of this societal change on childhood health and well-being have only recently been a focus of research. There are known increased perinatal risks associated with increasing maternal age, while paternal age seems to have a potentially greater negative impact on childhood health. Understanding the mechanisms underlying the aging of sperm and eggs, and how these changes impact offspring, is a critical next step as we work to help patients build healthy families. © 2015 American Society for Reproductive Medicine.

ABSTRACT As in other organisms, CRISPR/Cas9 methods provide a powerful approach for genome editing in the nematode Caenorhabditis elegans. Oligonucleotides are excellent repair templates for introducing substitutions and short insertions, as they are cost effective, require no cloning, and appear in other organisms to target changes by homologous recombination at DNA double-strand breaks (DSBs). Here, I describe a methodology in C. elegans to efficiently knock in epitope tags in 8–9 days, using a temperature-sensitive lethal mutation in the pha-1 gene as a co-conversion marker. I demonstrate that 60mer oligos with 29 bp of homology drive efficient knock-in of point mutations, and that disabling nonhomologous end joining by RNAi inactivation of the cku-80 gene significantly improves knock-in efficiency. Homology arms of 35–80 bp are sufficient for efficient editing and DSBs up to 54 bp away from the insertion site produced knock-ins. These findings will likely be applicable for a range of genome editing approaches in C. elegans, which will improve editing efficiency and minimize screening efforts. © 2015 by the Genetics Society of America

Mayadas T.N.,Harvard University | Cullere X.,Harvard University | Lowell C.A.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2014

Neutrophils and neutrophil-like cells are the major pathogen-fighting immune cells in organisms ranging from slime molds to mammals. Central to their function is their ability to be recruited to sites of infection, to recognize and phagocytose microbes, and then to kill pathogens through a combination of cytotoxic mechanisms. These include the production of reactive oxygen species, the release of antimicrobial peptides, and the recently discovered expulsion of their nuclear contents to form neutrophil extracellular traps. Here we discuss these primordial neutrophil functions, which also play key roles in tissue injury, by providing details of neutrophil cytotoxic functions and congenital disorders of neutrophils. In addition, we present more recent evidence that interactions between neutrophils and adaptive immune cells establish a feed-forward mechanism that amplifies pathologic inflammation. These newly appreciated contributions of neutrophils are described in the setting of several inflammatory and autoimmune diseases. © 2014 by Annual Reviews. All rights reserved.

Preservation of the nipple-areolar complex with total skin-sparing mastectomy is becoming a popular mastectomy technique. As experience increases, the patient inclusion criteria for total skin sparing mastectomy expand. The authors assessed outcomes of total skin-sparing mastectomy and immediate prosthetic reconstruction in women with a prior history of augmentation mammaplasty. Between 2005 and 2012, all women with a history of augmentation mammaplasty and implants in place, undergoing total skin-sparing mastectomy and immediate prosthetic reconstruction, were prospectively tracked. Patient demographics, expander coverage type, adjuvant treatment, and incidence of complications were analyzed. Outcomes in these patients were compared with those of patients undergoing the same operation, without prior augmentation history. Thirty-four women with prior augmentation underwent total skin-sparing mastectomy and immediate tissue expander placement on 51 breasts. Comparison to the nonaugmentation group showed similar rates of superficial nipple necrosis (0 percent, p=0.324), complete nipple necrosis (0 percent, p=0.324), and skin flap necrosis (4 percent, p=1.0). The prior augmentation group did have a higher rate of implant loss (10 percent, p=0.515), with all but one of these occurring in irradiated patients. Total skin-sparing mastectomy and immediate prosthetic reconstruction is a safe technique in women with a history of augmentation mammaplasty. The preferred reconstructive technique is immediate submuscular tissue expander placement. In the setting of no radiation history, this operation carries a safety profile similar to that of patients without a history of prior augmentation, and can be offered safely. Risk, II.

Foster S.A.,University of California at San Francisco | Morgan D.O.,University of California at San Francisco
Molecular Cell | Year: 2012

The fidelity of chromosome segregation depends on the spindle assembly checkpoint (SAC). In the presence of unattached kinetochores, anaphase is delayed when three SAC components (Mad2, Mad3/BubR1, and Bub3) inhibit Cdc20, the activating subunit of the anaphase-promoting complex (APC/C). We analyzed the role of Cdc20 autoubiquitination in the SAC of budding yeast. Reconstitution with purified components revealed that a Mad3-Bub3 complex synergizes with Mad2 to lock Cdc20 on the APC/C and stimulate Cdc20 autoubiquitination, while inhibiting ubiquitination of substrates. SAC-dependent Cdc20 autoubiquitination required the Mnd2/Apc15 subunit of the APC/C. General inhibition of Cdc20 ubiquitination in vivo resulted in high Cdc20 levels and a failure to establish a SAC arrest, suggesting that SAC establishment depends on low Cdc20 levels. Specific inhibition of SAC-dependent ubiquitination, by deletion of Mnd2, allowed establishment of a SAC arrest but delayed release from the arrest, suggesting that Cdc20 ubiquitination is also required for SAC inactivation. © 2012 Elsevier Inc.

Fields H.L.,University of California at San Francisco | Margolis E.B.,University of California at San Francisco
Trends in Neurosciences | Year: 2015

Opioids are the most potent analgesics in clinical use; however, their powerful rewarding properties can lead to addiction. The scientific challenge is to retain analgesic potency while limiting the development of tolerance, dependence, and addiction. Both rewarding and analgesic actions of opioids depend upon actions at the mu opioid (MOP) receptor. Systemic opioid reward requires MOP receptor function in the midbrain ventral tegmental area (VTA) which contains dopaminergic neurons. VTA dopaminergic neurons are implicated in various aspects of reward including reward prediction error, working memory, and incentive salience. It is now clear that subsets of VTA neurons have different pharmacological properties and participate in separate circuits. The degree to which MOP receptor agonists act on different VTA circuits depends upon the behavioral state of the animal, which can be altered by manipulations such as food deprivation or prior exposure to MOP receptor agonists. © 2015 Elsevier Ltd.

Homann O.R.,University of California at San Francisco | Johnson A.D.,University of California at San Francisco
BMC Biology | Year: 2010

Background: As high-throughput technologies rapidly generate genome-scale data, it becomes increasingly important to visually integrate these data so that specific hypotheses can be formulated and tested.Results: We present MochiView, a platform-independent Java software that integrates browsing of genomic sequences, features, and data with DNA motif visualization and analysis in a visually-appealing and user-friendly application.Conclusions: While highly versatile, the software is particularly useful for organizing, exploring, and analyzing large genomic data sets, such as those from deep RNA sequencing, chromatin immunoprecipitation experiments (ChIP-Seq and ChIP-Chip), and transcriptional profiling. MochiView provides an extensive suite of utilities to identify and to explore connections between these data sets and short sequence motifs present in DNA or RNA. © 2010 Homann and Johnson; licensee BioMed Central Ltd.

West T.W.,University of California at San Francisco | Cree B.A.C.,University of California at San Francisco
Annals of Neurology | Year: 2010

The risk of developing progressive multifocal leukoencephalopathy increases with the duration of treatment with natalizumab. Planned dosage interruptions have been proposed as a means of decreasing cumulative risk. The clinical consequences of dosage interruption were evaluated in a single center cohort of natalizumab-treated patients. Medical records were reviewed for 84 patients identified with multiple sclerosis who received 12 or more infusions of natalizumab at an academic multiple sclerosis center. Eighty-one percent (68/84) underwent a dosage interruption, and 19% (16/84) had no interruption in natalizumab treatment. Of those with a treatment interruption, 27.9% (19/68) experienced a clinical relapse within 6 months of the suspension, whereas none of the patients with ongoing treatment experienced a flare during months 12 to 18 of treatment (p = 0.017, Fisher exact test). Survival analysis showed that Kaplan-Meier curves comparing dosage interruption to ongoing treatment diverged (p = 0.025). Median time from treatment interruption to relapse onset was 3 months. No clinical predictors associated with an increased risk of developing flares during dosage interruption were identified. Among the 19 patients who had a flare, 7 had severe flares, with a mean number of 16 Gad+ lesions on brain magnetic resonance imaging (range, 6-40). Their median Expanded Disability Status Scale at natalizumab interruption was 3.0 and increased to 6.0 during the flare (p = 0.0008). Natalizumab dosage interruption is associated with clinical flares and return of radiographic inflammatory disease activity. Some of these flares can be clinically severe, with a high number of contrast-enhanced lesions, suggesting a possible rebound of disease activity.

Tan C.E.,University of California at San Francisco | Glantz S.A.,University of California at San Francisco
Circulation | Year: 2012

Background-Secondhand smoke causes cardiovascular and respiratory disease. Smoke-free legislation is associated with a lower risk of hospitalization and death from these diseases. Methods and Results-Random-effects meta-analysis was conducted by law comprehensiveness to determine the relationship between smoke-free legislation and hospital admission or death from cardiac, cerebrovascular, and respiratory diseases. Studies were identified by using a systematic search for studies published before November 30, 2011 with the use of the Science Citation Index, Google Scholar, PubMed, and Embase and references in identified articles. Change in hospital admissions (or deaths) in the presence of a smoke-free law, duration of follow-up, and law comprehensiveness (workplaces only; workplaces and restaurants; or workplaces, restaurants, and bars) were recorded. Forty-five studies of 33 smoke-free laws with median follow-up of 24 months (range, 2-57 months) were included. Comprehensive smoke-free legislation was associated with significantly lower rates of hospital admissions (or deaths) for all 4 diagnostic groups: coronary events (relative risk, 0.848; 95% confidence interval 0.816-0.881), other heart disease (relative risk, 0.610; 95% confidence interval, 0.440-0.847), cerebrovascular accidents (relative risk, 0.840; 95% confidence interval, 0.753-0.936), and respiratory disease (relative risk, 0.760; 95% confidence interval, 0.682-0.846). The difference in risk following comprehensive smoke-free laws does not change with longer follow-up. More comprehensive laws were associated with larger changes in risk. Conclusions-Smoke-free legislation was associated with a lower risk of smoking-related cardiac, cerebrovascular, and respiratory diseases, with more comprehensive laws associated with greater changes in risk. © 2012 American Heart Association, Inc.

Conte M.S.,University of California at San Francisco
Seminars in Vascular Surgery | Year: 2012

Diabetes is an independent risk factor for peripheral arterial disease and, when advancedperipheral arterial disease develops in the setting of diabetes, it portends a greatly increased threat to both life and limb. The management of severe limb ischemia in diabetic patients, particularly those with tissue loss and infection, remains a major surgical challenge in the new millennium. However, advances in multidisciplinary care, including an aggressive revascularization approach, can avoid major amputation in a large percentage of patients. The unique pattern of lower extremity atherosclerosis in diabetes is a critical determinant of the revascularization strategy. Most diabetics with critical ischemia have popliteal/tibial occlusions requiring below-the-knee intervention or bypass grafting. Bypass surgery with vein to crural or pedal arteries remains the gold standard of revascularization, but may be limited by patient risk, conduit availability, and a suitable target. Infrapopliteal angioplasty can have acceptable results for suitable lesions, particularly when there is not extensive tissue loss in the foot. However, restenosis rates after endovascular intervention in these vessels are high, and recent advances in drug-eluting balloons and stents have promise but remain largely unproven. There is limited high-quality evidence to support treatment choices in this arena, with only one randomized clinical trial to date. The available data suggest that patients with life expectancy of at least 2 years and more extensive disease have superior outcomes with open reconstruction. A selective revascularization strategy is advocated, using autogenous vein bypass as the initial approach in a significant percentage of patients, based on its greater overall efficacy and proven durability. However, endovascular therapies have an important role in current practice, which will increase further if restenosis can be overcome. Vascular specialists should understand and be able to apply both types of interventions to optimize patient outcomes. © 2012 Published by Elsevier Inc.

