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Vashi A.A.,Yale University | Fox J.P.,Wright State University | Carr B.G.,University of Pennsylvania | D'Onofrio G.,Yale University | And 5 more authors.
JAMA - Journal of the American Medical Association | Year: 2013

Importance: Current efforts to improve health care focus on hospital readmission rates as a marker of quality and on the effectiveness of transitions in care during the period after acute care is received. Emergency department (ED) visits are also a marker of hospital-based acute care following discharge but little is known about ED use during this period. Objectives: To determine the degree to which ED visits and hospital readmissions contribute to overall use of acute care services within 30 days of discharge from acute care hospitals, to describe the reasons patients return for ED visits, and to describe these patterns among Medicare beneficiaries and those not covered by Medicare insurance. Design, Setting, and Participants: Prospective study of patients aged 18 years or older (mean age: 53.4 years) who were discharged between July 1, 2008, and September 31, 2009, from acute care hospitals in 3 large, geographically diverse states (California, Florida, and Nebraska) with data recorded in the Healthcare Cost and Utilization Project state inpatient and ED databases. Main Outcome Measures: The 3 primary outcomes during the 30-day period after hospital discharge were ED visits not resulting in admission (treat-and-release encounters), hospital readmissions from any source, and a combined measure of ED visits and hospital readmissions termed hospital-based acute care. Results: The final cohort included 5 032 254 index hospitalizations among 4 028 555 unique patients. In the 30 days following discharge, 17.9% (95% CI, 17.9%-18.0%) of hospitalizations resulted in at least 1 acute care encounter. Of these 1 233 402 postdischarge acute care encounters, ED visits comprised 39.8% (95% CI, 39.7%-39.9%). For every 1000 discharges, there were 97.5 (95% CI, 97.2-97.8) ED treat-and-release visits and 147.6 (95% CI, 147.3-147.9) hospital readmissions in the 30 days following discharge. The number of ED treat-and-release visits ranged from a low of 22.4 (95% CI, 4.6-65.4) encounters per 1000 discharges for breast malignancy to a high of 282.5 (95% CI, 209.7-372.4) encounters per 1000 discharges for uncomplicated benign prostatic hypertrophy. Among the highest volume discharges, the most common reason patients returned to the ED was always related to their index hospitalization. Conclusions and Relevance: After discharge from acute care hospitals in 3 states, ED visits within 30 days were common among adults and accounted for 39.8% of postdischarge hospital-based acute care visits. Improving care transitions should focus not only on decreasing readmissions but also on ED visits. ©2013 American Medical Association. All rights reserved.


O'Malley S.S.,Yale University | O'Malley S.S.,Yale Comprehensive Cancer Center | Wu R.,Yale University | Mayne S.T.,Yale Comprehensive Cancer Center | Jatlow P.I.,Yale University
Nicotine and Tobacco Research | Year: 2014

Introduction: Lower concentrations of serum bilirubin, an endogenous antioxidant, have been associated with risk of many smoking-related diseases, including lung cancer and cardiovascular disease, and current smokers are reported to have lower bilirubin levels than nonsmokers and past smokers. This study evaluates the effects of smoking cessation on bilirubin levels. Methods: In a secondary analysis of a 6-week placebo-controlled trial of naltrexone for smoking cessation, indirect and total bilirubin concentrations were evaluated at baseline and following smoking cessation. Individuals who were continuously abstinent for 6 weeks (n = 155) were compared to those who were not (n = 193). Participants reported smoking ≥20 cigarettes daily at baseline and received smoking cessation counseling, 21mg nicotine patch daily, and either placebo or 1 of 3 doses of naltrexone (25, 50, or 100mg) for 6 weeks. Change in indirect and total bilirubin following the quit date was measured at Weeks 1, 4, and 6 compared to baseline. Results: Individuals who were continuously abstinent from smoking, independent of naltrexone condition, showed a significantly greater mean increase in indirect (~unconjugated) bilirubin (0.06mg/dl, SD = 0.165) compared to those who did not (mean = 0.02, SD = 0.148, p =.015). Similar results were obtained for total bilirubin (p =.037). Conclusions: Smoking cessation is followed by increases in bilirubin concentration that have been associated with lower risk of lung cancer and cardiovascular disease. © The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.


