MedicalResearch.com Interview with: Kevin M. Biglan, M.D., M.P.H
Professor of Neurology and the Associate Chair for Clinical Research
Department of Neurology and the Center for Human Experimental Therapeutics
University of Rochester School of Medicine and Dentistry
Rochester, New YorkMedical Research: What is the background for this study? What are the main findings?
Dr. Biglan: A therapeutic goal of research in Huntington Disease (HD) is the identification of treatments that delay the progression of disease and onset of illness in individuals at risk for developing manifest HD. Designing such efficacy trials is challenging. A major hurdle is the lack of practical primary outcome measures to assess the effect of an intervention on delaying disease onset. Use of the dichotomous endpoint of clinical diagnosis as the primary outcome requires large sample sizes and long duration of follow up in order to show a significant therapeutic effect on delaying disease onset. Continuous measures that can reliably distinguish cytosine-adenine-guanine (CAG) expanded individuals in the pre-manifest period may allow for the identification of potential disease modifying therapies using relatively smaller cohorts followed for shorter periods of time.
The Prospective Huntington At-Risk Observational Study (PHAROS)represents the largest observational study to clinically evaluate pre-manifest Huntington Disease wherein both research participants and investigators were unaware of Huntington Disease mutation status. Accordingly, PHAROS was uniquely designed to address, in an unbiased manner, those clinical features most associated with the CAG expansion during the prodromal phase in Huntington Disease. The identification of continuous outcome measures that are associated with HD in the pre-manifest period may facilitate the design and powering of future studies of potential disease modifying therapies prior to traditional motor diagnosis.
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MedicalResearch.com Interview with:
Samuel Klempner, M.D. Assistant Professor
Division of Hematology/Oncology
UC Irvine Health
Orange, CA 92868Medical Research: What is the background for this study? What are the main findings?
Dr. Klempner: The background for our series is the concept that little is known about the genetic landscape of rare tumors such as acinic cell tumors, and that understanding genetic changes in tumors can identify treatment options. This paradigm can, and should, be extended beyond rare tumor types and many researchers are currently studying various tumor types. Another important background idea is that tumor genomic alterations may be more important than that anatomic site of origin. For example, I would argue that a breast cancer that harbors an EGFR mutation common to lung cancer could be treated similar to a lung cancer based on the genomic changes.
In our study we found another way that the BRAF protein and its downstream signaling may become activated through duplicating part of the protein called the kinase domain. This genetic event causes the pathway to be always "on" which is not normal, and likely drives cancer growth. However, BRAF kinase domain duplication appears sensitive to currently available drugs that target the BRAF pathway, as evidenced by the response in our patient. Thus, finding this change is important and may be able to guide a more personalized therapy choice. Importantly, we found BRAF kinase domain duplication across multiple different tumor types, suggesting this may be a recurrent event in some cancers. A very similar finding, involving duplication of the EGFR kinase domain, was also just reported (Cancer Discovery 2015;5:1155-1163) lending further validation to this mechanism of pathway activation in cancer.
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MedicalResearch.com Interview with:
Frederick W. Vonberg, MA, MBBS
Research Fellow in Neurocritical Care
Boston Children's Hospital and Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Response: An association between schizophrenia and epilepsy has long been suspected, ever since people noticed similarities in some aspects of the presentation of the two conditions, and in their epidemiology. For example, people with epilepsy are thought to be more at risk of developing schizophrenia. Furthermore, a psychosis resembling schizophrenia can characterize some forms of epilepsy. Whether this link reflected an overlap in the genetics of the two conditions has remained a mystery, however. In this study, we used a recently developed computational technique to show that there is a significant positive correlation between the genetic variants that are associated with epilepsy and with those that are associated with schizophrenia.
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MedicalResearch.com Interview with:
Joan C. Han, MD
Director, Pediatric Obesity Program, Le Bonheur Children’s Hospital
Associate Professor, Division of Pediatric Endocrinology
Department of Pediatrics, University of Tennessee Health Science Center
Memphis, TN 38103
Medical Research: What is the background for this study? What are the main findings?
Dr. Han: Obesity has become a world-wide epidemic. Our research group studies the genetic factors that contribute to the development of obesity. Brain-derived neurotrophic factor (BDNF) is a protein that plays a key role in regulating appetite. We found that a common genetic variant of the BDNF gene is associated with lower expression of this gene in the hypothalamus, a region of the brain that controls energy balance. The mechanism of this reduced gene expression appears to be due to diminished binding of the transcription factor hnRNPD0B. We also observed that this genetic variant is associated with higher body mass index and higher body fat in children and adults. The obesity-predisposing variant of the BDNF gene occurs more commonly in people of African-American or Hispanic backgrounds, which could have important clinical implications given the higher rates of obesity in these populations.