Baranzini S.E.,University of California at San Francisco | Nickles D.,University of California at San Francisco
Current Opinion in Neurology | Year: 2012

Purpose of Review: Major advances in the genetics of multiple sclerosis (MS) have been reported in 2011. These include studies in gene mapping, functional characterization of previously associated genes, and the relationship between genes and the environment. While particularly true for gene discovery, each of these efforts requires substantial statistics and computational resources for adequate analysis. This review describes the major advances in the genetics of MS with a slight emphasis on data handling and analysis. Recent Findings: Articles discussed include a new genome-wide association study (GWAS) with almost 10 000 cases (a collaboration between the Wellcome Trust and the international MS Genetics Consortium) that identified new susceptibility loci, taking the total number of risk alleles to more than 50. An article describing the use of next-generation sequencing to identify a rare mutation in CYP27B1 in a MS family is also discussed. Moreover, a summary of recent reports describing functional studies of MS-associated genes as well as the latest research on the interactions between genes and the environment is provided. Summary: This review provides a concise summary of the most relevant studies in the genetics of MS in the past year. We raise awareness about analytical resources to successfully analyze the massive datasets characteristic of today's genetic studies. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Kerlikowske K.,University of California at San Francisco
JAMA Internal Medicine | Year: 2015

Importance Breast cancer is a leading cause of premature mortality among US women. Early detection has been shown to be associated with reduced breast cancer morbidity and mortality. OBJECTIVE To update the American Cancer Society (ACS) 2003 breast cancer screening guideline for women at average risk for breast cancer. PROCESS The ACS commissioned a systematic evidence review of the breast cancer screening literature to inform the update and a supplemental analysis of mammography registry data to address questions related to the screening interval. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. EVIDENCE SYNTHESIS Screening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health. Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages because of the greater number of mammograms, as well as the higher recall rate in younger women. The quality of the evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence. Analysis examining the screening interval demonstrates more favorable tumor characteristics when premenopausal women are screened annually vs biennially. Evidence does not support routine clinical breast examination as a screeningmethod for women at average risk. RECOMMENDATIONS The ACS recommends that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years (strong recommendation).Women aged 45 to 54 years should be screened annually (qualified recommendation).Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation).Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation).Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation). The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age (qualified recommendation). CONCLUSIONS AND RELEVANCE These updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer screening. © 2015 American Medical Association. All rights reserved.

Roberts J.P.,University of California at San Francisco
Liver Transplantation | Year: 2012

Key Points 1. The reporting of liver transplant center outcomes is required by the final rule of the Department of Health and Human Services. The reported patient and graft survival outcomes are risk-adjusted for specific donor and recipient factors, and the observed survival is compared to the expected survival. Both the Centers for Medicare and Medicaid Services and the Organ Procurement and Transplantation Network flag programs for corrective action when the observed survival is significantly less than the expected survival. Both agencies can take action up to the closure of a center. In the last 5 years, the Organ Procurement and Transplantation Network has not taken an adverse action that required the closure of a liver transplant center because of outcomes. 2. Center survey data suggest that centers may try to select donors and recipients to minimize poor outcomes. This strategy may not be effective if centers stop accepting donors or recipients according to factors that are included in the risk adjustment model. For example, limiting recipients to those less than 65 years old may improve the observed outcomes, but the expected outcomes will also improve because a recipient 65 years or older is included in the model's risk adjustment. 3. For factors such as cardiovascular risk that are not included in the model, it may be reasonable to exclude patients in an attempt to improve the observed outcomes without affecting the expected outcomes. Other examples of these types of factors are smoking, nutritional status, and donor liver biopsy findings. 4. Currently, there is no exemption for patients undergoing experimental protocols. Down-staging for hepatocellular carcinoma, transplantation for human immunodeficiency virus-positive recipients, and the use of left lobe grafts with inflow modification are relatively recent areas of innovation in liver transplantation. Because innovation is frequently associated with a learning curve and, therefore, poor outcomes, the inclusion of patients in innovative protocols potentially could lead to centers being subjected to an adverse action by the Organ Procurement and Transplantation Network or the Centers for Medicare and Medicaid Services. Active consideration is being given to the exclusion of patients in innovative protocols from center-specific outcomes. © 2012 AASLD.

Pogrel M.A.,University of California at San Francisco
Journal of Oral and Maxillofacial Surgery | Year: 2012

The purpose of this article is to summarize the literature that addresses the following question: "Among patients undergoing third molar removal, do patients who are younger, eg, <25 years, when compared with older patients, have a decreased risk for postoperative complications and more rapid recovery?" For the purposes of this study, relevant articles were identified through a search of PubMed, Scopus, and the Cochrane Database, using the Medical Subject Headings search terms "third molars" or "wisdom teeth," "complications" and "age," linked to "recovery," "infections," "periodontal conditions," "temporomandibular joint problems," "nerve involvement," "sinus communication," and "mandibular fracture." Relevant studies have been identified and are reported for the following complications and their relationship to the patient's age: 1) time to recovery; 2) incidence of fractures; 3) rates of infection; 4) periodontal complications; 5) nerve involvement; 6) temporomandibular joint complications; 7) nerve injury; and 8) sinus-related complications. Studies indicate that as one becomes older, third molars (M3s) become more difficult to remove, may take longer to remove, and may result in an increased risk for complications associated with removal. The age of 25 years appears in many studies to be a critical time after which complications increase more rapidly. Conversely, there are no studies indicating a decrease in complications with increasing age. It also appears that recovery from complications is more prolonged and is less predictable and less complete with increasing age. As such, many clinicians recommend removal of M3s in patients as young adults. Advocates of M3 retention need to review carefully with their patients the risks of delaying M3 removal with the same degree of emphasis as the risks associated with operative treatment. © 2012 American Association of Oral and Maxillofacial Surgeons.

Paulson A.S.,University of California at San Francisco | Tran Cao H.S.,The Surgical Center | Tempero M.A.,University of California at San Francisco | Lowy A.M.,University of California at San Diego
Gastroenterology | Year: 2013

Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better short-term outcomes, major progress toward increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5-10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of "borderline resectable pancreatic cancer" - a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients' lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future. © 2013 by the AGA Institute.

Devireddy L.R.,Case Western Reserve University | Hart D.O.,Howard Hughes Medical Institute | Goetz D.H.,University of California at San Francisco | Green M.R.,Howard Hughes Medical Institute
Cell | Year: 2010

Intracellular iron homeostasis is critical for survival and proliferation. Lipocalin 24p3 is an iron-trafficking protein that binds iron through association with a bacterial siderophore, such as enterobactin, or a postulated mammalian siderophore. Here, we show that the iron-binding moiety of the 24p3-associated mammalian siderophore is 2,5-dihydroxybenzoic acid (2,5-DHBA), which is similar to 2,3-DHBA, the iron-binding component of enterobactin. We find that the murine enzyme responsible for 2,5-DHBA synthesis, BDH2, is the homolog of bacterial EntA, which catalyzes 2,3-DHBA production during enterobactin biosynthesis. RNA interference-mediated knockdown of BDH2 results in siderophore depletion. Mammalian cells lacking the siderophore accumulate abnormally high amounts of cytoplasmic iron, resulting in elevated levels of reactive oxygen species, whereas the mitochondria are iron deficient. Siderophore-depleted mammalian cells and zebrafish embryos fail to synthesize heme, an iron-dependent mitochondrial process. Our results reveal features of intracellular iron homeostasis that are conserved from bacteria through humans. © 2010 Elsevier Inc.

Deo R.C.,University of California at San Francisco
Circulation: Cardiovascular Genetics | Year: 2016

Background-Truncating mutations in the giant sarcomeric gene Titin are the most common type of genetic alteration in dilated cardiomyopathy. Detailed studies have amassed a wealth of information about truncating variant position in cases and controls. Nonetheless, considerable confusion exists as to how to interpret the pathogenicity of these variants, hindering our ability to make useful recommendations to patients. Methods and Results-Building on our recent discovery of a conserved internal promoter within the Titin gene, we sought to develop an integrative statistical model to explain the observed pattern of Titin truncation variants in patients with dilated cardiomyopathy and population controls. We amassed Titin truncation mutation information from 1714 human dilated cardiomyopathy cases and >69 000 controls and found 3 factors explaining the distribution of Titin mutations: (1) alternative splicing, (2) whether the internal promoter Cronos isoform was disrupted, and (3) whether the distal C terminus was targeted (in keeping with the observation that truncation variants in this region escape nonsense-mediated decay and continue to be incorporated in the sarcomere). A model using these 3 factors had strong predictive performance with an area under the receiver operating characteristic curve of 0.81. Accordingly, individuals with either the most severe form of dilated cardiomyopathy or whose mutations demonstrated clear family segregation experienced the highest risk profile across all 3 components. Conclusions-We conclude that quantitative models derived from large-scale human genetic and phenotypic data can be applied to help overcome the ever-growing challenges of genetic data interpretation. Results of our approach can be found at∼deo/TTNtruncationvariant.html. © 2016 American Heart Association, Inc.

Green L.W.,University of California at San Francisco
Health Education and Behavior | Year: 2016

This reflection is on a health education professional’s rotation from professor in a school of public health to a government position and back parallels that of Professor Howard Koh’s journey to Assistant Secretary of Health, one level higher in the same federal bureaucracy. We both acknowledge the steep learning curve and some bureaucratic hassles and mazes that can attend government service, but similarly conclude that “.. it was worth it.” In this personalized case, I weigh some of the specific learning experiences and challenges I faced while in the government against the needs of the field of health promotion for more such revolving-door experiences among academic public health professionals. From my argument that to get more evidence-based practice we need more practice-based evidence, I conclude that more experience in practice among those returning to academia will render their teaching and research more relevant to the needs for evidence in policy and practice. © 2015, 2015 Society for Public Health Education.

Xu P.,University of California at San Francisco | Derynck R.,University of California at San Francisco
Molecular Cell | Year: 2010

Inflammatory stimuli activate ectodomain shedding of TNF-α, L-selectin, and other transmembrane proteins. We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38α MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr735, which is required for TACE-mediated ectodomain shedding. Activation of TACE by p38 MAP kinase results in the release of TGF-α family ligands, which activate EGF receptor signaling, leading to enhanced cell proliferation. Conversely, depletion of p38α MAP kinase activity suppresses EGF receptor signaling and downstream Erk MAP kinase signaling, as well as autocrine EGF receptor-dependent proliferation. Autocrine EGF receptor activation through TACE-mediated ectodomain shedding intimately links inflammation and cancer progression and may play a role in stress and conditions that relate to p38 MAP kinase activation. © 2010 Elsevier Inc. All rights reserved.

