Familial Members Without Genetic Mutation Can Still Have Increased Risk of Melanoma

MedicalResearch.com Interview with:

Hildur Helgadottir, M.D., Ph.D. Department of Oncology Karolinska University Hospit

Dr. Helgadottir

Hildur Helgadottir, M.D., Ph.D.
Department of Oncology
Karolinska University Hospital

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Malignant melanoma of the skin is one of the fastest increasing cancer types in the West.

The main risk factors for melanoma are UV light exposure and hereditary factors. It is therefore relatively common for the afflicted to have family members with the disease. Inherited mutations of the tumour suppressor gene CDKN2A are the strongest known risk factors for familial melanoma and mutations in this gene also increase the risk of other cancers. Children, siblings or parents of mutation carriers have a 50-50 chance of also having the mutation, which can be identified with a gene test.

The present study included Swedish and American families with inherited CDKN2A mutations. The researchers studied whether family members who have not inherited the mutation have any higher than normal risk of developing melanoma or other cancers.

Melanoma, but no other cancers, was more common in the non-carriers in these families compared to the normal population. The phenomenon whereby non-carriers of a specific mutation copy the phenotype (in this case melanoma) from their mutation-carrying relatives is known as phenocopy.

Phenocopy can be caused by other risk-modifying genes or exposure patterns that increase the probability of the specific phenotype manifesting itself. Previous studies have shown that people with the mutation who also have certain pigmentation variants run an even higher risk of melanoma.

Even though the CDKN2A mutation should be present in all populations, it has almost exclusively been identified in families with a Caucasian heritage.This suggests that dark-skinned people with this mutation probably don’t develop melanoma as often and are therefore not tested for this specific mutation, presumably because they lack the risk-modifying pigmentation variants that increase the risk of melanoma. The researchers believe that such pigmentation variants also contribute to a higher melanoma risk in the family members who do not carry the mutation.

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More Evidence That Higher Education May Lower Risk of Alzheimer’s Disease

MedicalResearch.com Interview with:

Susanna C. Larsson, PhD Associate Professor, Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden

Dr. Larsson

Susanna C. Larsson, PhD
Associate Professor, Karolinska Institutet,
Institute of Environmental Medicine,
Stockholm, Sweden

MedicalResearch.com: What is the background for this study?

Response: The causes of Alzheimer’s disease are largely unknown and there are currently no medical treatments that can halt or reverse its effects. This has led to growing interest in identifying risk factors for Alzheimer’s that are amenable to modification. Several observational studies have found that education and various lifestyle and vascular risk factors are associated with the risk of Alzheimer’s disease, but whether these factors actually cause Alzheimer’s is unclear.

We used a genetic epidemiologic method known as ‘Mendelian randomization’. This method involves the use of genes with an impact on the modifiable risk factor – for example, genes linked to education or intelligence – and assessing whether these genes are also associated with the disease. If a gene with an impact on the modifiable risk factor is also associated with the disease, then this provides strong evidence that the risk factor is a cause of the disease.

MedicalResearch.com:  What are the main findings?

Response: Our results, based on aggregated genetic data from 17 000 Alzheimer’s disease patients and 37 000 healthy controls, revealed that genetic variants that predict higher education were clearly associated with a reduced risk of Alzheimer’s disease. A possible explanation for this link is ‘cognitive reserve’, which refers to the ability to recruit and use alternative brain networks or structures not normally used to compensate for brain ageing. Previous research has shown that high education increases this reserve.

We found suggestive evidence for possible associations of intelligence, circulating vitamin D, coffee consumption, and smoking with risk of Alzheimer’s disease. There was no evidence for a causal link with other modifiable factors, such as vascular risk factors.

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Snowball Obesity Genes Lead To Constant Weight Gain Throughout Life

MedicalResearch.com Interview with:

David Meyre PhD Associate Professor, McMaster University, Dept. of Health Research Methods, Evidence, and Impact Hamilton, Ontario Canada Visiting Professor, University of Lorraine, Inserm Nutrition-Genetics-Environmental Risks

Dr. Meyre

David Meyre PhD
Associate Professor, McMaster University,
Dept. of Health Research Methods, Evidence, and Impact
Hamilton, Ontario Canada
Visiting Professor, University of Lorraine,
Inserm Nutrition-Genetics-Environmental Risks

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: While the average body mass index has reached a plateau in Western countries such as the United States, extreme forms of obesity are still on the rise. The origins of super obesity are still poorly understood. We studied the effects of 37 well-established obesity genes on body-mass index in 75,230 adults with European ancestry using innovative statistical methods (conditional quantile regression and meta-regression models).

We found that nine of the 37 genes (24%) make individuals gain more weight if they already have a high body mass index. The effect of these genes is amplified by four times, if we compare the 10% of the population at the low end of the body mass index, compared to the 10% at the high end. The plausible explanation is that there are interactions between these snowball obesity genes and risk environmental factors.
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Why Isn’t Your Diet Working? It’s In Your Genes

MedicalResearch.com Interview with:
“Scale model” by brett jordan is licensed under CC BY 2.0
William Barrington, PhD lead author on the study
Recently graduated PhD student from the Threadgill lab
David Threadgill, PhD
Texas A&M College of Medicine and
College of Veterinary Medicine & Biomedical Sciences, senior author

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Obesity and diet-induced diseases, such as cardiovascular disease, have reached epidemic proportions. The United States has offered universal dietary recommendations for decades, but they have been largely unsuccessful in reducing diet-induced diseases. These recommendations are largely built upon population-level data, which examines a large number of individuals and determines the average response to a dietary intervention. However, if there is large variation in responses within a population, then population-level data may be inadequate to improve health across genetically diverse individuals.

Our study used four genetically diverse types of mice to examine how one’s genetics interact with diet to influence obesity and risk factors for cardiometabolic disease. The study compared four popular human diets (American, Mediterranean, Japanese, and Maasai/ketogenic). While all mice suffered detrimental effects from the American diet, the severity of disease varied widely across the types of mice. In comparison, no single diet improved health across all strains, but there was one or more diets that improved health in each strain.

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Natural Selection For Skin Color Varies With Latitude

MedicalReseaerch.com Interview with:

These are South African individuals in a household that exemplify the substantial skin pigmentation variability in the Khomani and Nama populations. Picture taken with consent for publication.

These are South African individuals in a household that exemplify the substantial skin pigmentation variability in the Khomani and Nama populations. Picture taken with consent for publication.
Image by Brenna Henn

Alicia R. Martin PhD, Postdoc
Department of Genetics
Stanford University
Department of Medicine, Massachusetts General Hospital and Harvard Medical School
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA and

Brenna M. Henn, Phd, Assistant Professor
Department of Ecology and Evolution
SUNY Stony Brook, NY 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Skin pigmentation varies more in Africa than in any other continent, and yet genetic studies of this and other traits are massively underrepresented there. Previous Eurasian study biases have instead focused on populations that vary less and have fewer variants contributing to baseline skin color.

In our study, we compiled quantitative skin color measurements from a large, globally diverse set of individuals and populations to show that pigmentation varies more closer to the equator than in high latitude populations. We focused on the ‡Khomani San and Nama populations from South Africa, which diverged early along the modern human lineage from other populations and have lighter skin than equatorial Africans. We showed that skin pigmentation is roughly 100% heritable, but that previously identified genes make up a tiny fraction (~10%) of the variation present in these populations. We identified both known and new genes contributing to this variability.