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MedicalResearch.com Interview with:
Hans F.A. Vasen, MD
Department of Gastroenterology
Leiden University Medical Center and
Netherlands Foundation for the Detection of Hereditary Tumours
Leiden, the Netherlands
Medical Research: What is the background for this study?
Dr. Vasen: People with familial colorectal cancer (CRC) have a 3-6 fold increased risk of
colorectal cancer. It has been estimated that about 2% of the population have familial CRC (about 2.7 million people in the US). Previous studies showed that colonoscopic surveillance reduces the CRC-mortality by >80%. In people with hereditary CRC, i.e., Lynch syndrome (10 fold increased risk of CRC), an intensive screening program with colonoscopy 1x/1-2 years, is recommended. In familialcolorectal cancer, the optimal screening program is unknown.
Medical Research: What are the main findings?
Dr. Vasen: In this randomized trial with 528 individuals at risk for familial CRC, we compared screening intervals of 3 and 6 years. We found that patients had significant more high-risk adenomas (precursor lesions of CRC) at 6-years-follow-up compared to at 3-years-follow-up. However, because of the relatively low rate of high-risk adenomas at 6 years (7%) and the absence of colorectal cancer in the 6-years group, we consider a 6-year-interval safe.
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MedicalResearch.com Interview with:
Benjamin Freedman, Ph.D.
Assistant Professor | University of Washington
Department of Medicine | Division of Nephrology
Member, Kidney Research Institute
Member, Institute for Stem Cell and Regenerative Medicine
Seattle WA 98109Medical Research: What is the background for this study? What are the main findings?
Dr. Freedman: We are born with a limited number of kidney tubular subunits called nephrons. There are many different types of kidney disease that affect different parts of the nephron. The common denominator between all of these diseases is the irreversible loss of nephrons, which causes chronic kidney disease in 730 million patients worldwide, and end stage renal disease in 2.5 million. Few treatments have been discovered that specifically treat kidney disease, and the therapeutic gold standards, dialysis and transplant, are of limited availability and efficacy.
Pluripotent stem cells are a renewable source of patient-specific human tissues for regeneration and disease analysis. In our study, we investigated the potential of pluripotent cells to re-create functional kidney tissue and disease in the lab. Pluripotent cells treated with a simple chemical cocktail matured into mini-kidney 'organoids' that closely resembled nephrons. Using an advanced gene editing technique called CRISPR, we created stem cells with genetic mutations linked to two common kidney diseases, polycystic kidney disease (PKD) and glomerulonephritis. Mini-kidneys derived from these genetically engineered cells showed specific 'symptoms' of these two different diseases in the petri dish.
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MedicalResearch.com Interview with:
Urszula T. Iwaniec, Ph.D.
Associate Professor
Skeletal Biology Laboratory
School of Biological and Population Health Sciences
Oregon State University
Corvallis, OR 97331
Medical Research: What is the background for this study? What are the main findings?
Dr. Iwaniec: Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related bone loss. Leptin, a hormone produced by fat cells plays an essential role in weight regulation. Delivery of leptin directly into the hypothalamus by gene therapy normalizes body weight. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature female rats and determined the impact of leptin-induced weight loss on bone. Our findings show that hypothalamic leptin gene therapy reduced body weight with minimal effects on bone mass or microarchitecture.
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MedicalResearch.com Interview with:
Professor P. Elizabeth Rakoczy
Centre for Ophthalmology and Visual Sciences
The University of Western Australia
Head of Department - Molecular Ophthalmology
Lions Eye Institute Australia
Medical Research: What is the background for this study?
Prof. Rakoczy: Wet age related macular (wet-AMD) is the major cause of blindness in the developed world. It is treated with frequent anti-VEGF injections into the eye. Our preclinical studies demonstrated that following the subretinal injection of a recombinant adeno-associated vector (rAAV) carrying a natural inhibitor of neovascularization (sFlt-1), leaky new, abnormal vessels can be controlled and retinal anatomy improved. The rAAV.sFlt-1 based Ocular Biofactory™ platform has potentially significant advantages over existing technologies as it is designed to provide sustained production of a naturally occurring antiangiogenic agent, sFlt-1, in situ in the eye. In this trial we investigated the safety of rAAV.sFlt-1 in patients diagnosed with wet-AMD.