Burt T.D.,University of California at San Francisco
American Journal of Reproductive Immunology | Year: 2013

The developing fetus must actively learn to tolerate benign antigens or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) in the periphery. Fetal CD4+ T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in fetal tissues. As the fetus nears birth, a crucial transition must occur between the tolerogenic fetal immune system and a more defensive adult-type immune system that is able to combat pathogens. This paper will review the unique tolerogenic nature of fetal T cells and will examine evidence for a novel model of fetal immune development: the layered immune system hypothesis. © 2013 John Wiley & Sons A/S.

Miller R.H.,University of California at San Francisco
Health Affairs | Year: 2012

In June 2010 sixteen organizations representing California patients and consumers adopted nine principles for electronically exchanging health information among and within provider organizations. The principles were formulated with the goal of improving patient and population health care by increasing the availability and use of patient data while protecting patients' privacy. This study assesses to what extent five health care organizations-all in different stages of increasing their capacity for health information exchange-conformed to the principles in early 2011. Although an increasing amount of electronic data has been exchanged among organizations and with patients, progress has been modest, and patients still have little control over their data. For organizations to comply with all nine patient and consumer principles, clear "rules of the road" for information sharing must be defined, and patient education in health information exchange and control over personal data must be increased. © 2012 Project HOPE-The People-to-People Health Foundation, Inc.

Bauer L.,University of California at San Francisco
European journal of cardiovascular nursing : journal of the Working Group on Cardiovascular Nursing of the European Society of Cardiology | Year: 2012

Cognitive impairment is a recognized consequence of heart failure; however, there are no neuropsychological batteries with documented psychometric data in the chronic heart failure population. To document the psychometric properties of a brief neuropsychological battery in a chronic heart failure sample. The Repeatable Battery for the Assessment of Neuropsychological Status, Trail Making Test Part A and Part B, and letter fluency was administered to a sample of individuals with chronic heart failure. Eighty individuals with stable heart failure participated in this study. Individuals with chronic heart failure scored significantly lower than expected age and education adjusted norms in the domains of attention (p < 0.001), memory (p < 0.001), language (p < 0.001), executive function (p < 0.001), and psychomotor speed (p = 0.02). Scores on the tests of memory and executive function correlated to functional status (r = 0.28, p = 0.02 and r = 0.29, p = 0.03, respectively). Acceptable convergent validity and test-retest reliability were documented for this battery. The neuropsychological battery had adequate reliability and validity in individuals with chronic heart failure.

Papadopoulos V.,McGill University | Miller W.L.,University of California at San Francisco
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2012

Adrenal gonadal, placental and brain mitochondria contain several steroidogenic enzymes, notably the cholesterol side chain cleavage enzyme, P450scc, which is the enzymatic rate-limiting step in steroidogenesis which determines cellular steroidogenic capacity. Even before this step, the access of cholesterol to this enzyme system is both rate-limiting and the site of acute regulation via the steroidogenic acute regulatory protein (StAR) which interacts with a complex multi-component 'transduceosome' on the outer mitochondrial membrane (OMM). The components of the transduceosome include the 18 kDa translocator protein (TSPO), the voltage-dependent anion channel (VDAC-1), TSPO-associated protein 7 (PAP7, ACBD3 for acyl-CoA-binding-domain 3), and protein kinase A regulatory subunit 1α (PKAR1A). The precise fashion in which these proteins interact and move cholesterol from the OMM to P450scc, and the means by which cholesterol is loaded into the OMM, remain unclear. Human deficiency diseases have been described for StAR and for P450scc. Mitochondria also contain several 'downstream' steroidogenic enzymes. © 2012 Elsevier Ltd. All rights reserved.

Murrow L.,University of California at San Francisco | Debnath J.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2013

Autophagy, a vital catabolic process that degrades cytoplasmic components within the lysosome, is an essential cytoprotective response to pathologic stresses that occur during diseases such as cancer, ischemia, and infection. In addition to its role as a stress-response pathway, autophagy plays an essential quality-control function in the cell by promoting basal turnover of long-lived proteins and organelles, as well as by selectively degrading damaged cellular components. This homeostatic function protects against a wide variety of diseases, including neurodegeneration, myopathy, liver disease, and diabetes. This review discusses our current understanding of these two principal functions of autophagy and describes in detail how alterations in autophagy promote human disease. © 2013 by Annual Reviews. All rights reserved.

Chang E.F.,University of California at San Francisco
Neuron | Year: 2015

Direct human brain recordings have transformed the scope of neuroscience in the past decade. Progress has relied upon currently available neurophysiological approaches in the context of patients undergoing neurosurgical procedures for medical treatment. While this setting has provided precious opportunities for scientific research, it also has presented significant constraints on the development of new neurotechnologies. A major challenge now is how to achieve high-resolution spatiotemporal neural recordings at a large scale. By narrowing the gap between current approaches, new directions tailored to the mesoscopic (intermediate) scale of resolution may overcome the barriers towards safe and reliable human-based neurotechnology development, with major implications for advancing both basic research and clinical translation. © 2015 Elsevier Inc.

Willsey A.J.,University of California at San Francisco | State M.W.,University of California at San Francisco
Current Opinion in Neurobiology | Year: 2015

Advances in genome-wide technology, coupled with the availability of large cohorts, are finally yielding a steady stream of autism spectrum disorder (ASD) genes carrying mutations of large effect. These findings represent important molecular clues, but at the same time present notable challenges to traditional strategies for moving from genes to neurobiology. A remarkable degree of genetic heterogeneity, the biological pleiotropy of ASD genes, and the tremendous complexity of the human brain are prompting the development of new strategies for translating genetic discoveries into therapeutic targets. Recent developments in systems biology approaches that 'contextualize' these genetic findings along spatial, temporal, and cellular axes of human brain development are beginning to bridge the gap between high-throughput gene discovery and testable pathophysiological hypotheses. © 2014.

Cheng C.M.,University of California at San Francisco
Clinical Pharmacology and Therapeutics | Year: 2011

In its 2006 report Preventing Medication Errors, the Institute of Medicine (IOM) estimated that more than 1.5 million preventable adverse drug events (ADEs) occur annually in the United States. Many organizations, including the IOM, the Institute for Safe Medication Practices, the US Food and Drug Administration, and the Leap Frog Group for Patient Safety have advocated the implementation of technologies to reduce ADEs, particularly in the hospital setting. Many technologies have emerged in recent years to reduce ADEs at various points in the medication use process; however, interfacing some of these key technologies with existing hospital systems poses significant challenges. © 2011 American Society for Clinical Pharmacology and Therapeutics.

South A.P.,Ninewells Hospital and Medical School | Cho R.J.,University of California at San Francisco | Aster J.C.,Harvard University
Seminars in Cell and Developmental Biology | Year: 2012

Recent deep sequencing of cancer genomes has produced an explosion of new data implicating Notch signaling in several human cancers. Unlike most other pathways, these data indicate that Notch signaling can be either oncogenic or tumor suppressive, depending on the cellular context. In some instances, these relationships were predicted from mouse models or presaged by developmental roles for Notch, but in other cases were unanticipated. This review discusses the pathogenic and translational significance of these new findings. © 2012 Elsevier Ltd.

Kemere C.,University of California at San Francisco
PloS one | Year: 2013

Hippocampal information processing is often described as two-state, with a place cell state during movement and a reactivation state during stillness. Relatively little is known about how the network transitions between these different patterns of activity during exploration. Here we show that hippocampal network changes quickly and continuously as animals explore and become familiar with initially novel places. We measured the relationship between moment-by-moment changes in behavior and information flow through hippocampal output area CA1 in rats. We examined local field potential (LFP) patterns, evoked potentials and ensemble spiking and found evidence suggestive of a smooth transition from strong CA3 drive of CA1 activity at low speeds to entorhinal cortical drive of CA1 activity at higher speeds. These changes occurred with changes in behavior on a timescale of less than a second, suggesting a continuous modulation of information processing in the hippocampal circuit as a function of behavioral state.

Carvalheira J.B.,University of California at San Francisco
Blood | Year: 2013

The rise of obesity and its attendant pathological sequelae, including type 2 diabetes and coronary artery disease, constitute an ongoing public health catastrophe in both the developed and, more recently, the developing world. Although the underlying pathophysiology is complex, chronic low-grade inflammation has emerged as a central driver of both primary metabolic dysfunction and subsequent tissue failure. Importantly, this inflammation has been shown to arise as a consequence of both the disruption of homeostatic tissue resident leukocytes and the recruitment of antagonistic effector cells from the circulation. In this review, we discuss the roles of visceral adipose tissue's salient leukocyte lineages in the transition to obesity and highlight key points at which this emerging immune axis may be manipulated for therapeutic effect.

Ekstrand M.L.,University of California at San Francisco
Journal of the International AIDS Society | Year: 2013

HIV stigma inflicts hardship and suffering on people living with HIV (PLHIV) and interferes with both prevention and treatment efforts. Health professionals are often named by PLHIV as an important source of stigma. This study was designed to examine rates and drivers of stigma and discrimination among doctors, nurses and ward staff in different urban healthcare settings in high HIV prevalence states in India. This cross-sectional study enrolled 305 doctors, 369 nurses and 346 ward staff in both governmental and non-governmental healthcare settings in Mumbai and Bengaluru, India. The approximately one-hour long interviews focused on knowledge related to HIV transmission, personal and professional experiences with PLHIV, instrumental and symbolic stigma, endorsement of coercive policies, and intent to discriminate in professional and personal situations that involve high and low risk of fluid exposure. High levels of stigma were reported by all groups. This included a willingness to prohibit female PLHIV from having children (55 to 80%), endorsement of mandatory testing for female sex workers (94 to 97%) and surgery patients (90 to 99%), and stating that people who acquired HIV through sex or drugs "got what they deserved" (50 to 83%). In addition, 89% of doctors, 88% of nurses and 73% of ward staff stated that they would discriminate against PLHIV in professional situations that involved high likelihood of fluid exposure, and 57% doctors, 40% nurses and 71% ward staff stated that they would do so in low-risk situations as well. Significant and modifiable drivers of stigma and discrimination included having less frequent contact with PLHIV, and a greater number of transmission misconceptions, blame, instrumental and symbolic stigma. Participants in all three groups reported high rates of endorsement of coercive measures and intent to discriminate against PLHIV. Stigma and discrimination were associated with multiple modifiable drivers, which are consistent with previous research, and which need to be targeted in future interventions. Stigma reduction intervention programmes targeting healthcare providers in urban India need to address fear of transmission, improve universal precaution skills, and involve PLHIV at all stages of the intervention to reduce symbolic stigma and ensure that relevant patient interaction skills are taught.

