Kang N.,University of Minnesota |
Shah V.H.,Center for Individualized Medicine |
Urrutia R.,Center for Individualized Medicine |
Urrutia R.,GI Research Unit
Molecular Cancer Research | Year: 2015
Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment (TME), are a key source of the extracellular matrix (ECM) that constitutes the desmoplastic stroma. Through remodeling of the reactive tumor stroma and paracrine actions, CAFs regulate cancer initiation, progression, and metastasis, as well as tumor resistance to therapies. The CAFs found in stroma-rich primary hepatocellular carcinomas (HCC) and liver metastases of primary cancers of other organs predominantly originate from hepatic stellate cells (HSTC), which are pericytes associated with hepatic sinusoids. During tumor invasion, HSTCs transdifferentiate into myofibroblasts in response to paracrine signals emanating from either tumor cells or a heterogeneous cell population within the hepatic tumor microenvironment. Mechanistically, HSTC-tomyofibroblast transdifferentiation, also known as, HSTC activation, requires cell surface receptor activation, intracellular signal transduction, gene transcription, and epigenetic signals, which combined ultimately modulate distinct gene expression profiles that give rise to and maintain a new phenotype. The current review defines a paradigmthat explains how HSTCs are activated into CAFs to promote liver metastasis. Furthermore, a focus on the most relevant intracellular signaling networks and epigenetic mechanisms that control HSTC activation is provided. Finally, we discuss the feasibility of targeting CAF/activated HSTCs, in isolation or in conjunction with targeting cancer cells, which constitutes a promising and viable therapeutic approach for the treatment of primary stroma-rich liver cancers and liver metastasis. © 2014 American Association for Cancer Research.
News Article | November 6, 2015
CHICAGO (Reuters) - Just as 23andMe has made peace with the U.S. Food and Drug Administration, another direct-to-consumer genetics company is testing the regulatory waters with the launch of a $249 DNA test designed to predict drug response. The test, from tiny startup DNA4Life based in Mandeville, Louisiana, comes in the wake of 23andMe's two-year tussle with the FDA over its direct-to-consumer personal DNA testing service, which the FDA ordered off the market in 2013. Last month, 23andMe relaunched its service with a limited number of genetic tests for carrier screening - tests that show whether an individual carries genes associated with 36 different disorders that could be passed on to a child. But the agency has yet to approve direct-to-consumer tests for pharmacogenetics, a field experts believe could be much riskier in the hands of consumers, who might use the information to make decisions about the drugs they are taking. Richard Zimmer, chief executive of DNA4Life, said he has been watching developments at the FDA closely and said his regulatory advisers believe the test does not need FDA approval. Zimmer said tests such as his are regulated as lab-developed tests under guidelines established by the Clinical Laboratory Improvement Amendments or CLIA, which do not require companies to prove clinical validity or usefulness in aiding patient care. In response to a query by Reuters, FDA spokesman Eric Pahon said the agency "actively regulates genetic tests sold directly to consumers, including pharmacogenetics tests, to make sure they are safe and do what they claim to do." "Without FDA oversight, the safety and efficacy of the tests have not been determined and could potentially lead to patient harm," Pahon said. When told of FDA's stance, Zimmer said, "We would be delighted to have a conversation with the FDA," but added that it is not under the agency's purview. "Of course, the government can do what it likes." Currently, pharmacogenetics tests are ordered directly by a treating physician and are not available to consumers. One, GeneSight, made by Assurex Health, is covered by Medicare and some insurers. GeneSight's sticker price is more than $3,000, but the company says the average patient pays no more than $330. To get DNA4Life's $249 test and report, consumers must agree to share their results with their doctor and answer a few screening questions. A network of DNA4Life doctors uses those answers to determine whether to order the test, which assesses 12 common genes affecting drug metabolism and response. It is a setup similar to one used by Pathway Genomics, which in September launched a DNA cancer screening test for healthy people. They, too, offered online screening tests and physician ordering. Just a few weeks after the launch, FDA sent Pathway a warning letter expressing concern that test could harm public health. For Zimmer, the push is personal, born out of the experiences of his 16-year-old daughter, who suffered with severe depression while her doctor tried to find the right medication and dose to treat her. Zimmer believes consumers should have access to their own data through an affordable test. Dr. Keith Stewart of Mayo Clinic's Center for Individualized Medicine said there are no direct-to-consumer pharmacogenetic tests and "at this point, FDA approval is likely to be required." Stewart said studies showing the tests are clinically valuable are "few and far between," and those that have been done have been sponsored by the testing companies. The problem, said pharmacogenetics expert Dr. Josh Peterson of Vanderbilt University, is that patients, and even doctors, struggle to understand what to do with the results. "I think that is one of the FDA's concerns," he said. "I'm an internist. That would be one of my concerns as well."