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MedicalResearch.com Interview with:
Huma Q. Rana, MD
Clinical Director, Cancer Genetics and Prevention
Dana-Farber Cancer Institute in Boston
Medical Research: What is the background for this study? What are the main findings?
Dr. Rana: - Li-Fraumeni syndrome (LFS) is thought to be a rare, inherited condition that causes high lifetime risks for multiple cancers. It is caused by mutations in the TP53 gene. Traditionally, only people with striking personal or family histories of cancer underwent genetic testing for TP53 mutations, as there are well-established testing criteria. This gene was usually tested for in isolation, meaning not combined with testing of other genes. Due to technological advances, namely multi-gene panels (MGP), many more people are having their TP53gene analyzed. This included a patient of mine who somewhat surprisingly tested positive for a TP53 mutation. This led us to investigate whether people who test positive for TP53 mutations on MGPs are different from ones who test positive on traditional or single-gene (SG) testing.
We compared individuals tested for TP53 single gene versus multigene panel testing to determine if there were differences in the percent of mutation carriers meeting current testing criteria for LFS. Our data showed that 73% of individuals sent in for single gene testing of TP53 met Classic or Chompret (2009) criteria for LFS, whereas only 30% of those sent in for multi-gene panel testing met criteria (p=0.0000001). When we looked at the most up-to-date testing criteria, which includes Classic, Chompret, or a personal diagnosis of early-onset breast cancer (age at ≤35), 85% of individuals in the single gene group who were positive met criteria, while only 53% of the mutation carriers identified on a multi-gene panel did. These data suggest that multi-gene panel testing enables us to identify TP53 mutation carriers who may not have otherwise been identified if testing were limited to those who meet established LFS criteria.
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MedicalResearch.com Interview with:
Rajiv McCoy, PhD
Dept. of Genome Sciences
Univ. of Washington
Medical Research: What is the background for this study? What are the main findings?Dr. McCoy: Aneuploidy—the inheritance of extra or missing chromosomes compared to the typical 46-chromosome set—is extremely common in human embryos. The vast majority of aneuploidies result in preclinical pregnancy loss, often before the pregnancy is even recognized by the mother. This is thought to be the primary reason why only ~30% of all conceptions result in successful live birth.
Many aneuploidies arise during egg formation, with the frequency increasing with maternal age. In addition to meiotic errors, a large proportion of aneuploidies affecting cleavage-stage embryos are mitotic in origin, arising during the initial post-fertilization cell divisions. These initial divisions are controlled by machinery contributed by the mother in the egg (before the embryo's genome has been activated). While these mitotic errors are frequent in cleavage-stage embryos, we found that they are rare in embryos at day-5 of development (the blastocyst stage), suggesting that embryos and/or cells with extensive mitotic errors do not survive to day 5. We discovered that some women have a greater propensity to produce embryos with mitotic errors than others, and our idea was that maybe differences in the mitotic machinery could help explain this.
Using data from in vitro fertilized embryos screened by our collaborators at Natera, we found that women who have a particular version of a gene called PLK4 tend to produce more aneuploid embryos, regardless of age. This genetic variant is actually very common—more than half of people carry at least one copy—and is present in nearly all populations. PLK4 has a well-known role in ensuring the proper distribution of chromosomes. We also found that patients referred for embryo screening due to previous IVF failure had higher rates of mitotic error, which underscores the clinical importance of this form of whole-chromosome abnormality.
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MedicalResearch.com Interview with:
Keiji Tanimoto, D.D.S., Ph.D
Assistant Professor
Research Institute for Radiation Biology and Medicine
Hiroshima University
Hiroshima Japan
Medical Research: What is the background for this study?
Dr. Tanimoto: Hypoxia-inducible factor-2α (HIF-2αor EPAS1) is important for cancer progression, and its overexpression is considered a putative biomarker for poor prognosis in patients with lung cancer. However, molecular mechanisms underlying EPAS1 overexpression are not fully understood. Recently, several SNPs of EPAS1 have been reported to be associated with the development of various diseases including cancer.
Therefore, we focused on SNPs within EPAS1, and examined the roles of these SNPs in regulation of EPAS1 gene expression and the association of these SNPs with prognosis of non-small cell lung cancer (NSCLC) patients by bioinformatics analyses.
Medical Research: What are the main findings?