Conte M.S.,University of California at San Francisco
Seminars in Vascular Surgery | Year: 2010

Critical limb ischemia (CLI), the most advanced form of peripheral arterial disease, is associated with a high rate of limb loss and substantial mortality. Revascularization remains the cornerstone of limb salvage in the CLI patient, and surgical bypass is the established standard. Endovascular therapies, such as angioplasty, atherectomy, and stenting offer a less-invasive option, but evidence of efficacy is lacking, and no devices are currently approved specifically for CLI. Design and execution of clinical trials in the CLI population are challenging, in part because of the lack of consensus on cohort definitions and relevant endpoints. Recently, the Society for Vascular Surgery undertook an initiative to define therapeutic benchmarks, objective performance goals (OPGs), for CLI. Using surgical bypass with autogenous vein as the standard for comparison, OPGs were developed for nine safety and efficacy measures that could be utilized in the premarket assessment of new devices in CLI. Data from three large randomized controlled trials of surgical bypass for CLI were analyzed. We defined a major adverse limb event (MALE) as a key endpoint for revascularization therapies in CLI-inclusive of amputation (transtibial or above) or any major vascular reintervention (thrombectomy, thrombolysis, or major surgical procedure [new bypass graft, jump/interposition graft revision]) in the index limb. Freedom from perioperative (30-day) death or any MALE (MALE + POD) was suggested as the primary efficacy endpoint for a single-arm trial design in CLI, with an observed rate of 76.9% for the surgical bypass controls at 1 year. Specific high-risk subgroups were also defined from the surgical dataset-based on clinical (age older than 80 years and tissue loss), arterial anatomy (infrapopliteal disease), and conduit quality (inadequate saphenous vein) characteristics. Risk-adjusted OPG were developed for these subgroups of interest. These OPGs define a new set of benchmarks for assessing the performance of revascularization therapies in CLI, and should facilitate clinical trial design and device development in this arena. © 2010 Elsevier Inc.

Lord C.,Cornell College | Bishop S.L.,University of California at San Francisco
Annual Review of Clinical Psychology | Year: 2015

This article provides a selective review of advances in scientific knowledge about autism spectrum disorder (ASD), using DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, fifth edition) diagnostic criteria as a framework for the discussion. We review literature that prompted changes to the organization of ASD symptoms and diagnostic subtypes in DSM-IV, and we examine the rationale for new DSM-5 specifiers, modifiers, and severity ratings as well as the introduction of the diagnosis of social (pragmatic) communication disorder. Our goal is to summarize and critically consider the contribution of clinical psychology research, along with that of other disciplines, to the current conceptualization of ASD. © 2015 by Annual Reviews. All rights reserved.

Sbitany H.,University of California at San Francisco
Plastic and Reconstructive Surgery | Year: 2014

Background: Postoperative complications after total skin-sparing mastectomy and expander-implant reconstruction can negatively impact outcomes, particularly in the setting of postmastectomy radiation therapy. The authors studied whether rates of ischemic complications after postmastectomy radiation therapy are impacted by the total skin-sparing mastectomy incision. Methods: The authors queried a prospectively collected database of patients undergoing total skin-sparing mastectomy and immediate two-stage expanderimplant reconstruction. Their hypothesis was that, in the setting of radiation therapy, patients with inframammary incisions would be more likely to develop ischemic complications than those without incisions on the dependent portion of the breast. We divided our patient cohort into two groups, those with inframammary incisions and those with other incisions, and then analyzed the proportion that received radiation therapy. Results: Of 756 cases included in the analysis, 91 (12 percent) received postmastectomy radiation therapy, 62 (68.1 percent) with inframammary incisions and 29 (31.9 percent) with other incisions. Mean follow-up was 3.1 years. Rates of mastectomy skin flap necrosis (3.2 percent versus 6.9 percent, p = 0.4) following radiation therapy were not significantly higher in the inframammary group. However, breakdown of the total skin-sparing mastectomy incision was twice as likely in the inframammary group (21 percent versus 10.3 percent, p = 0.2) and was more likely to lead to subsequent implant removal when incisional breakdown occurred (77 percent versus 0 percent, p = 0.03). Conclusions: Total skin-sparing mastectomy incision type may impact rates of incisional breakdown and implant loss following postmastectomy radiation therapy, with higher rates seen with inframammary incisions. Multiple factors, including breast size, breast ptosis, and likelihood of radiation therapy, should be considered in determining optimal incision. Copyright © 2014 by the American Society of Plastic Surgeon.

Deutsch M.B.,University of California at San Francisco | Buchholz D.,University of California at San Francisco
Journal of General Internal Medicine | Year: 2015

Transgender (Trans, Trans*) persons may have a gender identity and a preferred name that differ from those assigned at birth, and/or those listed on their current legal identification (Gender ID, Birth-assigned Sex, Legal Sex). Transgender people who are referred to in a clinical setting using the wrong pronoun or name may suffer distress, ridicule or even assault by others in the waiting area, and may not return for further care. Furthermore, failure to accurately document (and therefore count) transgender identities has negative implications on quality improvement and research efforts, funding priorities and policy activities. The recent announcement that gender identity data may be included in Meaningful Use Stage 3 has accelerated the need for guidance for both vendors and local implementation teams on how to best record and store these data. A recent study demonstrated wide variation in current practices. This manuscript provides a description of identifiers associated with gender identity, and makes practical and evidence based recommendations for implementation and front-end functionality. © 2014, Society of General Internal Medicine.

Houde J.F.,University of California at San Francisco | Nagarajan S.S.,University of California at San Francisco
Frontiers in Human Neuroscience | Year: 2011

Spoken language exists because of a remarkable neural process. Inside a speaker's brain, an intended message gives rise to neural signals activating the muscles of the vocal tract. The process is remarkable because these muscles are activated in just the right way that the vocal tract produces sounds a listener understands as the intended message. What is the best approach to understanding the neural substrate of this crucial motor control process? One of the key recent modeling developments in neuroscience has been the use of state feedback control (SFC) theory to explain the role of the CNS in motor control. SFC postulates that the CNS controls motor output by (1) estimating the current dynamic state of the thing (e.g., arm) being controlled, and (2) generating controls based on this estimated state. SFC has successfully predicted a great range of non-speech motor phenomena, but as yet has not received attention in the speech motor control community. Here, we review some of the key characteristics of speech motor control and what they say about the role of the CNS in the process. We then discuss prior efforts to model the role of CNS in speech motor control, and argue that these models have inherent limitations-limitations that are overcome by an SFC model of speech motor control which we describe. We conclude by discussing a plausible neural substrate of our model. © 2011 Houde and Nagarajan.

Deo R.C.,University of California at San Francisco
Circulation | Year: 2015

Spurred by advances in processing power, memory, storage, and an unprecedented wealth of data, computers are being asked to tackle increasingly complex learning tasks, often with astonishing success. Computers have now mastered a popular variant of poker, learned the laws of physics from experimental data, and become experts in video games - tasks that would have been deemed impossible not too long ago. In parallel, the number of companies centered on applying complex data analysis to varying industries has exploded, and it is thus unsurprising that some analytic companies are turning attention to problems in health care. The purpose of this review is to explore what problems in medicine might benefit from such learning approaches and use examples from the literature to introduce basic concepts in machine learning. It is important to note that seemingly large enough medical data sets and adequate learning algorithms have been available for many decades, and yet, although there are thousands of papers applying machine learning algorithms to medical data, very few have contributed meaningfully to clinical care. This lack of impact stands in stark contrast to the enormous relevance of machine learning to many other industries. Thus, part of my effort will be to identify what obstacles there may be to changing the practice of medicine through statistical learning approaches, and discuss how these might be overcome. © 2015 American Heart Association, Inc.

Matthay M.A.,University of California at San Francisco
Annals of the American Thoracic Society | Year: 2015

Based on preclinical data, cell-based therapy with bone marrow-derived mesenchymal stem (stromal) cells (MSCs) is a potentially attractive new therapeutic option for treating patients with the acute respiratory distress syndrome. Small and large animal models of acute lung injury from endotoxin, live bacteria, and sepsis have shown that MSCs can decrease lung injury and increase survival. The mechanisms for benefit are mediated in part by paracrine release of several antiinfl ammatory cytokines, keratinocyte growth factor, angiopoietin-1, as well as the release of antimicrobial peptides. There is also evidence that MSCs can transfer mitochondria and restore normal bioenergetics to injured alveolar epithelium. Some of the beneficial effects are mediated by microvesicles. A phase 1 safety and dose-escalation trial was completed and a randomized, double-blind clinical trial is currently underway. Copyright © 2015 by the American Thoracic Society.

Hiatt R.A.,University of California at San Francisco
American Journal of Epidemiology | Year: 2015

The concept of translational cancer epidemiology has evolved since its early beginnings in 1937 with the establishment of the National Cancer Institute. Conceptual models of cancer control research have also evolved over the last 30 years, to the point where we now have 4 stages of translational research (T0-T4). The current review by Lam et al. (Am J Epidemiol. 2015;181(7):451-458) covers cancer epidemiology research supported by the National Cancer Institute and a selected sample of the cancer epidemiology literature. It suggests that most cancer epidemiology in the last 10 years has been in pure discovery research. Current drivers of cancer epidemiology research, including new technologies, team science multilevel research, and knowledge integration, are not strongly represented in the review. However, the use of epidemiology in the latter stages of translation may not have been captured by the scope of this review. The closer epidemiologists get to advanced stages of translation, the more likely they are to work with investigators in other disciplines in other sectors of society. An argument can be made that regardless of whether this kind of research is not happening or was just missed by the current review, the field of cancer epidemiology can expand its scope and further evolve towards more effective applications in population health. © 2015 The Author.

Background: Global health programs, as supported by organizations such as the Global Fund to Fight AIDS, Tuberculosis and Malaria and the President's Emergency Plan for AIDS Relief (PEPFAR), stand to make significant contributions to international medical outcomes. Traditional systems of monitoring and evaluation, however, fail to capture downstream, indirect, or collateral advantages (and threats) of intervention selection, design, and implementation from broader donor perspectives, including those of the diplomatic and foreign policy communities, which these programs also generate. This paper describes the development a new métier under which assessment systems designed to consider the diplomatic value of global health initiatives are described and applied based on previously-identified "Top Ten" criteria. Methods: The "Kevany Riposte" and the "K-Score" were conceptualized based on a retrospective and collective assessment of the author's participation in the design, implementation and delivery of a range of global health interventions related to the HIV/AIDS epidemic. Responses and associated scores reframe intervention worth or value in terms of global health diplomacy criteria such as "adaptability", "interdependence", "training," and "neutrality". Response options ranged from "highly advantageous" to "significant potential threat". Results: Global health initiatives under review were found to generate significant advantages from the diplomatic perspective. These included (1) intervention visibility and associations with donor altruism and prestige, (2) development of international non-health collaborations and partnerships, (3) adaptability and responsiveness of service delivery to local needs, and (4) advancement of broader strategic goals of the international community. Corresponding threats included (1) an absence of formal training of project staff on broader political and international relations roles and responsibilities, (2) challenges to recipient cultural and religious practices, (3) intervention-related environmental concerns, and (4) a lack of prima facie consideration of intervention diplomatic and foreign policy consequences. Conclusions: Global health interventions stand to generate significant diplomatic advantages for donor and recipient countries and organizations when appropriately selected, designed, targeted, and delivered. Conversely, in the absence of the application of standards such as those developed under the Kevany Riposte, threats to diplomacy and international relations may occur. With the application of related systems to other global health programmes and settings, comparative results on the relative worth of alternate approaches from the diplomatic perspective may be generated to better inform political, strategic, and global health policy and programmatic decisions. © 2015 Kevany.