Parthasarathy G.,Mayo Medical School |
Chen J.,Mayo Medical School |
Chen J.,Center for Individualized Medicine |
Chen X.,Mayo Medical School |
And 6 more authors.
Gastroenterology | Year: 2016
Background & Aims In fecal samples from patients with chronic constipation, the microbiota differs from that of healthy subjects. However, the profiles of fecal microbiota only partially replicate those of the mucosal microbiota. It is not clear whether these differences are caused by variations in diet or colonic transit, or are associated with methane production (measured by breath tests). We compared the colonic mucosal and fecal microbiota in patients with chronic constipation and in healthy subjects to investigate the relationships between microbiota and other parameters. Methods Sigmoid colonic mucosal and fecal microbiota samples were collected from 25 healthy women (controls) and 25 women with chronic constipation and evaluated by 16S ribosomal RNA gene sequencing (average, 49,186 reads/sample). We assessed associations between microbiota (overall composition and operational taxonomic units) and demographic variables, diet, constipation status, colonic transit, and methane production (measured in breath samples after oral lactulose intake). Results Fourteen patients with chronic constipation had slow colonic transit. The profile of the colonic mucosal microbiota differed between constipated patients and controls (P <.05). The overall composition of the colonic mucosal microbiota was associated with constipation, independent of colonic transit (P <.05), and discriminated between patients with constipation and controls with 94% accuracy. Genera from Bacteroidetes were more abundant in the colonic mucosal microbiota of patients with constipation. The profile of the fecal microbiota was associated with colonic transit before adjusting for constipation, age, body mass index, and diet; genera from Firmicutes (Faecalibacterium, Lactococcus, and Roseburia) correlated with faster colonic transit. Methane production was associated with the composition of the fecal microbiota, but not with constipation or colonic transit. Conclusions After adjusting for diet and colonic transit, the profile of the microbiota in the colonic mucosa could discriminate patients with constipation from healthy individuals. The profile of the fecal microbiota was associated with colonic transit and methane production (measured in breath), but not constipation. © 2016 AGA Institute.
Mariani J.,Yale University |
Coppola G.,Yale University |
Zhang P.,Yale University |
Abyzov A.,Yale University |
And 14 more authors.
Cell | Year: 2015
Summary Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD. © 2015 Elsevier Inc.
Dhokarh D.,Center for Individualized Medicine |
Abyzov A.,Center for Individualized Medicine
Genome Research | Year: 2016
Copy number variants (CNVs) are a class of structural variants that may involve complex genomic rearrangements (CGRs) and are hypothesized to have additional mutations around their breakpoints. Understanding the mechanisms underlying CNV formation is fundamental for understanding the repair and mutation mechanisms in cells, thereby shedding light on evolution, genomic disorders, cancer, and complex human traits. In this study, we used data from the 1000 Genomes Project to analyze hundreds of loci harboring heterozygous germline deletions in the subjects NA12878 and NA19240. By utilizing synthetic long-read data (longer than 2 kbp) in combination with high coverage short-read data and, in parallel, by comparing with parental genomes, we interrogated the phasing of these deletions with the flanking tens of thousands of heterozygous SNPs and indels. We found that the density of SNPs/indels flanking the breakpoints of deletions (in-phase variants) is approximately twice as high as the corresponding density for the variants on the haplotype without deletion (out-of-phase variants). This fold change was even larger for the subset of deletions with signatures of replication-based mechanism of formation. The allele frequency (AF) spectrum for deletions is enriched for rare events; and the AF spectrum for in-phase SNPs is shifted toward this deletion spectrum, thus offering evidence consistent with the concomitance of the in-phase SNPs/indels with the deletion events. These findings therefore lend support to the hypothesis that the mutational mechanisms underlying CNV formation are error prone. Our results could also be relevant for resolving mutation-rate discrepancies in human and to explain kataegis. © 2016 Dhokarh and Abyzov.