Dr. Tanimoto:
The SNP within the EPAS1 intron 1 region (rs13419896) may affect EPAS1 gene and protein expression;
The fragment with A allele of the SNP showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun;
The median survival time of NSCLC patients with at least one A allele of rs13419896 was significantly shorter than that with the G/G homozygote (28.0 vs. 52.5 months, P = 0.047, log-rank test);
The possession of A allele of rs13419896, along with clinical stage, was an independent variable for risk estimation of overall survival for NSCLC patients [hazard ratio (HR) = 2.31, 95% CI = 1.14-4.81, P = 0.021], after adjustment for age, gender, stage, histology, tumor size, and differentiation.
MedicalResearch.com Interview with:
Jacqueline Alvarez-Leite MD, Ph.D
Federal University of Minas Gerias in BrazilMedical Research: What is the background for this study? What are the main findings?
Dr. Alvarez-Leite : Obesity is now a global epidemic and bariatric surgery is now the main therapeutic option for those individuals with extreme obesity in which clinical treatments failed. However, a significant proportion of those patients regain the weight lost 3-4 years after surgery. Therefore, some metabolic or genetic trait may be related to weight regain. The rs9939609 single nucleotide polymorphism (SNP) in the fat mass and obesity- associated (FTO) gene is one of the most studied genes involved in obesity. However, few studies have been conducted on patients who underwent bariatric surgery. In our study, we evaluated the influence of this FTO SNP on body weight and composition, and weight regain in 146 patients during a 60-mo follow-up period after bariatric surgery. We observed that there was a different evolution of weight loss in individual with obesity carriers of the FTO gene variant after bariatric surgery. However, this pattern is evident at only 2 y post bariatric surgery, inducing a lower proportion of surgery success (percentage of excess weight loss >50%) and greater and earlier weight regain after 3-y of follow-up. Multiple regression analyses showed that the variation in rs9939609 was a significant and independent predictor for regaining weight during the 5-y follow-up period.
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MedicalResearch.com Interview with:
Dr. Annabel Christ PhD
Max-Delbrueck-Center for Molecular Medicine
Berlin, Germany
Medical Research: What is the background for this study?Dr. Christ: The development and function of the retina in all vertebrate species follow the same principles. Still, there is one important feature that distinguishes the mammalian eye from that of others inasmuch as it does not grow much after birth. In contrast, in fish or reptiles, the retina continuously grows, even in adults. The mechanism that restricts the growth of the mammalian eye remains enigmatic. Yet, understanding this mechanism may offer therapeutic strategies to block eye growth in cases of severe nearsightedness or to induce growth of the retina in patients with retina degeneration.
To explore the mechanisms that control human eye growth we studied a genetic form of extreme eye overgrowth (buphthalmia). It is caused by an inherited defect in the gene encoding LRP2, a receptor in the retina. We reasoned that this exceptional form of eye disease might tell us something about the concepts governing eye growth in all humans.
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MedicalResearch.com Interview with:
Harry H. Yoon, MD
Mayo Clinic
Rochester, MN 55905
Medical Research: What is the background for this study? What are the main findings?
Dr. Yoon: In the U.S., the survival of patients with colon cancer is known to differ by race, with individuals of black race having worse outcomes than those of white race.
However, it has been difficult to tease apart why the differences in survival exist.
It is generally believed that social or other non-biologic factors (eg, decreased access to care, suboptimal treatment) contribute to the discrepancy. It’s also known that differences in the general medical condition of patients could affect how long a patient lives.
However, it is unknown whether there are race-based differences in the biology of colon tumors themselves. This biology can be reflected in the genetic composition of tumors, as well as by whether and how quickly the cancer returns after the patient has undergone surgery and chemotherapy.
In addition, it is unknown whether race-based differences in biology may be related to the age of the patient at the time of diagnosis. Blacks with colorectal cancer typically have an earlier age of onset than whites do.
A major barrier to addressing these questions are that there are very few large populations of colon cancer patients where everyone had the same disease stage and received uniform treatment, and where patients were monitored for years afterward specifically to see whether the cancer returned. It is much harder to measure whether cancer has returned (ie, cancer recurrence), as compared to simply knowing whether a patient is alive or dead. This difference is important, because knowing about cancer recurrence sheds more light on cancer biology than only knowing about patient survival, since many factors unrelated to cancer biology (eg., heart disease) can affect whether a person is alive or dead.
The most reliable data on cancer recurrence (not just patient survival) generally comes from patients who have enrolled in a clinical trial. In the Alliance N0147 trial, all patients had the same cancer stage (ie, stage III), underwent surgery and received standard of care chemotherapy (ie, “FOLFOX”) after surgery. Patients had uniform, periodic monitoring after chemotherapy to see if the cancer returned.