Irby D.M.,University of California at San Francisco
Academic Medicine | Year: 2016

Current controversies in medical education associated with professionalism, including disagreements about curriculum, pedagogy, and assessment, are rooted in part in the differing frameworks that are used to address professionalism. Three dominant frameworks, which have evolved in the medical education community, are described. The oldest framework is virtue based and focuses on the inner habits of the heart, the development of moral character and reasoning, plus humanistic qualities of caring and compassion: The good physician is a person of character. The second framework is behavior based, which emphasizes milestones, competencies, and measurement of observable behaviors: The good physician is a person who consistently demonstrates competence in performing patient care tasks. The third framework is identity formation, with a focus on identity development and socialization into a community of practice: The good physician integrates into his or her identity a set of values and dispositions consonant with the physician community and aspires to a professional identity reflected in the very best physicians. Although each professionalism framework is useful and valid, the field of medical education is currently engaged in several different discourses resulting in misunderstanding and differing recommendations for strategies to facilitate professionalism. In this article, the assumptions and contributions of each framework are described to provide greater insight into the nature of professionalism. By examining each discourse in detail, underlying commonalities and differences can be highlighted to assist educators in more effectively creating professionalism curricula, pedagogy, and assessment. © 2016 by the Association of American Medical Colleges

London N.,University of California at San Francisco | Raveh B.,University of California at San Francisco | Schueler-Furman O.,Hebrew University of Jerusalem
Current Opinion in Chemical Biology | Year: 2013

Protein Interactions (PPIs) mediate numerous biological functions. As such, the inhibition of specific PPIs has tremendous therapeutic value. The notion that these interactions are 'undruggable' has petered out with the emergence of more and more successful examples of PPI inhibitors, expanding considerably the scope of potential drug targets. The accumulated data on successes in the inhibition of PPIs allow us to analyze the features that are required for such inhibition. Whereas it has been suggested and shown that targeting hot spots at PPI interfaces is a good strategy to achieve inhibition, in this review we focus on the notion that the most amenable interactions for inhibition are those that are mediated by a 'hot segment', a continuous epitope that contributes the majority of the binding energy. This criterion is both useful in guiding future target selection efforts, and in suggesting immediate inhibitory candidates - the dominant peptidic segment that mediates the targeted interaction. © 2013 Elsevier Ltd.

Rivera L.B.,University of California at San Francisco | Bergers G.,University of California at San Francisco
Trends in Immunology | Year: 2015

Angiogenesis is a hallmark of cancer because its induction is indispensable to fuel an expanding tumor. The tumor microenvironment contributes to tumor vessel growth, and distinct myeloid cells recruited by the tumor have been shown not only to support angiogenesis but also to foster an immune suppressive environment that supports tumor expansion and progression. Recent findings suggest that the intertwined regulation of angiogenesis and immune modulation can offer therapeutic opportunities for the treatment of cancer. We review the mechanisms by which distinct myeloid cell populations contribute to tumor angiogenesis, discuss current approaches in the clinic that are targeting both angiogenic and immune suppressive pathways, and highlight important areas of future research. © 2015 Elsevier Ltd.

Lukacs G.L.,McGill University | Verkman A.S.,University of California at San Francisco
Trends in Molecular Medicine | Year: 2012

Cystic fibrosis (CF), the most common lethal genetic disease in the Caucasian population, is caused by loss-of-function mutations of the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated plasma membrane chloride channel. The most common mutation, deletion of phenylalanine 508 (ΔF508), impairs CFTR folding and, consequently, its biosynthetic and endocytic processing as well as chloride channel function. Pharmacological treatments may target the ΔF508 CFTR structural defect directly by binding to the mutant protein and/or indirectly by altering cellular protein homeostasis (proteostasis) to promote ΔF508 CFTR plasma membrane targeting and stability. This review discusses recent basic research aimed at elucidating the structural and trafficking defects of ΔF508 CFTR, a prerequisite for the rational design of CF therapy to correct the loss-of-function phenotype. © 2011.

Klatzmann D.,Paris-Sorbonne University | Klatzmann D.,French Institute of Health and Medical Research | Klatzmann D.,Biotherapy and Departement Hospitalo University Inflammation Immunopathology Biotherapy | Abbas A.K.,University of California at San Francisco
Nature Reviews Immunology | Year: 2015

Depletion of regulatory T (T Reg) cells in otherwise healthy individuals leads to multi-organ autoimmune disease and inflammation. This indicates that in a normal immune system, there are self-specific effector T cells that are ready to attack normal tissue if they are not restrained by T Reg cells. The data imply that there is a balance between effector T cells and T Reg cells in health and suggest a therapeutic potential of T Reg cells in diseases in which this balance is altered. Proof-of-concept clinical trials, now supported by robust mechanistic studies, have shown that low-dose interleukin-2 specifically expands and activates T Reg cell populations and thus can control autoimmune diseases and inflammation.

Betjemann J.P.,University of California at San Francisco | Lowenstein D.H.,University of California at San Francisco
The Lancet Neurology | Year: 2015

Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes. © 2015 Elsevier Ltd.

Dever J.B.,VA San Diego Healthcare System | Sheikh M.Y.,University of California at San Francisco
Alimentary Pharmacology and Therapeutics | Year: 2015

Background Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with cirrhosis and ascites. Aim To review the known and changing bacteriology, risk factors, ascitic fluid interpretation, steps in performing paracentesis, treatment, prophylaxis and evolving perspectives related to SBP. Methods Information was obtained from reviewing medical literature accessible on PubMed Central. The search term 'spontaneous bacterial peritonitis' was cross-referenced with 'bacteria', 'risk factors', 'ascites', 'paracentesis', 'ascitic fluid analysis', 'diagnosis', 'treatment', 'antibiotics', 'prophylaxis', 'liver transplantation' and 'nutrition'. Results Gram-positive cocci (GPC) such as Staphylococcus, Enterococcus as well as multi-resistant bacteria have become common pathogens and have changed the conventional approach to treatment of SBP. Health care-associated and nosocomial SBP infections should prompt greater vigilance and consideration for alternative antibiotic coverage. Acid suppressive and beta-adrenergic antagonist therapies are strongly associated with SBP in at-risk individuals. Conclusions Third-generation, broad-spectrum cephalosporins remain a good initial choice for SBP treatment. Levofloxacin is an acceptable alternative for patients not receiving long-term flouroquinolone prophylaxis or for those with a penicillin allergy. For uncomplicated SBP, early oral switch therapy is reasonable. Alternative antibiotics such as pipercillin-tazobactam should be considered for patients with nosocomial SBP or for patients who fail to improve on traditional antibiotic regimens. Selective albumin supplementation remains an important adjunct in SBP treatment. Withholding acid suppressive medication deserves strong consideration, and discontinuing beta-adrenergic antagonist therapy in patients with end-stage liver disease and resistant ascites is standard care. Liver transplant evaluation should be undertaken for patients who develop SBP barring contraindications. © 2015 John Wiley & Sons Ltd.

Raghu G.,University of Washington | Anstrom K.J.,Duke Clinical Research Institute | King Jr. T.E.,University of California at San Francisco | Lasky J.A.,Tulane University | Martinez F.J.,University of Michigan
New England Journal of Medicine | Year: 2012

BACKGROUND: A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown. METHODS: In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups - receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo - in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period. RESULTS: When approximately 50% of data had been collected (with 77 patients in the combination- therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P = 0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here. CONCLUSIONS: Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; number, NCT00650091.) Copyright © 2012 Massachusetts Medical Society.

Reiter J.F.,University of California at San Francisco | Blacque O.E.,University College Dublin | Leroux M.R.,Simon Fraser University
EMBO Reports | Year: 2012

Both the basal body and the microtubule-based axoneme it nucleates have evolutionarily conserved subdomains crucial for cilium biogenesis, function and maintenance. Here, we focus on two conspicuous but underappreciated regions of these structures that make membrane connections. One is the basal body distal end, which includes transition fibres of largely undefined composition that link to the base of the ciliary membrane. Transition fibres seem to serve as docking sites for intraflagellar transport particles, which move proteins within the ciliary compartment and are required for cilium biogenesis and sustained function. The other is the proximal-most region of the axoneme, termed the transition zone, which is characterized by Y-shaped linkers that span from the axoneme to the ciliary necklace on the membrane surface. The transition zone comprises a growing number of ciliopathy proteins that function as modular components of a ciliary gate. This gate, which forms early during ciliogenesis, might function in part by regulating intraflagellar transport. Together with a recently described septin ring diffusion barrier at the ciliary base, the transition fibres and transition zone deserve attention for their varied roles in forming functional ciliary compartments. © 2012 European Molecular Biology Organization.

Verdin E.,University of California at San Francisco
Science | Year: 2015

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in all living cells. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and poly(adenosine diphosphate-ribose) polymerases. Cellular NAD+ concentrations change during aging, and modulation of NAD+ usage or production can prolong both health span and life span. Here we review factors that regulate NAD+ and discuss how supplementation with NAD+ precursors may represent a new therapeutic opportunity for aging and its associated disorders, particularly neurodegenerative diseases.

Zhang L.,University of California at San Francisco
Proceedings of the National Academy of Sciences of the United States of America | Year: 2012

Temporally restricted feeding (RF) can phase reset the circadian clocks in numerous tissues in mammals, contributing to altered timing of behavioral and physiological rhythms. However, little is known regarding the underlying molecular mechanism. Here we demonstrate a role for the gamma isotype of protein kinase C (PKCγ) in food-mediated entrainment of behavior and the molecular clock. We found that daytime RF reduced late-night activity in wild-type mice but not mice homozygous for a null mutation of PKCγ (PKCγ(-/-)). Molecular analysis revealed that PKCγ exhibited RF-induced changes in activation patterns in the cerebral cortex and that RF failed to substantially phase shift the oscillation of clock gene transcripts in the absence of PKCγ. PKCγ exerts effects on the clock, at least in part, by stabilizing the core clock component brain and muscle aryl hydrocarbon receptor nuclear translocator like 1 (BMAL1) and reducing its ubiquitylation in a deubiquitination-dependent manner. Taken together, these results suggest that PKCγ plays a role in food entrainment by regulating BMAL1 stability.