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LPA Gene Variant May Help Identify Increased Risk of Aortic Stenosis 

MedicalResearch.com Interview with:

Aortic Stenosis Blaus Image Wikipedia

Aortic Stenosis Blaus Image Wikipedia

Hao Yu Chen, MSc
Department of Medicine
McGill University
Montreal, Quebec, Canada
Senior author: George Thanassoulis, MD, MSc

MedicalResearch.com: What is the background for this study?

Response: Aortic stenosis, a narrowing of the main valve of the heart, is the most common type of valve disease in the US. Present in more than 2.5 million individuals in North America, aortic stenosis can lead to heart failure and death. However, there is little known about the causes of aortic stenosis and how it should be treated.

Previously, we have demonstrated that variants of the gene LPA are associated with the development of aortic stenosis. A better understanding of how this region contributes to aortic stenosis could identify higher-risk individuals and inform the development of new medical therapies for aortic stenosis.  Continue reading

Mechanism Identified Linking ASD and Intellectual Disability, Opening Door To Development of Treatment Options

MedicalResearch.com Interview with:

Woo-Yang Kim, Ph.D Associate Professor Department of Developmental Neuroscience  Munroe-Meyer Institute University of Nebraska Medical Center Omaha, NE 68198-5960

Dr-Woo-Yang Kim

Woo-Yang Kim, Ph.D
Associate Professor
Department of Developmental Neuroscience
Munroe-Meyer Institute
University of Nebraska Medical Center
Omaha, NE 68198-5960

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  Autism impairs the ability of individuals to communicate and interact with others. About 75 percent of individuals with autism also have intellectual disability, which is characterized by significant limitations in cognitive functions and adaptive behaviors. While autism and intellectual disability are currently defined using behavioral criteria, little is known about the neuropathogenesis of these conditions.

Recent genetic studies have reported that haploinsufficiency of ARID1B causes autism and intellectual disability. However, the neurobiological function of ARID1B during brain development is unknown.

Our study investigated the neurobiological role of the gene in brain development. Using genetically-modified mice, we found that Arid1b haploinsufficiency leads to an excitation-inhibition imbalance by reducing the number of GABAergic interneurons in the cerebral cortex. Furthermore, we showed that treatment with a GABAA-receptor positive allosteric modulator rescues ASD-like behavior and cognitive dysfunction in Arid1b-haploinsufficient mice, suggesting an association between lower numbers of GABAergic interneurons and behavioral outcomes.

Our findings suggest a pathogenic mechanism for Autism Spectrum Disorder and intellectual disability.

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Failure of Dental Fillings Is At Least Partially Genetically Determined

MedicalResearch.com Interview with:
“Dental Mold_002” by Ano Lobb is licensed under CC BY 2.0
Alexandre R. Vieira, DDS. MS, PhD
Professor, Director of Clinical Research,  Director of Student Research
Department of Oral Biology
Center for Craniofacial and Dental Genetics
Department of Pediatric Dentistry
School of Dental Medicine
Department of Human Genetics
Graduate School of Public Health
Clinical and Translational Sciences Institute
University of Pittsburgh 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: One aspect is the dilemma between continuing to use dental amalgams and the perception that composite resins are not as durable.

We show that composite resin restorations can perform similarly to dental amalgams for the first 5 years. But the most remarkable is that composite resin failures may be related to certain individual risk factors, such as genetic variation.

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Multispecies Study Identifies Critical Genes in OCD Neurobiology

MedicalResearch.com Interview with:

Hyun Ji Noh PhD Postdoc in the Genome Sequencing and Analysis Program Broad Institute of MIT and Harvard

Dr. Hyun Ji Noh

Hyun Ji Noh PhD
Computational Scientist, Medical and Population Genetics
Broad Institute of MIT and Harvard

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder, characterized by intrusive thoughts and repetitive behaviors. OCD is estimated to affect roughly 80 million people worldwide, but its neurobiology remains poorly understood. To understand the disorder’s underpinnings, we searched for genetic mutations that are associated with OCD.

For this, we first identified 608 genes that were most likely to be important  in OCD – some that have previously been identified in OCD-like behaviors in dogs and mice, and others in human autism, which also involves repetitive behaviors. We compared these genes in 592 people with OCD and 560 people without OCD, and found that 4 of these genes were significantly different between people with and without OCD: NRXN1, HTR2A, CTTNBP2 and REEP3. All of these four genes have important functions in the brain. Specifically, we found that the variants in NRXN1 are likely to change its ability to bind other synaptic proteins. Synaptic proteins link neurons together, and are critical for transmitting signals through the brain. We also found that the variants in CTTNBP2 and REEP3 don’t actually change the proteins made by these genes, but instead probably affect gene regulation (for example, how much of the protein is made). These ‘regulatory’ variants disrupt the binding of transcription factors (proteins that regulate expression of genes in the body) near the gene.

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Complexity of Animals Depends On Diverse Patterns of Gene Regulation

MedicalResearch.com Interview with:
Colin Sharpe

School of Biology
Institute of Biomolecular and Biomedical Science
School of Biological Sciences
University of Portsmouth
Portsmouth, United Kingdom 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We have long been fascinated by the question of what underpins the increasing complexity of multicellular animals. In a recent publication we looked at changes to the diversity of the NCoR family corepressors (NCoRs) across the Deuterostomes and found an increase in diversity from sea urchins to humans (1). This is due to gene duplication, an increase in alternative splicing and the encorporation of more protein motifs and domains.

In this study we devised a measure of functional diversity based on these three factors and calculated this value for over 12000 genes involved in transcription in nine species from the nematode worm to humans. Orthologues whose increase in diversity correlated with the increase in complexity of these animals were then selected and we looked for common features and interactions between the selected genes.

We found that proteins that regulate the dynamic organisation of chromatin were significantly enriched within the selection.

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Despite Evolution, Genetic Diseases Persist

MedicalResearch.com Interview with:

Carlos Eduardo G. Amorim PhD Columbia University Department of Systems Biology Irving Cancer Research Center

Dr. Amorim

Carlos Eduardo G. Amorim PhD
Columbia University Department of Systems Biology
Irving Cancer Research Center 

MedicalResearch.com: What is the background for this study?

Response: More generally, we were interested in understanding the determinants of the frequencies of mutations that cause disease in humans.

More specially, we wanted to test if a long-standing theory in population genetics (namely mutation-selection balance) was a good explanation for the observed frequencies of disease mutations in humans.

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Autism Spectrum Disorder Found To Be Highly Heritable

MedicalResearch.com Interview with:

Sven Sandin, PhD Assistant Professor Department of Psychiatry Icahn School of Medicine at Mount Sinai New York, NY 10029

D. Sandin

Sven Sandin, PhD Assistant Professor
Department of Psychiatry
Icahn School of Medicine at Mount Sinai
New York, NY 10029 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In 2014, we estimated the heritability of autism to be approximately 50%. Motivating us then was the lack of studies in autism heritability using population based and the findings from a twin-study in California finding the heritability to be substantially lower than the 80-90% estimated in previous studies. Since then continued efforts working with the questions on heritability and environmental factors for autism we found differences between different methods and different samples. When we went back to our previous data we found the heritability of autism to be higher than previously estimated. We found that our previous result was due to a methodological artifact where the adjustment for differences in follow-up used in that manuscript underestimated the heritability. Using methods used in other heritability studies the heritability is now estimated to 84%. Importantly, as previously concluded, there is no support for any ‘shared environmental factors’ in the etiology of autism, e.g. environmental factors shared between two siblings.