Kaddurah-Daouk R.,Duke University |
Weinshilboum R.M.,Molecular Therapeutics |
Weinshilboum R.M.,Center for Individualized Medicine
Clinical Pharmacology and Therapeutics | Year: 2014
Metabolomics, the study of metabolism at an "omic" level, has the potential to transform our understanding of mechanisms of drug action and the molecular basis for variation in drug response. It is now possible to define metabolic signatures of drug exposure that can identify pathways involved in both drug efficacy and adverse drug reactions. In addition, the "metabotype," the metabolic "signature" of a patient, is a unique identity that contains information about drug response and disease heterogeneity. The application of metabolomics for the study of drug effects and variation in drug response is creating "pharmacometabolomics," a discipline that will contribute to personalized drug therapy and will complement pharmacogenomics by capturing environmental and microbiome-level influences on response to drug therapy. This field has the potential to transform pharmacology and clinical pharmacology in significant ways and will contribute to efforts for personalized therapy. This overview highlights developments in the new discipline of pharmacometabolomics.
Feldman A.L.,Mayo Medical School |
Dogan A.,Mayo Medical School |
Smith D.I.,Mayo Medical School |
Law M.E.,Mayo Medical School |
And 7 more authors.
Blood | Year: 2011
The genetics of peripheral T-cell lymphomas are poorly understood. The most well-characterized abnormalities are translocations involving ALK, occurring in approximately half of anaplastic large cell lymphomas (ALCLs). To gain insight into the genetics of ALCLs lacking ALK translocations, we combined mate-pair DNA library construction, massively parallel ("Next Generation") sequencing, and a novel bioinformatic algorithm. We identified a balanced translocation disrupting the DUSP22 phosphatase gene on 6p25.3 and adjoining the FRA7H fragile site on 7q32.3 in a systemic ALK-negative ALCL. Using fluorescence in situ hybridization, we demonstrated that the t(6;7)(p25.3;q32.3) was recurrent in ALK-negative ALCLs. Furthermore, t(6;7)(p25.3; q32.3) was associated with down-regulation of DUSP22 and up-regulation of MIR29 microRNAs on 7q32.3. These findings represent the first recurrent translocation reported in ALK-negative ALCL and highlight the utility of massively parallel genomic sequencing to discover novel translocations in lymphoma and other cancers. © 2011 by The American Society of Hematology.
Kaddurah-Daouk R.,Duke University |
Weinshilboum R.,Molecular Therapeutics |
Weinshilboum R.,Center for Individualized Medicine
Clinical Pharmacology and Therapeutics | Year: 2015
The scaling up of data in clinical pharmacology and the merger of systems biology and pharmacology has led to the emergence of a new discipline of Quantitative and Systems Pharmacology (QSP). This new research direction might significantly advance the discovery, development, and clinical use of therapeutic drugs. Research communities from computational biology, systems biology, and biological engineering - working collaboratively with pharmacologists, geneticists, biochemists, and analytical chemists - are creating and modeling large data on drug effects that is transforming our understanding of how these drugs work at a network level. In this review, we highlight developments in a new and rapidly growing field - pharmacometabolomics - in which large biochemical data-capturing effects of genome, gut microbiome, and environment exposures is revealing information about metabotypes and treatment outcomes, and creating metabolic signatures as new potential biomarkers. Pharmacometabolomics informs and complements pharmacogenomics and together they provide building blocks for QSP. © 2015 American Society for Clinical Pharmacology and Therapeutics.