In other words, examining racial outcomes in this cohort largely eliminates some of the key factors (eg, decreased access to care, suboptimal treatment) that are believed to contribute to racial discrepancies, and provides a unique opportunity to determine if differences in cancer biology between races may exist.
This study was done to see if colon cancers are genetically different based on race, and whether race-based differences exist in cancer recurrence rates.
The study found that tumors from whites, blacks, and Asians were different in terms of the frequency of mutations in two key cancer-related genes, BRAF and KRAS. Tumors from whites were twice as likely to have mutated BRAF (14% in whites compared to 6% in Asians and 6% in blacks). Tumors from blacks had the highest frequency of KRAS mutations (44% in blacks compared to 28% in Asians and 35% in whites). Tumors from Asians were the mostly likely to have normal copies of both genes (67% in Asians compared to 50% in blacks and 51% in whites).
Next, the study found that the colon cancers among blacks had more than double the risk of cancer recurrence, compared to whites. However, this discrepancy was only evident among young patients (ie, aged less than 50 years). Almost 50% of younger black patients experienced colon cancer recurrence within 5 years, compared to ~30% of black patients over age 50, or compared to white or Asian patients regardless of age. The worse outcome among young blacks remained evident even after adjusting for many potential confounding factors, such as tumor grade, the number of malignant nodes, or the presence of BRAF or KRASmutations. Because this question was examined in a clinical trial cohort of uniform stage and treatment, the role of multiple important potential confounders was diminished.
To our knowledge, this is the first report indicating that colon cancers from young black individuals have a higher chance of relapsing after surgery and chemotherapy, compared to those from white individuals.
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MedicalResearch.com Interview with:
Dr. David Brent MD
Department of Psychiatry
Western Psychiatric Institute and Clinic
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
Medical Research: What is the background for this study? Dr. Brent: Youth with a parent with a history of depression are at increased risk for having a depressive episode themselves.
Medical Research: What are the main findings?Dr. Brent: Those who received a cognitive behavioral educational group program were less likely to have had a depressive episode, and were functioning better than those who did to receive the program 6 years later, especially if their parent was NOT depressed at the time that they received the program. If the parent was depressed then the program was no better than usual care.
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MedicalResearch.com Interview with:
Dr. Kathy D. Miller, MD
Indiana University Melvin and Bren Simon Cancer Center
Medical Research: What is the background for this study? What are the main findings?
Dr. Miller: Previous studies had found a small but real benefit with the addition of chemotherapy to anti-estrogen treatment in patients with hormone sensitive disease. The challenge for patients and clinicians has always been that the benefit of chemotherapy is quite small and the toxicity can be substantial. The Oncotype Dx recurrence score assay was developed to identify patients who could safely be treated with anti-estrogen therapy alone (and conversely those who truly need and would derive a much larger benefit from chemotherapy). When the Oncotype Dx RS was applied to samples stored from a previous randomized trial, patients with low risk scores didn't seem to benefit from chemotherapy. While those initial results had some impact on treatment, many were concerned about eliminating chemotherapy on the basis of one small retrospective trial.
The overall trial enrolled 10,253 women. 1626 (15.9%) had a Recurrence Score of 0-10 and were assigned to receive antiestrogen therapy alone without chemotherapy. After five years 99.3% (98.7, 99.6%) for were free of distant relapse (that is to say, 99.3% of women had NOT had recurrence of breast cancer at distant sites in the body). Overall survival was 98%.
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MedicalResearch.com Interview with:
Aditya Bardia MBBS, MPH
Attending Physician, Massachusetts General Hospital Cancer Center,
Assistant Professor, Harvard Medical School
Boston, MA 02114
Medical Research: What is the background for this study? What are the main findings?
Response: Multiple studies have consistently shown that African American women with cancer, including breast cancer, have worse outcomes than Caucasian counterparts. While socioeconomic issues, including access to care plays an important role, the contribution of tumor biology has been less clear.
In this study, utilizing exome sequencing data, we linked the racial distribution of primary breast cancer with tumor genotypic traits, including somatic mutations, gene-expression profiles and intra-tumor heterogeneity. We observed that in addition to having a higher prevalence of triple negative breast cancer than Caucasian women (something that has been documented in the literature), African American women had a significantly higher prevalence of TP53 mutations, TNBC basal-like 1 and mesenchymal stem-like tumors, and intratumor genetic heterogeneity, and all of which suggest more aggressive tumor biology, suggesting that differences in tumor genomic profile contribute, at least partly, to the known racial disparity in survival between African Americans and Caucasians breast cancer patients.