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Prostate Cancer: Immune Content May Predict Response To Post-Op Radiation

MedicalResearch.com Interview with:

Dr. Shuang George Zhao, MD House Officer, Radiation Oncology University Hospital Ann Arbor, MI 48109-5010

Dr. Zhao

Dr. Shuang George Zhao, MD
House Officer, Radiation Oncology
University Hospital
Ann Arbor, MI 48109

MedicalResearch.com: What is the background for this study?

Response: Targeting cancer through the immune system has been a longstanding goal of cancer research, and with recent advances in immunotherapy, it is now a reality. However, the role of immunotherapy in prostate cancer is still being defined. Sipuleucel-T was the first FDA approved immunotherapy in prostate cancer, and is a personalized cellular therapy that has been shown to prolong survival in patients with metastatic prostate cancer. On the other hand, two recent phase III randomized trials looking at ipilimumab, a CTLA-4 checkpoint inhibitor in metastatic prostate cancer have both been negative for their primary endpoint of OS. Interestingly, there was a PSA response, suggesting that there may be some therapeutic effect in a subset of patients. Therefore, understanding the immune infiltrate is likely critical to selecting patients and therapeutic strategies utilizing the immune system. Unfortunately, it is difficult and laborious to histologically assess immune infiltrate directly. Therefore, we used existing high throughput transcriptomic data with new computational methods in order to more fully characterize the immune landscape of localized prostate cancer.

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Study Opens Door To Reducing Melanoma Risk in Redheads

MedicalResearch.com Interview with:

Rutao Cui, MD/PhD Professor  Vice Chair for Laboratory Administration  Director, Laboratory of Melanoma Biology Department of Pharmacology and Experimental Therapeutics Professor of Dermatology Boston University Boston, Mass 02118

Dr. Cui

Rutao Cui, MD/PhD
Professor
Vice Chair for Laboratory Administration
Director, Laboratory of Melanoma Biology
Department of Pharmacology and Experimental Therapeutics
Professor of Dermatology
Boston University
Boston, Mass 02118


MedicalResearch.com: What is the background for this study?

Response: Red-headed people are making up to 1~2% of the world’s population. They carry “red hair color” variants of MC1R (MC1R-RHC) which are responsible for their characteristic features, including red hair, pale skin, freckles and poor tanning ability.

MC1R-RHC also increases risk of melanoma, the deadliest form of skin cancer. People without red hair but with a single copy of MC1R-RHC also have an increased melanoma risk, who may make more than 50% of the northern European population. It is unknown why redheads are more prone to melanoma, and whether the activity of red hair color variants could be restored for therapeutic benefits.

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Genetic Variants Demonstrate Humans Continue To Evolve Through Natural Selection

MedicalResearch.com Interview with:

Hakhamanesh Mostafavi, MS PhD student Department of Chemical Engineering Columbia University

Mostafavi Hakhamanesh

Hakhamanesh Mostafavi, MS
PhD student
Department of Biological Sciences
Columbia University 

MedicalResearch.com: What is the background for this study?

Response: We know very little about the genetic variants that underlie adaptation in humans. This is in part because we have mostly been limited to methods that search for footprints of ancient selection (that has acted for over thousands to millions of years) in the genomes of present-day humans; so by design are indirect and make strong assumptions about the nature of selection.

These days, thanks to advances in genomic technologies, genetic data for large numbers of people is being collected, mostly for biomedical purposes. Accompanied by information on survival and reproductive success of these individuals, such large datasets provide unprecedented opportunities for more direct ways to study adaptation in humans.

In this work, we introduced an approach to directly observe natural selection ongoing in humans. The approach consists in searching for mutations that change in frequency with the age of the individuals that carry them, and so are associated with survival. We applied it to around 210,000 individuals from two large US and UK datasets.

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Gene Helps Explain Why More Women Than Men Have Alzheimer’s

MedicalResearch.com Interview with:

Arthur W. Toga PhD Provost Professor of Ophthalmology, Neurology, Psychiatry and The Behavioral Sciences, Radiology and Engineering Ghada Irani Chair in Neuroscience Director, USC Mark and Mary Stevens Neuroimaging and informatics institute USC Institute for Neuroimaging and Informatics Keck School of Medicine of USC University of Southern California Los Angeles, CA  90032

Dr. Toga

Arthur W. Toga PhD
Provost Professor of Ophthalmology, Neurology, Psychiatry and The Behavioral Sciences,
Radiology and Engineering
Ghada Irani Chair in Neuroscience
Director, USC Mark and Mary Stevens Neuroimaging and informatics institute
USC Institute for Neuroimaging and Informatics
Keck School of Medicine of USC
University of Southern California
Los Angeles, CA  90032 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The ε4 allele of the Apolipoprotein E (APOE) gene is the main genetic risk factor for late-onset Alzheimer’s disease.  This study reexamines and corrects the sex-dependent risks that white men and women with one copy of the ε4 allele face for developing Alzheimer’s disease using a very large data set of 57,979 North Americans and Europeans from the Global Alzheimer’s Association Interactive Network (GAAIN).

The study results show that these men and women between the ages of 55 and 85 have the same odds of developing Alzheimer’s disease, with the exception that women face significantly higher risks than men between the ages of 65 and 75.  Further, these women showed increased risk over men between the ages of 55 and 70 for mild cognitive impairment (MCI), which is often a transitional phase to dementia.

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Familial Hypercholesterolemia: “Junk” RNA May Facilitate Gene Therapy

MedicalResearch.com Interview with:

Tamer Sallam, MD PhD Assistant Professor of Medicine Co-Director UCLA Center for Lipid Management Lauren B. Leichtman and Arthur E. Levine CDF Investigator Assistant Director, STAR Program Division of Cardiology, Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California 90095-1679 

Dr. Sallam

Tamer Sallam, MD PhD
Assistant Professor of Medicine
Co-Director UCLA Center for Lipid Management
Lauren B. Leichtman and Arthur E. Levine CDF Investigator
Assistant Director, STAR Program
Division of Cardiology, Department of Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California 90095-1679

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study is extension of our previous work published in Nature showing that a gene we named LeXis (Liver expressed LXR induced sequence) plays an important role in controlling cholesterol levels. What is unique about  LeXis is that it belongs to a group of newly recognized mediators known as long noncoding RNAs. These fascinating factors were largely thought to be unimportant and in fact referred to as “junk DNA” prior the human genome project but multiple lines of evidence suggest that they can be critical players in health and in disease.

In this study we tested whether we can use  LeXis “gene therapy”  to lower cholesterol and  heart disease risk. This type of approach is currently approved or in testing for about 80 human diseases.