Song I.Y.,University of California at San Francisco | Balmain A.,University of California at San Francisco
Seminars in Cancer Biology | Year: 2015

Early primitive stem cells have long been viewed as the cancer cells of origin (tumor initiating target cells) due to their intrinsic features of self-renewal and longevity. However, emerging evidence suggests a surprising capacity for normal committed cells to function as reserve stem cells upon reprogramming as a consequence of tissue damage resulting in inflammation and wound healing. This results in an alternative concept positing that tumors may originate from differentiated cells that can re-acquire stem cell properties due to genetic or epigenetic reprogramming. It is likely that both models are correct, and that a continuum of potential cells of origin exists, ranging from early primitive stem cells to committed progenitor or even terminally differentiated cells. A combination of the nature of the target cell and the specific types of gene mutations introduced determine tumor cell lineage, as well as potential for malignant conversion. Evidence from mouse skin models of carcinogenesis suggests that initiated cells at different stages within a stem cell hierarchy have varying degrees of requirement for reprogramming (e.g. inflammation stimuli), depending on their degree of differentiation. This article will present evidence in favor of these concepts that has been developed from studies of several mouse models of skin carcinogenesis. © 2014 Elsevier Ltd.

Hagerling C.,University of California at San Francisco | Casbon A.-J.,University of California at San Francisco | Werb Z.,University of California at San Francisco
Trends in Cell Biology | Year: 2015

Cells of the innate immune system have a dual role in cancer development in both tumor initiation and progression. Innate immune cells can, on the one hand, aid malignant transformation and tumor outgrowth and, on the other hand, prevent tumor progression. The innate immune system has the ability to tune the inflammatory response and is a key player in cancer-related inflammation, which can precede the development of malignancy or be induced by oncogenic changes promoting a protumor inflammatory milieu. In this review, we discuss the emerging cellular and molecular mechanisms of the innate immune system and inflammation in tumor initiation and progression, and point to the outstanding questions that remain. © 2014 Elsevier Ltd.

Yeh I.,University of California at San Francisco
Journal of the National Cancer Institute | Year: 2013

BRAF(V600E) mutations are frequent in melanomas originating from intermittently sun-exposed skin and also in common acquired melanocytic nevi, suggesting that BRAF mutation is an early event in melanocytic neoplasia. All neoplastic melanocytes within such a nevus would be expected to carry the BRAF mutation, and thus we evaluated the frequency of cells with BRAF(V600E) mutations within acquired nevi by droplet digital polymerase chain reaction. In BRAF-mutant nevi the number of BRAF mutant alleles equaled the number of wild-type (WT) alleles in the neoplastic cell population, consistent with a fully clonal heterozygous BRAF mutation. The allelic ratio of BRAF(V600E) to BRAF(WT) in the eight VE1-positive nevi, adjusted for degree of stromal contamination, ranged from 0.84 to 1.12 with an average ratio of 1.01. This was confirmed by immunohistochemistry with an antibody specific for BRAF(V600E), which uniformly labeled the neoplastic cells without any evidence of heterogeneity. We found BRAF(V600E) mutations in the melanocytic nevi to be fully clonal, strongly suggesting that BRAF-activating mutations typically are early initiating events in melanocytic neoplasia.

Van Den Bedem H.,Stanford University | Van Den Bedem H.,SLAC | Fraser J.S.,University of California at San Francisco
Nature Methods | Year: 2015

Biomolecules adopt a dynamic ensemble of conformations, each with the potential to interact with binding partners or perform the chemical reactions required for a multitude of cellular functions. Recent advances in X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and other techniques are helping us realize the dream of seeing - in atomic detail - how different parts of biomolecules shift between functional substates using concerted motions. Integrative structural biology has advanced our understanding of the formation of large macromolecular complexes and how their components interact in assemblies by leveraging data from many low-resolution methods. Here, we review the growing opportunities for integrative, dynamic structural biology at the atomic scale, contending there is increasing synergistic potential between X-ray crystallography, NMR and computer simulations to reveal a structural basis for protein conformational dynamics at high resolution.

Elias P.M.,University of California at San Francisco
Seminars in cutaneous medicine and surgery | Year: 2013

The healthy stratum corneum allows optimum permeability of water and provides the first line of defense against pathogenic and environmental assaults. The barrier functions of the stratum corneum are interrelated, coregulated, and interdependent. Research has demonstrated that three lipid species, which usually comprise 10% of the stratum corneum, are crucial to both its structure and its function; these must be present in sufficient quantities and in the correct proportions to provide optimum barrier function. The clinical implications of how the skin barrier works--and is supported and restored--can be seen in the current and emerging understanding of atopic dermatitis management.

Chaumeil M.M.,University of California at San Francisco
Nature communications | Year: 2013

Gain-of-function mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade gliomas and secondary glioblastoma. They lead to intracellular accumulation of the oncometabolite 2-hydroxyglutarate, represent an early pathogenic event and are considered a therapeutic target. Here we show, in this proof-of-concept study, that [1-(13)C] α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity, and can inform on IDH1 status. Using (13)C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of hyperpolarized [1-(13)C] α-ketoglutarate is studied in isogenic glioblastoma cells that differ only in their IDH1 status. In lysates and tumours that express wild-type IDH1, only hyperpolarized [1-(13)C] α-ketoglutarate can be detected. In contrast, in cells that express mutant IDH1, hyperpolarized [1-(13)C] 2-hydroxyglutarate is also observed, both in cell lysates and in vivo in orthotopic tumours.

Loh M.L.,University of California at San Francisco
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2010

Expansion of myeloid blasts with suppression of normal hematopoiesis is a hallmark of acute myeloid leukemia (AML). In contrast, myeloproliferative neoplasms (MPNs) are clonal disorders characterized by overproliferation of one or more lineages that retain the ability to differentiate. Juvenile myelomonocytic leukemia (JMML) is an aggressive MPN of childhood that is clinically characterized by the overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. Major progress in understanding the pathogenesis of JMML has been achieved by mapping out the genetic lesions that occur in patients. The spectrum of mutations described thus far in JMML occur in genes that encode proteins that signal through the Ras/mitogen-activated protein kinase (MAPK) pathways, thus providing potential new opportunities for both diagnosis and therapy. These genes include NF1, NRAS, KRAS, PTPN11, and, most recently, CBL. While the current standard of care for patients with JMML relies on allogeneic hematopoietic stem-cell transplant, relapse is the most frequent cause of treatment failure. Rarely, spontaneous resolution of this disorder can occur but is unpredictable. This review is focused on the genetic abnormalities that occur in JMML, with particular attention to germ-line predisposition syndromes associated with the disorder. Current approaches to therapy are also discussed.

Seeley W.W.,University of California at San Francisco
Brain structure & function | Year: 2010

The human anterior insula is anatomically and functionally heterogeneous, containing key nodes within distributed speech-language and viscero-autonomic/social-emotional networks. The frontotemporal dementias selectively target these large-scale systems, leading to at least three distinct clinical syndromes. Examining these disorders, researchers have begun to dissect functions which rely on specific insular nodes and networks. In the behavioral variant of frontotemporal dementia, early-stage frontoinsular degeneration begets progressive "Salience Network" breakdown that leaves patients unable to model the emotional impact of their own actions or inactions. Ongoing studies seek to clarify local microcircuit- and cellular-level factors that confer selective frontoinsular vulnerability. The search for frontotemporal dementia treatments will depend on a rich understanding of insular biology and could help clarify specialized human language, social, and emotional functions.

McDonagh A.F.,University of California at San Francisco
Seminars in Fetal and Neonatal Medicine | Year: 2010

Despite a century of research, several clinically relevant areas of bilirubin biochemistry remain controversial, poorly understood, or unrecognized. These include: (i) The structure and molecularity of bilirubin under physiological environments such as membranes, brain tissue and when bound to proteins. Related to this is the large number of structurally different bilirubin species that may occur in blood under pathological conditions and their potential effects on measurements of bilirubin and free bilirubin. (ii) The mechanism of phototherapy, the neurotoxicity of the photoisomers produced and their influence on measurements of bilirubin and free bilirubin. (iii) The role of membrane transporters in the passage of unconjugated bilirubin across the placenta, intestine, vascular epithelium, blood-brain barrier, and into the liver. (iv) Biochemical mechanisms of bilirubin toxicity, pharmacologic prevention of kernicterus, the contribution of bilirubin to antioxidant defenses, and the practical value of free bilirubin measurements for identifying infants at most risk of kernicterus. © 2009 Elsevier Ltd. All rights reserved.

Ott M.,University of California at San Francisco | Geyer M.,Max Planck Institute of Molecular Physiology | Zhou Q.,University of California at Berkeley
Cell Host and Microbe | Year: 2011

Thirteen years ago, human cyclin T1 was identified as part of the positive transcription elongation factor b (P-TEFb) and the long-sought host cofactor for the HIV-1 transactivator Tat. Recent years have brought new insights into the intricate regulation of P-TEFb function and its relationship with Tat, revealing novel mechanisms for controlling HIV transcription and fueling new efforts to overcome the barrier of transcriptional latency in eradicating HIV. Moreover, the improved understanding of HIV and Tat forms a basis for studying transcription elongation control in general. Here, we review advances in HIV transcription research with a focus on the growing family of cellular P-TEFb complexes, structural insights into the interactions between Tat, P-TEFb, and TAR RNA, and the multifaceted regulation of these interactions by posttranscriptional modifications of Tat. © 2011 Elsevier Inc.

Fischbach M.A.,University of California at San Francisco | Sonnenburg J.L.,Stanford University
Cell Host and Microbe | Year: 2011

In bacterial communities, "tight economic times" are the norm. Of the many challenges bacteria face in making a living, perhaps none are more important than generating energy, maintaining redox balance, and acquiring carbon and nitrogen to synthesize primary metabolites. The ability of bacteria to meet these challenges depends heavily on the rest of their community. Indeed, the most fundamental way in which bacteria communicate is by importing the substrates for metabolism and exporting metabolic end products. As an illustration of this principle, we will travel down a carbohydrate catabolic pathway common to many species of Bacteroides, highlighting the interspecies interactions established (often inevitably) at its key steps. We also discuss the metabolic considerations in maintaining the stability of host-associated microbial communities. © 2011 Elsevier Inc.

CYP3A4, an integral endoplasmic reticulum (ER)-anchored protein, is the major human liver cytochrome P450 enzyme responsible for the disposition of over 50% of clinically relevant drugs. Alterations of its protein turnover can influence drug metabolism, drug-drug interactions, and the bioavailability of chemotherapeutic drugs. Such CYP3A4 turnover occurs via a classical ER-associated degradation (ERAD) process involving ubiquitination by both UBC7/gp78 and UbcH5a/CHIP E2-E3 complexes for 26 S proteasomal targeting. These E3 ligases act sequentially and cooperatively in CYP3A4 ERAD because RNA interference knockdown of each in cultured hepatocytes results in the stabilization of a functionally active enzyme. We have documented that UBC7/gp78-mediated CYP3A4 ubiquitination requires protein phosphorylation by protein kinase (PK) A and PKC and identified three residues (Ser-478, Thr-264, and Ser-420) whose phosphorylation is required for intracellular CYP3A4 ERAD. We document herein that of these, Ser-478 plays a pivotal role in UBC7/gp78-mediated CYP3A4 ubiquitination, which is accelerated and enhanced on its mutation to the phosphomimetic Asp residue but attenuated on its Ala mutation. Intriguingly, CYP3A5, a polymorphically expressed human liver CYP3A4 isoform (containing Asp-478) is ubiquitinated but not degraded to a greater extent than CYP3A4 in HepG2 cells. This suggests that although Ser-478 phosphorylation is essential for UBC7/gp78-mediated CYP3A4 ubiquitination, it is not sufficient for its ERAD. Additionally, we now report that CYP3A4 protein phosphorylation by PKA and/or PKC at sites other than Ser-478, Thr-264, and Ser-420 also enhances UbcH5a/CHIP-mediated ubiquitination. Through proteomic analyses, we identify (i) 12 additional phosphorylation sites that may be involved in CHIP-CYP3A4 interactions and (ii) 8 previously unidentified CYP3A4 ubiquitination sites within spatially associated clusters of Asp/Glu and phosphorylatable Ser/Thr residues that may serve to engage each E2-E3 complex. Collectively, our findings underscore the interplay between protein phosphorylation and ubiquitination in ERAD and, to our knowledge, provide the very first example of gp78 substrate recognition via protein phosphorylation.