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MedicalResearch.com Interview with:
Ahmad M. Khalil, PhD
Department of Genetics
School of Medicine
Case Western Reserve University
Cleveland, Ohio 44106-4955
Medical Research: What is the background for this study? What are the main findings?
Dr. Khalil: DNA in human cells is modified chemically by methylation. The process of DNA methylation plays important roles in protecting human DNA and ensures proper gene expression. In cancer cells, the process of DNA methylation becomes deregulated, however, the mechanisms of how this occurs are not known. In our study, we have uncovered a novel mechanism on how colon cancer cells change their DNA methylation, and consequently, become more tumorigenic. We specifically identified a long non-coding RNA that interacts with and regulates the enzyme that modifies DNA with methylation - the enzyme is called DNMT1. This lncRNA become suppressed in colon tumors, which we believe is a key step in loss of DNA methylation in colon cancer cells.
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MedicalResearch.com Interview with: Thomas N. Darling, MD, PhD
Department of Dermatology
Uniformed Services University of the Health Sciences
Bethesda, MD 20814
Medical Research: What is the background for this study? What are the main findings?
Dr. Darling: Many people with tuberous sclerosis complex (TSC) have skin tumors that can bleed or cause distress. Only surgical approaches were useful for treating these skin tumors in the past. Recently, drugs called mTOR inhibitors, including sirolimus, were shown to shrink internal tumors in those affected by tuberous sclerosis complex. We wanted to document what happens to the skin tumors in those being treated with oral sirolimus. We found that most patients taking oral sirolimus showed improvement in their skin tumors, and that these effects were maintained during a couple years of treatment. We did not observe any evidence for the skin tumors becoming resistant to the drug.
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MedicalResearch.com Interview with:
Binbin Wang, PhD
Center for Genetics, National Research Institute for Family Planning
Beijing China
Medical Research: What is the background for this study? What are the main findings?
Dr.Wang:Homosexuality has become an important issue all around the world, as well as in China. Beside of the human right problems it poses, the reality that more and more HIV cases are infected through homosexual activity,especially men who have sex with men
(MSM), should be concerned. People are wondering how homosexuality develops.
As a genetic researcher, I'd like to find the answers in the field of genetics.
This study is based on previous evidence that genes may have impact on homosexuality. Besides, animal models have provided clues that abnormality in some neurotransmitters, such
as dopamine, may alter the sex behavior of animals. Therefore, we choose COMT (the gene catechol-O-methyltransferase) as the
target, which is important for the synthesis of dopamine. We find that an amino acid
residue change in COMT could increase the risk of developing male homosexuality.
Our results provide some evidence that male homosexuality is connected with genes.
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MedicalResearch.com Interview with:
Dr. Morgan Elyse Levine PhD
Postdoctoral Fellow
Department of Human Genetics
University of California, Los Angeles
Medical Research: What is the background for this study? What are the main findings?
Dr. Levine: Studies using mice, worms, and flies have suggested that longevity may be linked to stress resistance. All of us are constantly encountering things that damage our cells and tissue and disrupt physiological functioning. Therefore, people who are genetically predisposed to better prevent or repair this damage may age slower. Smoking is one of the most damaging things someone can do to their health, yet some smokers are able to survive to extreme ages. This study looked at long-lived smokers to see if we could identify a "genetic signature". We generated a genetic risk score that was found to be associated with longevity both in smokers and non-smokers, and also appeared to be associated with cancer risk.
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MedicalResearch.com Interview with:
Dr. Elisa Long PhD
Assistant professor
UCLA Anderson School of Management
Medical Research: What is the background for this study? What are the main findings?
Dr. Long: The study was motivated by my own diagnosis of triple-negative breast cancer last year, at the age of 33. I also learned that I carried a BRCA1 mutation, despite no family history. As a patient, I would have benefitted tremendously from a universal BRCA screening program, but as a health services researcher, I had to ask if indiscriminate screening of all women in the U.S.—where only 1 in 400 carry a mutation—is a good use of resources.
Using a previously published decision analytic model, we calculated the cost-effectiveness of universal BRCA screening. We find that compared to screening based on family history, it is not cost-effective, assuming a test price of $2,000 to $4,000. However, as the price of genetic testing continues to fall, as indicated by the $249 test now offered by Color Genomics, universal BRCA screening becomes much more affordable. Additionally, population screening of Ashkenazi Jewish women—among whom 1 in 50 carry a BRCA mutation—is very cost-effective, because the chances of finding a carrier are much higher.