Our finding was that a single injection of LeXis compared with control significantly  reduced heart disease burden in mouse subjects. Although the effect size was moderate we specifically used a model that mimics a very challenging to treat human condition known as familial hypercholesterolemia..Familial hypercholesterolemia is one of the most common genetic disorders affecting up to 2 million Americans and characterized by 20 fold  fold increase risk of early heart attacks and often suboptimal response to currently available treatments.

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DNA Analysis Identifies Subtype of Pancreatic Cancer With Good Prognosis

MedicalResearch.com Interview with:

Nancy You, MD, MHSc, FACS Department of Surgical Oncology The University of Texas MD Anderson Cancer Center Houston

Dr. You

Nancy You, MD, MHSc, FACS
Department of Surgical Oncology
The University of Texas MD Anderson Cancer Center
Houston 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This study was motivated by the emerging promise of precision medicine and the emerging evidence that immunotherapy may have phenomenal efficacy in particular molecular subtypes of cancers.  This specific molecular subtype shows deficiency in DNA mismatch repair mechanisms and therefore is thought to be more immunogenic.  DNA mismatch repair deficiency can arise from germline defects such as in the case of patients with Lynch Syndrome, an inherited cancer syndrome, or from epigenetic inactivation DNA mismatch repair genes.

Overall, pancreas cancer has seen limited success with conventional chemotherapy.  In our study, we demonstrated that there is a particular molecular subtype of pancreas cancer that is characterized by defect in DNA mismatch repair genes and by microsatelie instability that has a different prognosis than other pancreas cancers.  This subtype of pancreas cancer is suspected to also respond to immunotherapy.

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16 New Genetic Links To Longevity Discovered

MedicalResearch.com Interview with:

Dr. Zoltán Kutalik, PhD Group Leader Swiss Institute of Bioinformatics

Dr. Kutalik

Dr. Zoltán Kutalik, PhD
Group Leader
Swiss Institute of Bioinformatics
Assistant professor at the Institute of Social and Preventive Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Why do some of us live longer than others? While the environment in which we live – including our socio-economic status or the food we eat – plays the biggest part, about 20 to 30% of the variation in human lifespan comes down to our genome. Changes in particular locations in our DNA sequence, such as single-nucleotide polymorphisms (SNPs), could therefore hold some of the keys to our longevity. Until now, the most comprehensive studies had found only two hits in the genome.

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Study Finds Link Between Genetic Variant, Opioid Addiction and Binge Eating

MedicalResearch.com Interview with:

Camron D. Bryant Ph.D Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry Boston University, Boston, MA

Dr. Bryant

Camron D. Bryant Ph.D
Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry
Boston University, Boston, MA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We previously used genome-wide linkage analysis, fine mapping, gene validation, and pharmacological targeting to identify a negative regulatory role for the gene casein kinase 1-epsilon (Csnk1e) in behavioral sensitivity to drugs of abuse, including psychostimulants and opioids.

Parallel human candidate genetic association studies identified an association between multiple genetic variants in CSNK1E with heroin addiction in multiple populations. Drug addiction is a multi-stage process that begins with the initial acute subjective and physiological responses that can progress to chronic administration, tolerance, and withdrawal. The recovery process begins with abstinence from drug taking but can quickly be derailed by relapse to drug taking behavior. Preclinical pharmacological studies also support a role for CSNK1E in reinstatement of opioid self-administration and relapse to alcohol drinking.

Despite the evidence that disruption of Csnk1e gene and protein function can affect various behaviors associated with drug and alcohol addiction, it is unclear what stage of the addiction process these genetic and pharmacological manipulations modulate. In this study, we show that disruption of the Csnk1e gene resulted in an enhancement of the rewarding properties of the highly potent and addictive opioid, fentanyl.  Unexpectedly, we also discovered that disruption of Csnk1e also enhanced binge eating – but only in female mice.

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Gene Linked To Decreased Plasma Amyloid and Lower Alzheimer’s Disease Risk

MedicalResearch.com Interview with:

Mikko Hiltunen, PhD Professor of Tissue and Cell Biology University of Eastern Finland School of Medicine, Institute of Biomedicine Kuopio,  Finland

Dr. Hiltunen

Mikko Hiltunen, PhD
Professor of Tissue and Cell Biology
University of Eastern Finland
School of Medicine, Institute of Biomedicine
Kuopio,  Finland 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  We wanted to assess among the population-based METSIM (METabolic Syndrome In Men) cohort whether protective variant in APP gene (APP A673T) affects the beta-amyloid levels in plasma. The rationale behind this was that previous genetic studies have discovered that the APP A673T variant decreases the risk of having Alzheimer’s disease (AD).

However, the protective functional outcome measures related to this variant were lacking and thus we anticipated that the elucidation of plasma samples in terms of beta-amyloid levels would provide the much needed link between APP A673T variant and potential protective functions.

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Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

MedicalResearch.com Interview with:

Antonis Antoniou PhD Reader in Cancer Risk Prediction Academic Course Director MPhil in Epidemiology Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care Strangeways Research Laboratory Cambridge University of Cambridge

Dr. Antoniou

Antonis Antoniou PhD
Reader in Cancer Risk Prediction
Academic Course Director MPhil in Epidemiology
Centre for Cancer Genetic Epidemiology
Department of Public Health and Primary Care
Strangeways Research Laboratory Cambridge
University of Cambridge

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Several studies demonstrated that women with genetic faults in the BRCA1 and BRCA2 genes are at increased risk of developing breast and ovarian cancer. Having accurate age-specific cancer risk estimates for women with mutations is essential for their optimal clinical management.

Most studies to date that estimated cancer risks for BRCA1 and BRCA2 mutation carriers have been “retrospective”, in other words they look at what happened in the past. Estimates from such studies are prone to biases because they rely on the experience of women who have already developed cancer and on self-reported cancer family history information on relatives – which may have inaccuracies.

The ideal epidemiological study design for estimating cancer risks are prospective studies.  In prospective studies, healthy women with genetic faults are followed over time and overcome these potential biases. However, to date, published  prospective studies have been very small.

In the present study we used data from a prospective cohort of women with BRCA1 and BRCA2 mutations who were recruited from 1997 to 2011 and were followed over time. The study included almost 10,000 women who were included in the analyses, and was made possible through collaborations between scientists from Europe, North America and Australia.  The prospective study design explains why it has taken 20 years of hard work to get these results. Most importantly, it took an enormous long-term contribution and commitment from the women themselves to allow the scientists to be able to assemble this dataset.

Here, we were able to estimate more precisely the breast and ovarian cancer risks for women with faults in BRCA1 and BRCA2.  These risk estimates will provide more confidence in the counseling and clinical management of women with faults in the BRCA1 and BRCA2  genes.

A novel finding in this study is that breast cancer risk for women with faults in BRCA1 and BRCA2  increases rapidly at a young age then remains at a constant high level for the rest of their lives. It peaks in the 40’s for BRCA1 mutation carriers and in the 50’s for BRCA2 carriers, but  carriers of mutations in both genes  are at about the same high risk in later life. This is important information to inform the clinical management of older mutation carriers.

This study also shows clearly that for women with a mutation, there are other factors that are important in modifying the breast cancer risk. The study has demonstrated that the extent of the woman’ family history of cancer and the exact place on the gene where her mutation is located are very important in determining the actual risk.