Taylor A.,Yale Comprehensive Cancer Center | Tang W.,Vascular Biology and Therapeutics Program | Bruscia E.M.,Yale University | Bruscia E.M.,San Raffaele Scientific Institute | And 5 more authors.
Blood | Year: 2014

Serum response factor (SRF) is a ubiquitously expressed transcription factor and master regulator of the actin cytoskeleton. We have previously shown that SRF is essential for megakaryocyte maturation and platelet formation and function. Here we elucidate the role of SRF in neutrophils, the primary defense against infections. To study the effect of SRF loss in neutrophils, we crossed Srffl/fl mice with select Cre-expressing mice and studied neutrophil function in vitro and in vivo. Despite normal neutrophil numbers, neutrophil function is severely impaired in Srf knockout (KO) neutrophils. Srf KO neutrophils fail to polymerize globular actin to filamentous actin in response to N-formyl-methionine-leucine-phenylalanine, resulting in significantly disrupted cytoskeletal remodeling. Srf KO neutrophils fail to migrate to sites of inflammation in vivo and along chemokine gradients in vitro. Polarization in response to cytokine stimuli is absent and Srf KO neutrophils show markedly reduced adhesion. Integrins play an essential role in cellular adhesion, and although integrin expression levels are maintained with loss of SRF, integrin activation and trafficking are disrupted. Migration and cellular adhesion are essential for normal cell function, but also for malignant processes such as metastasis, underscoring an essential function for SRF and its pathway in health and disease. © 2014 by The American Society of Hematology.


Devita V.T.,Yale Comprehensive Cancer Center | Eggermont A.M.M.,Cancer Institute | Hellman S.,University of Chicago | Kerr D.J.,University of Oxford
Nature Reviews Clinical Oncology | Year: 2014

In the past decade, we have witnessed unprecedented changes and some remarkable advances that have enabled true personalized medicine. Nevertheless, many challenges in clinical cancer research remain and need to be overcome if we are to witness similar progress in the next decade. Such hurdles include, but are not limited to, clinical development and testing of multiple agents in combination, design of clinical trials to best accommodate the ever increasing knowledge of heterogeneity of the disease, regulatory challenges relating to drug development and trial design, and funding for basic research. With this in mind, we asked four leading cancer researchers from around the world, and who have been associated with the journal since its launch in November 2004 what, in their opinion, we have learnt over the past 10 years and how we should progress in the next 10 years. © 2014 Macmillan Publishers Limited. All rights reserved.


Kidane D.,University of Texas at Austin | Murphy D.L.,Yale Comprehensive Cancer Center | Sweasy J.B.,Yale Comprehensive Cancer Center
Oncogenesis | Year: 2014

Helicobacter pylori infection of the human stomach is associated with inflammation that leads to the release of reactive oxygen and nitrogen species (RONs), eliciting DNA damage in host cells. Unrepaired DNA damage leads to genomic instability that is associated with cancer. Base excision repair (BER) is critical to maintain genomic stability during RONs-induced DNA damage, but little is known about its role in processing DNA damage associated with H. pylori infection of normal gastric epithelial cells. Here, we show that upon H. pylori infection, abasic (AP) sites accumulate and lead to increased levels of double-stranded DNA breaks (DSBs). In contrast, downregulation of the OGG1 DNA glycosylase decreases the levels of both AP sites and DSBs during H. pylori infection. Processing of AP sites during different phases of the cell cycle leads to an elevation in the levels of DSBs. Therefore, the induction of oxidative DNA damage by H. pylori and subsequent processing by BER in normal gastric epithelial cells has the potential to lead to genomic instability that may have a role in the development of gastric cancer. Our results are consistent with the interpretation that precise coordination of BER processing of DNA damage is critical for the maintenance of genomic stability. © 2014 Macmillan Publishers Limited All rights reserved.