Seo S.,Center for Individualized Medicine |
Grzenda A.,Center for Individualized Medicine |
Lomberk G.,Center for Individualized Medicine |
Ou X.-M.,University of Mississippi Medical Center |
And 2 more authors.
Journal of Pain | Year: 2013
Epigenetic regulation of gene expression is a rapidly growing area of research. Considering the longevity and plasticity of neurons, the studies on epigenetic pathways in the nervous system should be of special interest for both epigeneticists and neuroscientists. Activation or inactivation of different epigenetic pathways becomes more pronounced when the cells experience rapid changes in their environment, and such changes can be easily caused by injury and inflammation, resulting in pain perception or distortion of pain perception (eg, hyperalgesia). Therefore, in this regard, the field of pain is at an advantage to study the epigenetic pathways. More importantly, understanding pain from an epigenetics point of view would provide a new paradigm for developing drugs or strategies for pain management. In this review, we introduce basic concepts of epigenetics, including chromatin dynamics, histone modifications, DNA methylation, and RNA-induced gene silencing. In addition, we provide evidence from published studies suggesting wide implication of different epigenetic pathways within pain pathways. Perspective: This article provides a brief overview of epigenetic pathways for gene regulation and highlights their involvement in pain. Our goal is to expose the readers to these concepts so that pain-related phenotypes can be investigated from the epigenetic point of view. © 2013 by the American Pain Society.
News Article | December 1, 2016
A Minnesota company today announced it has launched an innovative physician-ordered test for identifying which medications may work best for individual patients. OneOme, a growing pharmacogenomics company, has introduced the RightMed test, making it possible for physicians to quickly and accurately personalize medications for individual patients – even before they take the first dose. Pharmacogenomics is a new, emerging field that combines the study of how drugs affect biological systems (pharmacology) with the study of genes and their functions (genomics). Recently, OneOme launched the physician-ordered RightMed test, which makes it possible to identify how a patient may or may not respond to certain medications – based on their genetic makeup. This helps to eliminate some of the trial-and-error that can often precede identification of the most effective medication. “The RightMed test was developed to address the fact that around half of the four billion prescriptions issued each year do not work as intended, and that adverse drug reactions account for seven percent of hospital admissions and 20 percent of readmissions,” said OneOme CEO, Paul Owen. By using a cheek-swab test taken as part of a routine doctor’s visit or by taking the test at home and submitting it directly to OneOme, physicians will have a better idea of how their patients’ 22 genes analyzed through the test will respond to a list of more than 340 medications. The hope is for physicians to be able to identify the best options for their patients. While anyone can take the RightMed test, patients who may benefit most include: those who take some classes of medication, such as cardiovascular prescriptions; those who are struggling with adverse drug reactions, unwanted side effects, medications that are not working; or those who are on multiple medications. OneOme is a privately owned company located in Minnesota, a state well known and recognized for its medical innovation. The RightMed test was created in collaboration with Mayo Clinic and is available worldwide. Currently the test is used in Centra Health’s Stroobants Cardiovascular Center, Mayo Clinic’s Center for Individualized Medicine (CIM), and Ridgeview Medical Center, among others. Because of OneOme’s recent progress in making the test more affordable and increasing interest in DNA testing from patients, the RightMed test is rapidly gaining popularity among physicians and patients. Paired with OneOme’s ability to secure lab accreditation through the College of American Pathologists (CPA), considered the “gold standard” of lab standards, more and more physicians, pharmacists and patients are considering the test before starting a path of prescription treatment options. OneOme also recently began integrating the test results into what is commonly called an EMR, or electronic medical record. This will make it easier for physicians to order the RightMed test and see its results electronically throughout the patient’s lifetime. To learn more about OneOme or the RightMed test, please visit oneome.com/patient and then discuss with your healthcare provider. Editor’s Note: Mayo Clinic has a financial investment in the technology referenced in this news release. The revenue that Mayo Clinic will receive is used to support its not-for-profit mission in patient care, education and research.