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Rapid Improvements Coming to Gene Editing Techniques

MedicalResearch.com Interview with:

Michael Farzan PhD Co-chair and Professor Department of Immunology and Microbiology  Florida Campus  The Scripps Research Institute Jupiter, Florida

Dr. Farzan

Michael Farzan PhD
Co-chair and Professor
Department of Immunology and Microbiology
Florida Campus
The Scripps Research Institute
Jupiter, Florida

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: CRISPR is system for immune protection of bacteria.  It has now been widely adopted for use in editing mammalian cells.  The most commonly used CRISPR effector protein is Cas9.  Cas9 binds a guide RNA to recognize a DNA target, for example an incoming virus infecting a bacterium, or a gene in a human chromosome.  In bacteria, Cas9 requires a second protein to clear the guide RNA from a longer “CRISPR array”, basically a string of guide RNAs.

We have been studying a CRISPR effector protein related to Cas9 called Cpf1.  In bacteria it was know that, unlike Cas9, Cpf1 could cleave a CRISPR array by itself, without assistance from a second protein.  We knew that if it could do the same thing in human cells, it would help to simplify a number of gene-editing applications.  We were able to show that Cas9 could indeed excise multiple guide RNAs from a single message RNA in human cells.  We further showed that this approach was more efficient than the previous ways that guide RNAs were generated for gene editing, even more so when multiple guide RNAs were needed.

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Mind–Body Interventions Reduce Inflammatory Activity of Genes

MedicalResearch.com Interview with:

Ivana Buric Brain, Belief, and Behaviour Lab Centre for Psychology, Behaviour, and Achievement, Faculty of Health and Life Sciences Coventry University, Coventry, United Kingdom Donders Institute for Brain, Cognition and Behaviour Radboud University, Nijmegen, Netherlands

Ivana Buric

Ivana Buric
Brain, Belief, and Behaviour Lab
Centre for Psychology, Behaviour, and Achievement, Faculty of Health and Life Sciences
Coventry University, Coventry, United Kingdom
Donders Institute for Brain, Cognition and Behaviour
Radboud University, Nijmegen, Netherlands

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  Genes that we inherited can change their activity – the​y can be active and produce proteins, but they can also stop producing proteins and remain silent. We are now beginning to understand what aspects of our environment affect the activity of which genes.

In this study, we analysed all the existing studies that examined the effects of mind-body interventions on the expression of our genes and found that mind-body techniques reduce the activity of genes that produce inflammatory proteins.

This pattern was found in all studies despite the fact that they vary in the amount of physical activity: Tai Chi, yoga, breathing techniques and different types of meditation. We believe that this effect is observed due to reduced stress.

When we experience something stressful, the brain regions associated with pain get activated and send that signal further to sypmathetic nervous system that produces epinephrine and norepinefrine, and activates nuclear factor kappa B – a molecule that travels to and activated the genes that produce inflammatory proteins. When we do yoga or meditation, we learn to perceive situations differently and consequently experience less stress, which then prevents the production of inflammatory proteins.

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Genetic Cause of Cushing’s Disease Detected

MedicalResearch.com Interview with:

Constantine A. Stratakis, MD, DMSci Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Bethesda

Dr. Stratakis

Constantine A. Stratakis, MD, DMSci
Section on Endocrinology and Genetics
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health, Bethesda 

MedicalResearch.com: What is the background for this study?

Response: The pituitary and adrenal glands operate on a kind of feedback loop.  In response to stress, the pituitary release ACTH (Adrenocorticotropic hormone), which signals the adrenal glands to release cortisol.  Rising cortisol levels then act on the pituitary, to shut down ACTH production. In a previous study, Jacque Drouin of the Institute for Clinical Research in Montreal and colleagues had determined that the CABLES1 protein was a key player in this feedback mechanism, switching off pituitary cell division in cultures exposed to cortisol. Since this feedback mechanism appears to be impaired in many corticotropinomas, we investigated the presence of Cables1 gene mutations and copy number variations in a large group of patients with Cushing’s disease.

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Which Diet Is Best For You? It Depends On Your Genes

MedicalResearch.com Interview with:

Kaixiong (Calvin) Ye, PhD Post-doctoral Associate Dept. of Biological Statistics & Computational Biology Cornell University thaca, NY

Dr. Kaixong Ye

Kaixiong (Calvin) Ye, PhD
Post-doctoral Associate
Dept. of Biological Statistics & Computational Biology
Cornell University
thaca, NY

MedicalResearch.com: What is the background for this study?

Response: Omega-6 and omega-3 fatty acids are critical for human brain development, cognitive function, immune response, and cardiovascular health. Physiologically active forms of omega-6 and omega-3 fatty acids, such as AA, EPA, and DHA, are readily available in meat and seafood, but are absent in most plant-based foods (e.g. fruits and vegetables). Instead, plant-based foods contain two precursor fatty acids, LA and ALA, which could be metabolized in our body and converted into physiologically active forms. Fatty acid desaturase (FADS) genes encode key enzymes for this biosynthesis.

We hypothesized that genetic variations in FADS genes that enhance the biosynthesis efficiency were adaptive to plant-based diets in traditional farming populations and thus became more frequent over time. Our study compiled a huge data set of genetic information (DNA) from both present-day and ancient individuals. For the first time, we examined the action of natural selection on humans for the past 30,000 years in Europe.

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Epigenetic Changes Identified In Children Who Develop Early Onset Conduct Problems

MedicalResearch.com Interview with:
Charlotte Cecil, PhD

ESRC FRL Fellow
Edward Barker, PhD
Lab Director, DEVELOPMENTAL PSYCHOPATHOLOGY LAB

Department of Psychology
Institute of Psychiatry, Psychology& Neuroscience
King’s College London

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Conduct problems (CP) are the most common reason for child treatment referral in the UK, costing an estimated £22 billion per year. Children with CP engage in a range of aggressive and antisocial behaviours (e.g. fighting, stealing, lying), that affect their ability to follow rules and adapt to society, do well in school, and form healthy relationships. Those who do not receive treatment are also at increased risk for many negative outcomes in adulthood, including lower job prospects and earnings, more contact with the police and a lower quality of life. Therefore, it is important to understand how CP develop in the first place, in order to create more effective prevention and intervention strategies.

Studies have found that children who develop conduct problems before the age of 10 (early-onset CP) are at greatest risk for poor outcomes across the lifespan. Compared to other children, those showing early-onset CP tend to have experienced more adversity in early life (e.g. prenatal stress, poverty) as well as having more genetic risk. However, little is known about about how genetic factors interact with environmental influences – especially during foetal development – to increase the risk for early-onset conduct problems.

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Genetic Cause and Clinical Cure Found For Rare Skin Disorder

MedicalResearch.com Interview with:

Keith Adam Choate, MD, PhD, FAAD Associate Professor of Dermatology, of Genetics and of Pathology Director of Research, Dermatology Yale University School of Medicine New Haven, CT

Dr Choate

Keith Adam Choate, MD, PhD, FAAD
Associate Professor of Dermatology,
Genetics and Pathology
Director of Research, Dermatology
Yale University School of Medicine
New Haven, CT

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  Over the last 10 years, we have systematically been examining patients with ichthyosis to identify new genetic causes of this group of disorders.  We found that autosomal recessive mutations in KDSR cause ichthyosis and that the resulting skin disease is effectively treated with isotretinoin.