News Article | December 13, 2016
Site: www.businesswire.com

BRISBANE, Calif.--(BUSINESS WIRE)--Harpoon Therapeutics, Inc., a preclinical stage biotechnology company founded by MPM Capital that is developing novel T-cell recruiting antibody therapies for treating cancer patients, today announced the appointment of Gerald (Jerry) McMahon, Ph.D., as President and CEO. Dr. McMahon succeeds Harpoon’s interim CEO and co-founder Patrick A. Baeuerle, Ph.D. Dr. Baeuerle, an MPM Managing Director, will continue to serve on the company’s board of directors. Dr. McMahon brings more than 25 years of exceptional biotechnology leadership, scientific innovation and creative deal-making experience to his new role. With broad disease-area expertise and a specialty in oncology therapeutics, he has held industry-influencing scientific, pharmaceutical and venture capital positions, has been the CEO of multiple drug development companies and has discovered, developed, and licensed novel therapeutics leading to value-creating portfolios including drug approvals. “We’re honored that Jerry is joining Harpoon as President and CEO. He is a visionary and hands-on leader with a broad range of strategic expertise in private and public biotechnology companies,” said MPM co-founder and Managing Director Luke Evnin, who also co-founded Harpoon and chairs its board of directors. “His proven experience with a focus on oncology and immuno-oncology therapeutics will enable Harpoon’s growth as we advance the development of our novel T-cell recruiting cancer treatments for patients in need.” Most recently, Dr. McMahon was President and CEO of Kolltan Pharmaceuticals and led its acquisition by Celldex to advance the Kolltan biologics portfolio in oncology and immuno-oncology. Prior to this role, he held positions at MedImmune, the biologics arm of AstraZeneca, where he was Senior Vice President of R&D Oncology, and at Bay City Capital, where he was a Venture Partner. Dr. McMahon was also head of two oncology development companies, Poniard Pharmaceuticals, where he was chairman and CEO, and NeoRx, where was CEO and President. He also served as President of SUGEN, ultimately acquired by Pfizer, where he was a key player in the successful discovery, development and regulatory approvals of innovative oncology drugs, including Sutent® and Palladia®. Previously, Dr. McMahon was also Director at Sandoz, serving in various R&D roles prior to the company’s merger with Ciba-Geigy to form Novartis. Dr. McMahon holds an academic appointment at the Yale Comprehensive Cancer Center at Yale University, and held previous appointments at Tufts University School of Medicine, Department of Hematology & Oncology at the New England Medical Center, and the Massachusetts Institute of Technology. He is the author of more than 100 publications and holds 67 issued U.S. patents. He received his B.S. in Biology and Ph.D. in Biochemistry from Rensselaer Polytechnic Institute. About Harpoon Therapeutics — Harpoon is a preclinical stage biotechnology company founded by MPM Capital that is developing two novel classes of T-cell recruiting therapies for cancer patients. About MPM Capital — MPM Capital (http://www.mpmcapital.com) is an early-stage life sciences venture firm founding and investing in companies that seek to cure major diseases by translating scientific innovations into positive clinical outcomes. MPM’s portfolio of companies aims to revolutionize the face of medicine across multiple areas including cancer, diabetes, obesity, pain, eHealth and more. With its experienced and dedicated team of operating executives and medical and scientific advisory board, MPM is powering novel medical breakthroughs that transform patient lives. MPM invested in Harpoon from its two funds ─ the BV2014 and UBS Oncology Impact Funds.


Lee S.-K.,Chung - Ang University | Kim D.-J.,Chonbuk National University | Lee G.,Chung - Ang University | Kim G.-S.,Chonbuk National University | And 3 more authors.
Biosensors and Bioelectronics | Year: 2014

We report on the rapid and direct quantification of specific cell captures using a micro-patterned streptavidin (STR)-functionalized silicon nanowire (SiNW) platform, which was prepared by Ag-assisted wet chemical etching and a photo-lithography process. This platform operates by high-affinity cell capture rendered by the combination of antibody-epithelial cell surface-binding, biotin-streptavidin binding, and the topologically enhanced cell-substrate interaction on a 3-dimensional SiNWs array. In this work, we developed a micro-patterned nanowire platform, with which we were able to directly evaluate the performance enhancement due to nanotopography. An excellent capture efficiency of ~96.6±6.7%, which is the highest value achieved thus far for the targeting specific A549 cells on a selective area of patterned SiNWs, is demonstrated. Direct comparison between the nanowire region and the planar region on the same substrate indicates dramatically elevated cell-capture efficiency on nanotopological surface identical surface chemistry (<2% cell-capture efficiency). An excellent linear response was seen for quantifying captured A549 cells with respect to loaded cells. This study suggests that the micro-patterned STR-functionalized SiNWs platform provides additional advantage for detecting rare cells populations in a more quantitative and specific manner. © 2013 Elsevier B.V.