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MedicalResearch.com Interview with:
Rutao Cui M. D., Ph. D.
Vice Chair, Professor
Department of Pharmacology and Experimental Therapeutic
Associate Professor of Pharmacology and Dermatology, and Member The Cancer Center
Director The Laboratory of Skin Cancer Therapeutics (LSCT)
Boston University
Medical Research: What is the background for this study? What are the main findings?Dr. Cui: Recent studies have revealed that the APC/CCdh1 E3 ubiquitin ligase may function as a tumor suppressor. However, the tumor suppressor role of APC/CCdh1 in melanoma remains largely unclear. Here, we report sporadic mutations occurring in APC components, including Cdh1 in human melanoma samples and that loss of APC/CCdh1 may predispose human melanomagenesis.
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MedicalResearch.com Interview with:
Beate W. Hygen PhD Student
Department of Psychology
Norwegian University of Science and Technology Social Science
Medical Research: What is the background for this study?
Response: The study is part of the Trondheim Early Secure Study (TESS) conducted at the Department of Psychology, Norwegian University of Science and Technology (NTNU) and NTNU Social Science. The main aim of TESS is to detect risk and protective factors with regards to children’s mental health and well-being. TESS examines multiple factors which may play a role in children`s development.
There is substantial research, based on diathesis-stress theorizing, indicating that some individuals, including children, are more susceptible to the negative effects of contextual adversity than are others. However, according to differential susceptibility theory, such "vulnerable" individuals may also be the ones that benefit the most from positive environmental conditions. Thus, some individuals are more malleable for "better and for worse" to environmental exposures. The articleChild exposure to serious life events, COMT, and aggression: Testing differential susceptibility theory was designed to examine if the COMT polymorphism moderated the effect of early-life adversity on aggressive behavior. Thus, we sought to competitively evaluate which model of person X environment interaction best accounted for the anticipated differential effects of life event stress on children's aggressive behavior.
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MedicalResearch.com Interview with:
Sameek Roychowdhury, MD, PhD
Assistant Professor, Internal Medicine, College of Medicine
Assistant Professor, Department of Pharmacology
College of Pharmacy
Department of Internal Medicine
Division of Medical Oncology
Wexner Medical Center
The Ohio State University
Medical Research: What is the background for this study? What are the main findings?
Dr. Roychowdhury: Precision cancer medicine is a new paradigm to match patients to therapies based on the molecular alterations in their cancer. Novel genomic testing of cancer using next generation sequencing can reveal numerous mutations for each patient across many genes and types of cancer, and this requires detailed time-intensive interpretation. Driver mutations can confer a selective growth or survival advantage to cancer cells, while passenger mutations do not.
Cancer Driver Log, or CanDL, is meant to aid interpretation of mutations by providing the latest literature evidence for individual driver mutations, and thereby aiding pathologists, lab directors, and oncologists in interpreting mutations found in their patient’s cancer.
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Medicalresearch.com Interview with:Roger Packer MD
Senior Vice President
Center for Neuroscience & Behavioral Health
Children's National Medical Center
Washington, D.C.
MedicalResearch: What is the background for this study? What are the main findings? Dr. Packer: The background is that medulloblastoma is the most common childhood malignant brain tumor. It carries with it a variable prognosis. For some subsets of patients, with current available treatment which includes surgery, radiation and chemotherapy, we see survival rates as high as 90% (and often cures) 5 years following diagnosis and treatment. However, for some subsets of patients, survival rates are much poorer, in those with higher risk characteristics as low as 40% at 5 years. Current treatment also carries with it a significant risk for long term sequelae, including intellectual loss secondary to radiation therapy and persistent, at times devastating neurologic complications such as unsteadiness.
To try to improve our understanding and ultimately our therapy for medulloblastoma, an international working group has shared patient specimens and patient information to attempt to determine what the molecular predictors of outcome are for children with medulloblastoma and if such molecular genetic findings can be used to develop better, safer therapies. Children’s National is part of this international collective of institutions, which published this and other studies.
The main findings of this study are that complex, integrated genetic analysis of tumor specimens can be used to better understand and set the scene for better treatment of medulloblastoma. Medulloblastoma can be broken into relatively distinct, molecular subtypes each with its own prognosis and potential therapy. A major finding of this study was that within a given tumor, different areas showed the same molecular genetic pattern. The importance of this is that since the tumors are relatively the same in different areas, molecularly-targeted therapies have an excellent chance of working on the entire tumor, resulting in better tumor control and safer treatments.