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Familial History Improves Predictive Value of TOMM40 Gene in Alzheimer’s Disease

MedicalResearch.com Interview with:

Auriel Willette, M.S., Ph.D. Assistant Professor Departments of Food Science and Human Nutrition and Psychology Iowa State University

Dr. Willette

Auriel Willette, M.S., Ph.D.
Assistant Professor
Departments of Food Science and Human Nutrition and Psychology
Iowa State University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Translocase of Outer Mitochondrial Membrane 40 (TOMM40) is a gene that regulates the width of the outer mitochondrial pore, facilitating the transport of ribosomal pre-proteins into the inner mitochondrial matrix for translational modification into functional proteins. In 2010, Dr. Allen Roses, who discovered the Apolipoprotein E (APOE) gene, Dr. Michael Lutz, and other colleagues found that a variation in poly-T length at locus rs10524523 (‘523) within intron 6 predicted Alzheimer’s disease onset. Specifically, a “long” versus “short” poly-T length was related to earlier age of onset by 8 years.

However, several multi-cohort studies either failed to replicate the findings or found the opposite relationship, where a “long” or “very long” poly-T length was related to later age of onset. The literature has remained mixed to this day.

We were interested in testing factors that might change the relationship between TOMM40 and both cognitive decline and risk for having Alzheimer’s disease. It is known that a family history (FH) of Alzheimer’s disease has been associated with mitochondrial dysfunction. We reasoned, then, that FH may interact with TOMM40 to modulate how it was related to our outcomes of interest. We investigated this hypothesis in two separate cohorts: the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a late middle-aged cohort, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a well-characterized sample of aged participants from across the Alzheimer’s spectrum.

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TeloView Measures Genomic Stability To Predict Disease Aggressiveness

MedicalResearch.com Interview with:

3D SignaturesJason Flowerday, CEO
Director of 3D Signatures 

MedicalResearch.com: What is the background for 3D Signatures?

Response: 3D Signatures, and its clinical lab tests, which incorporate its proprietary TeloViewTM software analytics, is the culmination of over 20 years of ground-breaking research conducted by Dr. Sabine Mai and her colleagues. It is the only technology in the world that quantifies genomic instability, which is the hallmark of cancer and other proliferative diseases at the whole-cell level.

By measuring the degree of genomic instability from different tissues, TeloViewTM has produced clinically actionable distinctions in the stage of disease, rate of progression of disease, drug efficacy, and drug toxicity. The technology is well developed and supported by 22 clinical studies on over 2,000 patients on 13 different cancers including Alzheimer’s disease. The results have been exceptional and represent a universal biomarker platform across all disease areas that the company has investigated to date.

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Gene Delivered By Nanoparticle System Can Potentially Cure Congenital Blindness

MedicalResearch.com Interview with:
Zheng-Rong Lu, Ph.D.

M. Frank Rudy and Margaret Domiter Rudy Professor of Biomedical Engineering
Department of Biomedical Engineering
Case Western Reserve University
Cleveland, OH 44106

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Genetic vision disorders are a major cause of severe vision loss and blindness, especially in children and young adults. Currently, there are no approved therapies to treat these types of disorders.

This study focused on one such disease known as Leber’s congenital amaurosis type 2 (LCA2). Patients with LCA2 are born with some degree of vision loss, and are often legally blind by early adulthood. LCA2 is a recessive disease caused by a mutation in one of the genes responsible for visual processing. LCA2 is a good candidate for gene therapy, and clinical trials underway to test viral vectors that deliver a healthy copy of the mutated gene into the eye have demonstrated considerable therapeutic efficacy. These trials have validated the feasibility of gene therapy to treat this disease, however viral vectors are limited by potential safety issues, complex preparation methods, and limitations on the size of genes that can be delivered.

In this study, we successfully treated LCA2 in mice for 120 days by delivering the gene responsible for LCA2 in a synthetic lipid nanoparticle instead of a viral vector. Our delivery system, called ECO, specifically targets the cells in the retinal pigmented epithelium, where the mutation behind LCA2 occurs. Our nanoparticle delivery system is easy to produce, safe, and has unlimited cargo capacity. Most important, our nanoparticle gene delivery system is a platform that can be used to deliver any gene into the retina, opening the door for safe and effective gene therapy for any genetic vision disorder.

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Do Our Genes Influence Our Attraction to Social Media?

MedicalResearch.com Interview with:

Chance York, Ph.D. Assistant Professor of Mass Communication Kent State University

Dr. Chance York

Chance York, Ph.D.
Assistant Professor of Mass Communication
Kent State University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This research used twin study survey data from the Midlife in the United States (MIDUS) to investigate the relative influence of genetics and environment on social media use.

While the research cannot directly examine the gene-level influence on social media behavior, I was able to leverage known levels of genetic relatedness between identical and fraternal twins to suss out how much genetic traits and environmental factors impact frequency of using social media.

The results showed that between one- and two-thirds of variance in social media use is explained by genes, while environmental factors (parental socialization, peers, work, school, individual characteristics, etc.) explained the rest. In other words, this very specific communication behavior—social media use—is partially guided by our genetic makeup.

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GeneStrat Test Provides Quick Analysis of Genetic Lung Cancer Mutations

MedicalResearch.com Interview with:
Hestia Mellert, PhD

Director, Molecular Product Development
Biodesix: Making Medicine Personal
Boulder, CO

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Identifying specific genetic mutations in non-small cell lung cancer patients helps clinicians choose the best treatment options; specific therapies that target mutations can improve patient outcomes, including reducing the risk of death or lessening the severity of the disease. However, nearly 80% of cancer patients do not have genetic mutation results available at initial oncology consultation; up to 25% of patients begin treatment before receiving their results. These factors hinder physicians’ ability to pursue optimal treatment strategies.

This study found that a blood-based assay, the GeneStrat test, provides results in 72 hours for 94% of patients, which expands testing options, and supports faster treatment decisions by physicians.

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Proove Opioid Risk Profile Predictive of Opioid Use Disorder

MedicalResearch.com Interview with:

Maneesh Sharma, M.D</strong> Director of Pain Medicine MedStar Good Samaritan Hospital Medical Director of the Interventional Pain Institute Baltimore, Maryland

Dr. Maneesh Sharma

Maneesh Sharma, M.D
Director of Pain Medicine
MedStar Good Samaritan Hospital
Medical Director of the Interventional Pain Institute
Baltimore, Maryland

MedicalResearch.com: What is the background for this study?