Lee S.-K.,Yale University | Lee S.-K.,Chonbuk National University | Kim G.-S.,Chonbuk National University | Wu Y.,Yale University | And 11 more authors.
Nano Letters | Year: 2012

We report on the development of a nanowire substrate-enabled laser scanning imaging cytometry for rare cell analysis in order to achieve quantitative, automated, and functional evaluation of circulating tumor cells. Immuno-functionalized nanowire arrays have been demonstrated as a superior material to capture rare cells from heterogeneous cell populations. The laser scanning cytometry method enables large-area, automated quantitation of captured cells and rapid evaluation of functional cellular parameters (e.g., size, shape, and signaling protein) at the single-cell level. This integrated platform was first tested for capture and quantitation of human lung carcinoma cells from a mixture of tumor cells and leukocytes. We further applied it to the analysis of rare tumor cells spiked in fresh human whole blood (several cells per mL) that emulate metastatic cancer patient blood and demonstrated the potential of this technology for analyzing circulating tumor cells in the clinical settings. Using a high-content image analysis algorithm, cellular morphometric parameters and fluorescence intensities can be rapidly quantitated in an automated, unbiased, and standardized manner. Together, this approach enables informative characterization of captured cells in situ and potentially allows for subclassification of circulating tumor cells, a key step toward the identification of true metastasis-initiating cells. Thus, this nanoenabled platform holds great potential for studying the biology of rare tumor cells and for differential diagnosis of cancer progression and metastasis. © 2012 American Chemical Society.


Hurwitz M.,Yale Comprehensive Cancer Center
Current Oncology Reports | Year: 2015

For approximately a decade, chemotherapy has been shown to prolong life in patients with metastatic castration-resistant prostate cancer (mCRPC). Since that time, however, only two agents have proven to prolong life (docetaxel and cabazitaxel). However, in the last year, the addition of chemotherapy to primary hormonal therapy became a standard of care for high-volume castration-sensitive metastatic disease. Here I will review current prostate cancer chemotherapies, mechanisms of resistance to those therapies, and ongoing clinical studies of chemotherapy combinations and novel chemotherapeutics. © 2015, Springer Science+Business Media New York.


Zhou J.,Yale University | Wu Y.,Yale University | Lee S.-K.,Yale University | Lee S.-K.,Chonbuk National University | And 2 more authors.
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2012

High-content cellomic analysis is a powerful tool for rapid screening of cellular responses to extracellular cues and examination of intracellular signal transduction pathways at the single-cell level. In conjunction with microfluidics technology that provides unique advantages in sample processing and precise control of fluid delivery, it holds great potential to transform lab-on-a-chip systems for high-throughput cellular analysis. However, high-content imaging instruments are expensive, sophisticated, and not readily accessible. Herein, we report on a laser scanning cytometry approach that exploits a bench-top microarray scanner as an end-point reader to perform rapid and automated fluorescence imaging of cells cultured on a chip. Using high-content imaging analysis algorithms, we demonstrated multiplexed measurements of morphometric and proteomic parameters from all single cells. Our approach shows the improvement of both sensitivity and dynamic range by two orders of magnitude as compared to conventional epifluorescence microscopy. We applied this technology to high-throughput analysis of mesenchymal stem cells on an extracellular matrix protein array and characterization of heterotypic cell populations. This work demonstrates the feasibility of a laser microarray scanner for high-content cellomic analysis and opens up new opportunities to conduct informative cellular analysis and cell-based screening in the lab-on-a-chip systems. © The Royal Society of Chemistry 2012.

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