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MedicalResearch.com Interview with:
Nely Aldrich, MD
Department of Dermatology
University Hospitals Case Medical Center
Medical Research: What is the background for this study? What are the main findings?
Dr. Aldrich: To our knowledge, no formal studies have been performed on the genetic vs. environmental factors that lead to the development of rosacea. Our department has the unique opportunity to attend the Twins Days festival in Twinsburg, Ohio. This is a yearly festival where thousands of twin pairs come from all over the world. This was the perfect setting to ask our research question. Our main finding was that there is an approximately 50% contribution of genetics to rosacea and the other 50% can be attributed to environmental factors. Sun exposure, smoking, alcohol use, skin cancer history, and heart disease were also found to be correlated with a higher rosacea severity.
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MedicalResearch.com Interview with:
Michaela Ann Dinan Ph.D.
Assistant Professor in Medicine
Member of Duke Cancer Institute
Duke University School of Medicine
Medical Research: What is the background for this study? What are the main findings?
Dr. Dinan: For many years we have known that overall, women with early stage, hormone receptor positive breast cancer show an overall survival benefit from the receipt of adjuvant chemotherapy. However, depending on the age of the patient, we have also known that between 3 to 10% of patients appear to be truly experiencing this survival benefit and that we are treating a lot of women unnecessarily. The use of the Oncotype DX assay has provided additional information for patients to assess who at low risk of disease progression and can forgo chemotherapy.
In this study we looked to see whether the adoption of this assay was associated with reduce rates of chemotherapy in women over the age of 65. We found that somewhat surprisingly, there was no overall association with receipt of the assay and use of chemotherapy. However, in women who had high risk disease, receipt of the assay was associated with reduced rates of chemotherapy use. In patients with low risk disease, receipt of the assay was associated with increased chemotherapy use.(more…)
MedicalResearch.com Interview with:
Tuya Pal MD
Division of Population Sciences
Department of Health Outcomes and Behavior
Moffitt Cancer Center
Tampa, Florida
Medical Research: What is the background for this study?
Dr. Pal: Young Black women bear a disproportionate burden associated with breast cancer incidence and mortality compared to their White counterparts. Given that inherited mutations in the BRCA1 and BRCA2 genes are more common among young breast cancer survivors, we questioned to what extent mutations in these genes might contribute to the racial disparity in breast cancer incidence among young women.
Medical Research: What are the main findings?
Dr. Pal: Through conducting the largest U.S. based study of BRCA mutation frequency in young black women diagnosed with breast cancer at or below age 50, we discovered they have a much higher BRCA mutation frequency than that previously reported among young white women with breast cancer. Specifically, of the 396 Black women with breast cancer diagnosed at or below age 50, 12.4% had mutations in either BRCA1 or BRCA2. Furthermore, over 40 percent of those with a mutation had no close relatives with breast or ovarian cancer, which suggests that family history alone may not identify those at risk for carrying a BRCA mutation.(more…)
MedicalResearch.com Interview with:
Hendrik Marks Ph.D
Group leader Epigenetics of Stem Cells
Radboud University, Department of Molecular Biology, RIMLS
Nijmegen, The Netherlands
Medical Research: What is the background for this study? What are the main findings?
Dr. Marks: In mammals, sex is determined by two so-called "sex" chromosome: males have a single X chromosome as well as a Y chromosome, whereas females have two copies of the X chromosome. However, if both X chromosomes were to be active in female cells, these cells would have a double dosis of X-chromosomal gene products as compared to male cells. As this is lethal for almost all cells, female cells shut off one X chromosome in every cell in a process called X inactivation. This process occurs during early embryonic development.
A lot is known about how this process is turned on, but is was unclear how such a silencing process spreads along a full chromosome. In order to further study this, we used female mouse embryonic stem cells (mESCs) as a model system and initiated X inactivation by means of differentiation. With the latest technologies, we were able to keep the two X chromosomes apart and measure one of them – with its 166 million base pairs (Mbs) – in detail. Every day we checked which parts of the chromosome had been switched off. The whole process took about eight days, and the inactivation spreads out from the centre of the X chromosome towards the ends. That doesn’t happen gradually but moves jumpwise from domain to domain. Domains are long pieces of DNA (of around 1Mb) that cluster together in knots. As it seems that X inactivation jumps from domain to domain, we now know that these domains are co-regulated. Also, we collected strong evidence that the same process is occurring in human.
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