Response: Opioid abuse in chronic pain patients is a major public health issue, with rapidly increasing addiction rates and deaths from unintentional overdose more than quadrupling since 1999. Just in the last year alone according to the CDC, synthetic opioid deaths have increased 72%. As a practicing interventional pain specialist, I am confronted with the challenge of assessing patient risk for opioids as I evaluate multi-modal approaches to effective pain management. Existing tools are inadequate, as they either rely on a urine toxicology test to evaluate a patient’s current potential substance abuse as a predictor of future abuse, or on a patient’s honesty to fill out a questionnaire. We know that many patients who are not currently abusing illicit drugs or misusing prescription medications can develop prescription opioid tolerance, dependence, or abuse—especially with prolonged opioid therapy. Furthermore, we know that patients who are looking to abuse medications or divert those prescriptions will obviously lie on questionnaires.
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CRISPR Gene Editing May Lead To Cure For Retinitis Pigmentosa

MedicalResearch.com Interview with:

Kang Zhang, M.D., Ph.D.</strong> Professor of Ophthalmology Chief, Ophthalmic Genetics Founding Director, Institute for Genomic Medicine Co-Director, Biomaterials and Tissue Engineering, Institute for Engineering in Medicine Board Certification in Ophthalmology Fellowship in Vitreoretinal Disease and Surgery Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou China

Dr. Kang Zhang

Kang Zhang, M.D., Ph.D.
Professor of Ophthalmology
Chief, Ophthalmic Genetics
Founding Director, Institute for Genomic Medicine
Co-Director, Biomaterials and Tissue Engineering, Institute for Engineering in Medicine
Board Certification in Ophthalmology
Fellowship in Vitreoretinal Disease and Surgery
Guangzhou Women and Children’s Medical Center
Guangzhou Medical University
Guangzhou China
MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Retinitis pigmentosa is a common blinding condition characterized by mutations in rod photoreceptor specific genes, night blindness and tunnel visual with eventual loss of day vision. Since it can be caused by numerous different mutations in many genes therefore it has been difficult to provide treatment benefits to a majority of patients. Traditional gene therapy has been in a piece-meal fashion, meaning to create a therapy for a particular gene or mutation. In this paper, we describe a universal gene therapy approach using the latest gene editing technology CRISPR/CAS9 to reprogram rod photoreceptors to cone photoreceptors with reversal of RP and restoration of vision.

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Trunk and Branch Drivers Distinguish Early vs Late Mutations in Hepatocellular Carcinoma

MedicalResearch.com Interview with:
Sara Torrecilla Recio

PhD Student
Mount Sinai Liver Cancer Program – Division of Liver Diseases Icahn School of Medicine at Mount Sinai
New York, NY

MedicalResearch.com: What is the background for this study?

Response: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which represents the second-leading cause of cancer related death worldwide. The landscape of molecular alterations in HCC has been thoroughly explored using next-generation sequencing technologies in single biopsies of tumors. However, in the recent years it has been demonstrated that not all the regions of a tumor harbor the same molecular alterations. This intra-tumor heterogeneity may lead to a misinterpretation of the molecular landscape of the malignancy since not all the molecular alterations would be captured by single-biopsies.

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New Breast Cancer Genes May Identify Women Who Can Benefit From Enhanced Screening

MedicalResearch.com Interview with:

Fergus J. Couch, Ph.D. Zbigniew and Anna M. Scheller Professor of Medical Research Chair, Division of Experimental Pathology Department of Laboratory Medicine and Pathology Mayo Clinic Rochester, MN 55905

Dr. Couch

Fergus J. Couch, Ph.D.
Zbigniew and Anna M. Scheller Professor  of Medical Research
Chair, Division of Experimental Pathology
Department of Laboratory Medicine  and Pathology
Mayo Clinic
Rochester, MN

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The main finding is that RAD51D, BARD1, and MSH6 can now be included in the list of moderate risk breast cancer genes. In contrast, other genes such as MRE11A and RAD50 do not increase risk of breast cancer. In addition, we provide initial estimates of the level of breast cancer risk associated with mutations in the genes that cause breast cancer. The “new” breast cancer genes may now be useful for identifying women who can benefit from enhanced screening. These new data will need to be considered by the National Comprehensive Cancer Network (NCCN) which provides guidelines for clinical management of individuals with mutations in cancer predisposition genes. These results will also be useful for identifying members of families who are at increased risk of breast cancer.

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Gene Involved in Defective Skin Barrier and Eczema and Ichthyosis Identified

MedicalResearch.com Interview with:

Akio Kihara, PhD. Laboratory of Biochemistry Faculty of Pharmaceutical Sciences, Hokkaido University Sapporo, Japan

Dr. Akio Kihara

Akio Kihara, PhD.
Laboratory of Biochemistry
Faculty of Pharmaceutical Sciences, Hokkaido University
Sapporo, Japan

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The skin barrier is the most powerful defensive mechanism terrestrial animals possess against pathogens and harmful substances such as allergens and pollutants. Recent studies indicate that lipids play a central role in skin barrier formation. Multi-lamellar structures consisting of lipids are formed extracellularly in the stratum corneum, the outermost layer of epidermis, and their high hydrophobicity prevents the invasion of external pathogens and compounds.

The stratum corneum-specific lipid acylceramide is especially important for skin barrier formation. Decreases in acylceramide levels are associated with cutaneous disorders such as ichthyosis and atopic dermatitis. However, the mechanism behind acylceramide production is poorly understood, especially regarding the last step of acylceramide production: i.e., esterification of ω-hydroxyceramide with linoleic acid. This means that the broader picture of the molecular mechanisms behind skin barrier formation still remained unclear.

Although PNPLA1 has been identified as an ichthyosis-causative gene, its function in skin barrier formation remains unresolved. In the present study, we revealed that PNPLA1 catalyzes the last step of acylceramide synthesis. Our finding completes our knowledge of the entire pathway of the acylceramide production, providing important insights into the molecular mechanisms of skin barrier formation.

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26 Additional Genes Linked to Intellectual Disability Identified

MedicalResearch.com Interview with:
Dr. Muhammad Ayub MBBS, MRCPsych, MSc., MD

Professor of Psychiatry Chair Division of Developmental Disabilities
Department of Psychiatry Queens
University Kingston
Kingston ON Canada

MedicalResearch.com: What is the background for this study? 

Response: Intellectual Disability affects about 1 percent of the population worldwide. Genetics play a major role in its etiology. Better understanding of the genetic causes is a necessary step in development of improved diagnosis and treatment. Recessive inheritance where the affected child inherits a defective copy of a gene from both the parents is an important genetic mechanism for prevalence of the disease in populations where within family marriages are common. These types of marital bonds are common in South Asia and Middle Eastern countries. The families where parents are related are an effective resource to study recessive forms of Intellectual Disability.

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Colorectal Cancer Risk Model Using Environmental and Genetic Factors

MedicalResearch.com Interview with:

Victor Moreno, PhD. Director of Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain Department of Clinical Sciences, Faculty of Medicine University of Barcelona Barcelona, Spain

Dr. Moreno

Victor Moreno, PhD.
Director of Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Spain
Department of Clinical Sciences, Faculty of Medicine
University of Barcelona
Barcelona, Spain

Gemma Ibáñez-Sanz, MD Gastroenterologist. *Cancer Prevention and Control Unit, Catalan Institute of Oncology. L’Hospitalet deLlobregat, Barcelona, SPAIN *Gastroenterology Department, Bellvitge University Hospital-IDIBELL,  L’Hospitalet de Llobregat, Spain

Dr. Ibáñez-Sanz

Gemma Ibáñez-Sanz, MD
Gastroenterologist.
*Cancer Prevention and Control Unit, Catalan Institute of Oncology. L’Hospitalet deLlobregat, Barcelona, SPAIN
*Gastroenterology Department, Bellvitge University Hospital-IDIBELL,
L’Hospitalet de Llobregat, Spain 

MedicalResearch.com: What is the background for this study?