Julius D.,University of California at San Francisco
Cold Spring Harbor perspectives in biology | Year: 2012

Sensory systems detect small molecules, mechanical perturbations, or radiation via the activation of receptor proteins and downstream signaling cascades in specialized sensory cells. In vertebrates, the two principal categories of sensory receptors are ion channels, which mediate mechanosensation, thermosensation, and acid and salt taste; and G-protein-coupled receptors (GPCRs), which mediate vision, olfaction, and sweet, bitter, and umami tastes. GPCR-based signaling in rods and cones illustrates the fundamental principles of rapid activation and inactivation, signal amplification, and gain control. Channel-based sensory systems illustrate the integration of diverse modulatory signals at the receptor, as seen in the thermosensory/pain system, and the rapid response kinetics that are possible with direct mechanical gating of a channel. Comparisons of sensory receptor gene sequences reveal numerous examples in which gene duplication and sequence divergence have created novel sensory specificities. This is the evolutionary basis for the observed diversity in temperature- and ligand-dependent gating among thermosensory channels, spectral tuning among visual pigments, and odorant binding among olfactory receptors. The coding of complex external stimuli by a limited number of sensory receptor types has led to the evolution of modality-specific and species-specific patterns of retention or loss of sensory information, a filtering operation that selectively emphasizes features in the stimulus that enhance survival in a particular ecological niche. The many specialized anatomic structures, such as the eye and ear, that house primary sensory neurons further enhance the detection of relevant stimuli.

Chen J.,University of California at San Francisco
Nature cell biology | Year: 2013

Germ cells divide and differentiate in a unique local microenvironment under the control of somatic cells. Signals released in this niche instruct oocyte reentry into the meiotic cell cycle. Once initiated, the progression through meiosis and the associated programme of maternal messenger RNA translation are thought to be cell autonomous. Here we show that translation of a subset of maternal mRNAs critical for embryo development is under the control of somatic cell inputs. Translation of specific maternal transcripts increases in oocytes cultured in association with somatic cells and is sensitive to EGF-like growth factors that act only on the somatic compartment. In mice deficient in amphiregulin, decreased fecundity and oocyte developmental competence is associated with defective translation of a subset of maternal mRNAs. These somatic cell signals that affect translation require activation of the PI(3)K-AKT-mTOR pathway. Thus, mRNA translation depends on somatic cell cues that are essential to reprogramme the oocyte for embryo development.

Toettcher J.E.,University of California at San Francisco | Weiner O.D.,University of California at San Francisco | Lim W.A.,University of California at San Francisco | Lim W.A.,Howard Hughes Medical Institute
Cell | Year: 2013

The complex, interconnected architecture of cell-signaling networks makes it challenging to disentangle how cells process extracellular information to make decisions. We have developed an optogenetic approach to selectively activate isolated intracellular signaling nodes with light and use this method to follow the flow of information from the signaling protein Ras. By measuring dose and frequency responses in single cells, we characterize the precision, timing, and efficiency with which signals are transmitted from Ras to Erk. Moreover, we elucidate how a single pathway can specify distinct physiological outcomes: by combining distinct temporal patterns of stimulation with proteomic profiling, we identify signaling programs that differentially respond to Ras dynamics, including a paracrine circuit that activates STAT3 only after persistent (>1 hr) Ras activation. Optogenetic stimulation provides a powerful tool for analyzing the intrinsic transmission properties of pathway modules and identifying how they dynamically encode distinct outcomes. © 2013 Elsevier Inc.

Nair G.,University of California at San Francisco | Hebrok M.,University of California at San Francisco
Current Opinion in Genetics and Development | Year: 2015

The Islets of Langerhans are crucial 'micro-organs' embedded in the glandular exocrine pancreas that regulate nutrient metabolism. They not only synthesize, but also secrete endocrine hormones in a modulated fashion in response to physiologic metabolic demand. These highly sophisticated structures with intricate organization of multiple cell types, namely endocrine, vascular, neuronal and mesenchymal cells, have evolved to perform this task to perfection over time. Not surprisingly, islet architecture and function are dissimilar between humans and typically studied model organisms, such as rodents and zebrafish. Further, recent findings also suggest noteworthy differences in human islet development from that in mouse, including delayed appearance and gradual resolution of key differentiation markers, a single-phase of endocrine differentiation, and prenatal association of developing islets with neurovascular milieu. In light of these findings, it is imperative that a systematic study is undertaken to compare islet development between human and mouse. Illuminating inter-species differences in islet development will likely be critical in furthering our pursuit to generate an unlimited supply of truly functional and fully mature β-cells from human pluripotent stem cell (hPSC) sources for therapeutic purposes. © 2015 Elsevier Ltd.

Horn B.,University of California at San Francisco | Cowan M.J.,University of California at San Francisco
Journal of Allergy and Clinical Immunology | Year: 2013

In this review we discuss recent outcomes of hematopoietic cell transplantation (HCT) for patients with severe combined immunodeficiency (SCID), including survival, T- and B-cell reconstitution, and late effects, particularly those related to genotype, use of conditioning regimen, and use of alternative donors. We identify the following issues that require additional data, which can be obtained through cooperative studies: outcomes of patients with SCID who did not receive conditioning before alternative donor HCT; outcomes of patients with SCID who did not receive graft-versus-host disease prophylaxis after T cell-replete HCT; late effects of HCT for patients with SCID, including neurocognitive outcomes, growth, and development; and their relationship to genotype and use of alkylating agents for conditioning. Careful follow-up of outcomes of all newborns receiving diagnoses based on newborn screening programs for SCID is essential because data are scarce on the effects of conditioning regimens in very young patients. A consensus on the definition of T- and B-cell recovery, criteria for additional "boosts," pharmacokinetic data of chemotherapy agents used in young children, and uniformity of the use of various chemotherapy agents are needed to compare results among institutions. Finally, development of new nontoxic conditioning regimens for HCT that can be safely used in very young children is required. © 2012 American Academy of Allergy, Asthma & Immunology.

Schickedanz A.,University of California at San Francisco
The oncologist | Year: 2010

The U.S. spends far more per person than any other country in the world in treating cancer, without demonstrably superior results. Though the pursuit and pace of innovation in oncology are perhaps unmatched and promise great benefit for cancer patients, this explosion of innovation has been accompanied by dramatic increases in cost, often without significant increases in patient survival. These trends have led to a growing interest in addressing value--understood as treatment benefits or quality weighed against economic cost--in cancer care. In February 2009, the Institute of Medicine convened a group of experts with diverse perspectives, including those of clinical oncology, patient advocacy, the insurance industry, pharmaceutical manufacturing, health economics, and bioethics, to identify challenges to value in cancer care, suggest potential solutions, and discuss what value entails in oncology. This article presents many of the ideas that emerged from this symposium, including ways to correct misaligned economic incentives, improve clinical communication, and generate evidence to promote value in cancer care.

Mehling W.,University of California at San Francisco
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Based on prior research, multiple discriminable dimensions of interoception have been defined: awareness, accuracy and sensibility. Some investigators defined interoceptive awareness as metacognitive awareness of interoceptive accuracy, assessed as correspondence between subjective confidence in and objective accuracy of one’s heartbeat detection. However, metacognitive awareness has been understood quite differently: ‘a cognitive set in which negative thoughts/feelings are experienced as mental events, rather than as the self’ or as ‘error awareness’. Interoceptive sensibility, defined as self-reported interoception, distinguishes self-reported interoception from objective interoceptive accuracy, but does not differentiate between anxietydriven and mindful attention styles towards interoceptive cues, a distinction of key clinical importance: one attention style is associated with somatization and anxiety disorders; the other has been viewed as healthy, adaptive, resilience-enhancing. The self-report Multidimensional Assessment of Interoceptive Awareness was developed to differentiate these attention styles. It has been translated into 16 languages and applied in cross-sectional and longitudinal studies. Findings from these applications suggest that differentiating interoceptive sensibility according to attention style and regulatory aspects (i) provides insights into the psychology of interoceptive awareness, (ii) differentiates between clinically maladaptive and beneficial interoceptive attention, and (iii) helps elucidate therapeutic approaches that claim to provide health benefits by training mindful styles of bodily awareness. This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’. © 2016 The Author(s) Published by the Royal Society. All rights reserved.

Geschwind D.H.,Semel Institute | State M.W.,University of California at San Francisco
The Lancet Neurology | Year: 2015

Autism spectrum disorder is typical of the majority of neuropsychiatric syndromes in that it is defined by signs and symptoms, rather than by aetiology. Not surprisingly, the causes of this complex human condition are manifold and include a substantial genetic component. Recent developments in gene-hunting technologies and methods, and the resulting plethora of genetic findings, promise to open new avenues to understanding of disease pathophysiology and to contribute to improved clinical management. Despite remarkable genetic heterogeneity, evidence is emerging for converging pathophysiology in autism spectrum disorder, but how this notion of convergent pathways will translate into therapeutics remains to be established. Leveraging genetic findings through advances in model systems and integrative genomic approaches could lead to the development of new classes of therapies and a personalised approach to treatment. © 2015 Elsevier Ltd.

Gray J.A.,University of California at San Francisco | Nicoll R.A.,University of California at San Francisco
Cell | Year: 2012

In this issue, Papouin et al. show that glycine is the endogenous coagonist for extrasynaptic NMDA receptors (NMDARs), unlike at synapses where the coagonist is d-serine. By enzymatically degrading endogenous glycine, they begin to address the enigmatic physiological and pathological roles for extrasynaptic NMDARs. © 2012 Elsevier Inc.

Harrison-Uy S.J.,University of California at San Francisco | Pleasure S.J.,University of California at San Francisco
Cold Spring Harbor Perspectives in Biology | Year: 2012

Components of the Wnt signaling pathway are expressed in a tightly regulated and spatially specific manner during development of the forebrain, and Wnts are key regulators of regional forebrain identity. Wnt signaling from the cortical hem regulates the expansion and cell-type specification of the adjacent neuroepithelium and, in conjunction with Bmp, Fgf, and Shh signaling, controls dorsal-ventral forebrain patterning. Subsequently, Wnt signaling dynamically regulates the behavior of cortical progenitor cells, initially promoting the expansion of radial glia progenitor cells and later inducing neurogenesis by promoting terminal differentiation of intermediate progenitor cells. A role for Wnt signaling in cell-type specification has also been proposed. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.

Pierce A.A.,University of California at San Francisco | Xu A.W.,University of California at San Francisco
Journal of Neuroscience | Year: 2010

The ability to develop counter-regulatory mechanisms to maintain energy balance in response to environmental and physiologic insults is essential for survival, but the mechanisms underlying these compensatory regulations are poorly understood. Agouti-related peptide (AGRP) and Neuropeptide Y are potent orexigens and are coexpressed in neurons in the arcuate nucleus of the hypothalamus. Acute ablation of these neurons leads to severe anorexia and weight loss, whereas progressive degeneration of these neurons has minimal impact on food intake and body weight, suggesting that compensatory mechanisms are developed to maintain orexigenic drive. In this study, we show that cell proliferation is increased in the hypothalamus of adult mutant animals in which AgRP neurons undergo progressive neurodegeneration due to deletion of mitochondrial transcription factor A, and that a subset of these newly generated cells differentiate into AgRP neurons along with other resident neuronal subtypes. Furthermore, some of the newly generated cells are capable of responding to leptin, and a central blockade of cell proliferation in adult animals results in decreases in food intake and body adiposity in mutant but not in control animals. Our study indicates that neurons important for energy homeostasis can be regenerated in adult feeding centers under neurodegenerative conditions. It further suggests that de novo neurogenesis might serve as a compensatory mechanism contributing to the plastic control of energy balance in response to environmental and physiologic insults. Copyright © 2010 the authors.

Sangha S.,University of California at San Francisco | Chadick J.Z.,University of California at San Francisco | Janak P.H.,University of California at San Francisco
Journal of Neuroscience | Year: 2013

Learning to fear and avoid life-threatening stimuli are critical survival skills but are maladaptive when they persist in the absence of a direct threat. Thus, it is important to detect when a situation is safe and to increase behaviors leading to naturally rewarding actions, such as feeding and mating. It is unclear how the brain distinguishes between dangerous and safe situations. Here, we present a novel protocol designed to investigate the processing of cues that predict danger, safety, or reward (sucrose). In vivo single unit recordings were obtained in the basal amygdala of freely behaving rats undergoing simultaneous reward, fear, and safety conditioning. We observed a population of neurons that did not respond to a Fear Cue but did change their firing rate during the combined presentation of a fear cue simultaneous with a second, safety, cue; this combination of Fear + Safety Cues signified "no shock." This neural population consisted of two subpopulations: neurons that responded to the Fear+Safety Cue but not the Fear or Reward Cue ("safety" neurons), and neurons that responded to the Fear+Safety and Reward Cue but not the Fear Cue ("safety+reward" neurons). These data demonstrate the presence of neurons in the basal amygdala that are selectively responsive to Safety Cues. Furthermore, these data suggest that safety and reward learning use overlapping mechanisms in the basal amygdala. Copyright © 2013 the authors.

Glenn O.A.,University of California at San Francisco
Pediatric Radiology | Year: 2010

Fetal MRI is clinically performed to evaluate the brain in cases where an abnormality is detected by prenatal sonography. These most commonly include ventriculomegaly, abnormalities of the corpus callosum, and abnormalities of the posterior fossa. Fetal MRI is also increasingly performed to evaluate fetuses who have normal brain findings on prenatal sonogram but who are at increased risk for neurodevelopmental abnormalities, such as complicated monochorionic twin pregnancies. This paper will briefly discuss the common clinical conditions imaged by fetal MRI as well as recent advances in fetal MRI research.

Hwang E.S.,University of California at San Francisco
Journal of the National Cancer Institute - Monographs | Year: 2010

Mastectomy has been the historical mainstay of treatment for ductal carcinoma in situ (DCIS), but over time, there have been significant changes in its use for preinvasive breast cancer. Although there was an early reduction in mastectomy rates for DCIS with the introduction of breast-conserving surgery, in some groups, the rates of both mastectomy and contralateral mastectomy for DCIS have increased in recent years. Due to advances in breast cancer screening as well as improvements in breast reconstruction, mastectomy will continue to be an important and acceptable treatment option. Recurrence is rare following mastectomy for DCIS. Nevertheless, there remains a need to follow patients for in-breast, nodal, or contralateral breast events, which can occur long after the index DCIS has been treated. Since up to 70% of women with newly diagnosed DCIS have disease that can be managed with breast-conserving surgery, patient counseling is imperative to ensure the best use of this option for DCIS, given that mastectomy does not significantly impact survival in this setting. © The Author 2010. Published by Oxford University Press. All rights reserved.

Kim C.C.,University of California at San Francisco
Current opinion in immunology | Year: 2013

The Immunological Genome Consortium has generated a public resource ( that provides a compendium of gene expression profiles of ∼270 leukocyte subsets in the mouse. This effort established carefully standardized operating procedures that resulted in a transcriptional dataset of unprecedented comprehensiveness and quality. The findings have been detailed recently in a series of publications providing molecular insights into the development, heterogeneity, and/or function of these cellular lineages and distinct subpopulations. Here, we review the key findings of these studies, highlighting what has been gained and how the knowledge can be used to accelerate progress toward a comprehensive understanding of the immune system. Copyright © 2013 Elsevier Ltd. All rights reserved.

Husebye E.S.,University of Bergen | Anderson M.S.,University of California at San Francisco
Immunity | Year: 2010

Autoimmune diseases such as type 1 diabetes are complex in their pathogenesis. One approach to improving our understanding of type 1 diabetes is the study of diseases that represent more extreme examples of autoimmunity. Autoimmune polyendocrine syndromes (APS) are relatively rare diseases that often include type 1 diabetes as part of the disease phenotype. Recently, there has been tremendous progress in unraveling some of the underlying mechanisms of APS. Here, we highlight the APS disorders with the perspective of the clues they can offer to the pathogenesis and treatment of type 1 diabetes. © 2010 Elsevier Inc.

Baron R.B.,University of California at San Francisco
Academic Medicine | Year: 2013

Calls for greater public accountability for graduate medical education (GME) outcomes continue to come from a broad array of stakeholders. Creation of ways to measure accountability requires a clear understanding of the domains of GME outcomes and the creation of specific measures that are reliable and accurate and do not create an undue measurement burden. Three domains of outcomes are necessary: individual trainee competence, the quality and diversity of the training environment, and workforce factors that address workforce size, specialty mix, diversity, and geographic distribution. The Accreditation Council for Graduate Medical Education has begun to develop measures that have the potential to form the basis of the first two domains, and other data sources exist to measure the quality of the training environment. Little progress, however, has been made to accurately describe institution-specific workforce outcomes. The article by Chen and colleagues in this issue makes a major contribution in the measurement of institution-specific outcomes. Their article creates optimism that a system that incentivizes and rewards specific desirable GME outcomes can be designed. This commentary further defines some practical next steps to achieve this desired GME accountability.

Helbig I.,University of Kiel | Lowenstein D.H.,University of California at San Francisco
Current Opinion in Neurology | Year: 2013

Purpose of Review: We aim to review the most recent advances in the field of epilepsy genetics with particular focus on the progress in gene discovery in monogenic epilepsies, identification of risk genes in complex genetic epilepsies and recent findings in the field of epilepsy pharmacogenomics. Purpose of Review: During the last 12 months, the use of massive parallel sequencing technologies has allowed for the discovery of several genes for monogenic epilepsies. Most importantly, PRRT2 was identified as the long-sought gene for benign familial infantile seizures. Mutations in KCNT1 were found in two seemingly unrelated monogenic epilepsies including malignant migrating partial seizures of infancy and severe autosomal dominant nocturnal frontal lobe epilepsy. A genome-wide association study in idiopathic generalized epilepsy revealed the first common risk variants for human seizure disorders including variants in VRK2, PNPO and SCN1A. Furthermore, a landmark study provided evidence that screening for the HLA-B1502 variant may prevent carbamazepine CBZ-induced side effects in the Taiwanese population. Also, HLA-A3101 variants were identified as a risk factor for carbamazepine side effects in Europeans. Summary: Novel technologies and an unprecedented level of international collaboration have resulted in identification of novel genes for monogenic and complex genetic epilepsies as well as risk factors for side effects of antiepileptic drugs. This review provides an overview of the most relevant studies in the last year and highlights the future direction of the field. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Bellodi C.,University of California at San Francisco | Kopmar N.,University of California at San Francisco | Ruggero D.,University of California at San Francisco
EMBO Journal | Year: 2010

Defects in ribosome biogenesis and function are present in a growing list of human syndromes associated with cancer susceptibility. One example is X-linked dyskeratosis congenita (X-DC) in which the DKC1 gene, encoding for an enzyme that modifies ribosomal RNA, is found to be mutated. How ribosome dysfunction leads to cancer remains poorly understood. A critical cellular response that counteracts cellular transformation is oncogene-induced senescence (OIS). Here, we show that during OIS, a switch between cap-and internal ribosome entry site (IRES)-dependent translation occurs. During this switch, an IRES element positioned in the 5′untranslated region of p53 is engaged and facilitates p53 translation. We further show that in DKC1 m cells, p53 IRES-dependent translation is impaired during OIS ex vivo and on DNA damage in vivo. This defect in p53 translation perturbs the cellular response that counteracts oncogenic insult. We extend these findings to X-DC human patient cells in which similar impairments in p53 IRES-dependent translation are observed. Importantly, re-introduction of wild-type DKC1 restores p53 expression in these cells. These results provide insight into the basis for cancer susceptibility in human syndromes associated with ribosome dysfunction. © 2010 European Molecular Biology Organization.

Ley B.,University of California at San Francisco | Collard H.R.,University of California at San Francisco
Clinical Epidemiology | Year: 2013

Idiopathic pulmonary fibrosis is a chronic fibrotic lung disease of unknown cause that occurs in adults and has a poor prognosis. Its epidemiology has been difficult to study because of its rarity and evolution in diagnostic and coding practices. Though uncommon, it is likely underappreciated both in terms of its occurrence (ie, incidence, prevalence) and public health impact (ie, health care costs and resource utilization). Incidence and mortality appear to be on the rise, and prevalence is expected to increase with the aging population. Potential risk factors include occupational and environmental exposures, tobacco smoking, gastroesophageal reflux, and genetic factors. An accurate understanding of its epidemiology is important, especially as novel therapies are emerging. © 2013 Ley and Collard.

Hoffman J.I.E.,University of California at San Francisco
Cardiovascular Journal of Africa | Year: 2013

Although the incidence of congenital heart disease (CHD) is similar worldwide, the burden of supporting these patients falls more heavily on countries with high fertility rates. In a country with a fertility rate of about eight per woman, the population has to support four times as many children with CHD as in a country with a fertility rate of two. Countries with the highest fertility rates tend to have the lowest incomes per capita, thus accentuating the disparity. Countries with high fertility rates have more children with congenital heart disease per wage earner. Improving local health services and controlling infectious diseases (diarrhoeal illness, rheumatic fever, measles, rotoviral infection) are important but are mere 'band-aids' compared to improving education, empowering women and reducing birth rates.

Shiloh M.U.,University of California at San Francisco | DiGiuseppe Champion P.A.,University of Notre Dame