Response: Colorectal cancer (CRC) screening by faecal occult blood testing has been demonstrated to reduce CRC incidence and mortality, as well as being a cost-effective strategy compared to no screening. Currently, the target population is defined basically by age (≥50 years old), which has been called a ‘one-size-fits-all’ strategy. This strategy implies performing unnecessary screening tests in low-risk people leading to avoidable risks for patients and extra costs for the healthcare system. On the other hand, high-risk patients may receive non-invasive testing, which is a suboptimal screening technique in their case. Several risk prediction models, either for  colorectal cancer or advanced neoplasia, have been previously developed, all with limited discriminating ability.

We have developed a risk stratification model that combines environmental factors with family history and genetic susceptibility. Furthermore, we have assessed the relative contribution of these factors and the utility of the model for risk stratification and public health intervention.

MedicalResearch.com: What are the main findings?

Response: Data from common genetic susceptibility loci could be useful to stratify colorectal cancer screening in average-risk population. Individuals in the top quintile of risk alleles have an 82% increased risk compared to those in the lower quintile. We have estimated the impact of determining an individual environmental and genetic risk score in a Spanish CRC screening population. In our model, although the genetic factors are significant contributors, the modifiable risk factors contribute more strongly. Risk assessment may increase screening participation and adoption of healthier lifestyles.

MedicalResearch.com: What should readers take away from your report?

Response: On average, each environmental risk factor increases CRC risk by 35%, while each risk allele only increases it by 7%. This implies that the change of one modifiable risk factor towards healthier lifestyle might offset the effect of 4 risk alleles. Given the fact that environmental factors explain part of the CRC risk, we believe it to be important to give thought to incorporating clinical data to encourage individuals to achieve a healthier lifestyle. As the European Code Against Cancer recommends, and our findings confirm, one should have a healthy diet, a healthy body weight, be physically active and should not smoke or a high consumption of alcohol.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: Future prospective studies should aim to analyse if stratifying by genetic and lifestyle risk scores is useful and cost-effective to improve screening. Subjects with higher predicted risk should probably start screening earlier and decrease the intervals between tests, while low risk individuals could start later or space more the between test intervals.

MedicalResearch.com: Is there anything else you would like to add? 

Response: Population acceptability of genetic tests is not well known. We are currently recruiting subjects from colorectal cancer screening and gastroenterology clinics in a study called COLSCREEN to assess risk perception and attitudes regarding genetic testing to prevent cancer.

No disclosures

Citation:

Sci Rep. 2017 Feb 24;7:43263. doi: 10.1038/srep43263.

Risk Model for Colorectal Cancer in Spanish Population Using Environmental and Genetic Factors: Results from the MCC-Spain study.

Ibáñez-Sanz G1, Díez-Villanueva A1, Alonso MH1,2, Rodríguez-Moranta F2,3, Pérez-Gómez B2,4,5, Bustamante M2,6, Martin V2,7, Llorca J2,8, Amiano P2,9, Ardanaz E2,10, Tardón A2,11, Jiménez-Moleón JJ2,12, Peiró R2,13, Alguacil J2,14, Navarro C2,15, Guinó E1,2, Binefa G1,2, Navarro PF2,4,5, Espinosa A2,6, Dávila-Batista V7, Molina AJ2,7, Palazuelos C8, Castaño-Vinyals G2,6,16,17, Aragonés N2,4,5, Kogevinas M2,6,16,17,18, Pollán M2,4,5, Moreno V1,2,19.

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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BRCA Testing Shifts From Cancer Patients to Unaffected Women

MedicalResearch.com Interview with:

Fangjian Guo, MD, PhD Department of Obstetrics and Gynecology Center for Interdisciplinary Research in Women’s Health University of Texas Medical Branch Galveston TX

Dr. Fangjian Guo

Fangjian Guo, MD, PhD
Department of Obstetrics and Gynecology
Center for Interdisciplinary Research in Women’s Health
University of Texas Medical Branch
Galveston TX

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: BRCA testing in patients diagnosed with early-onset breast or ovarian cancer can identify women with high-risk mutations, which can guide treatment. Women who learn they have a high-risk mutation may also want to inform family members that they may also carry a high-risk mutation.

Additionally, BRCA testing can be used to identify high-risk mutation carriers before they develop breast or ovarian cancer. Carriers can then manage their cancer risks with screening (MRI/mammogram), chemoprevention, or prophylactic surgery. Current guidelines recommend BRCA testing for individuals who are considered high-risk for breast or ovarian cancer based on personal or family history.  However, this practice fails to identify most BRCA mutation carriers. It is estimated that more than 90% of mutation carriers have not been identified. One of the issues is that many women who do get tested are actually low-risk and do not have any personal or family history of breast or ovarian cancer.

This study assessed how BRCA testing was used in the US health care system during the past decade. We found that in 2004 most of the tests (75.7%) were performed in patients who had been diagnosed with breast or ovarian cancer. Only 24.3% of tests were performed in unaffected women. However, since 2006, the proportion of BRCA tests performed in unaffected women has increased sharply, with over 60% of the tests performed in unaffected women in 2014.

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Based on Genetic Profile, Longer Adjuvant Treatment Recommended for Some GIST Tumors

MedicalResearch.com Interview with:
Heikki Joensuu, MD

Department of Oncology
Helsinki University Hospital
University of Helsinki
Helsinki, Finland 

MedicalResearch.com: What is the background for this study?

Response: The randomized Scandinavian Sarcoma Group (SSG) XVIII trial compared three years of adjuvant imatinib to one year of adjuvant imatinib as adjuvant treatments of patients who had undergone macroscopically complete surgery for a GIST with a high risk for tumor recurrence. In this trial, patients treated with 3 years of imatinib had improved overall survival as compared to those who were allocated to one year of adjuvant imatinib. In 2 other randomized trials that compared either 1 year of adjuvant imatinib to one year or placebo, or 2 years of adjuvant imatinib to observation, no improvement in overall survival was found, although in all three trials adjuvant imatinib improved recurrence-free survival (RFS). The reasons for the discrepant findings with respect of overall survival in the 3 trials have been unclear.

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Discovery of New Gene That Causes Sudden Death in Young Athletes

MedicalResearch.com Interview with:
Lia Crotti, MD, PhD

Department of Cardiovascular, Neural and Metabolic Sciences
San Luca Hospital
IRCCS Istituto Auxologico Italiano

MedicalResearch.com: What is the background for this study?

Response: Sudden cardiac death in one of the major cause of death in Western Countries and among the causes of these deaths in young people under the age of 35, inherited forms of cardiomyopathy have a prominent role. Among these cardiomyopathies, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) plays a major role. In ARVC, the heart tissue is replaced by fatty and fibrous tissue. This process encourages the development of life-threatening arrhythmias, such as ventricular fibrillation, that causes a cardiac arrest and sudden death in few minutes without a ready device to shock the heart. Intense physical activity favors the progression of the disease and arrhythmias are frequently triggered by adrenergic activation: those are the reason why young athletes with this disease are at high risk.

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70-Gene Signature Changes 50% of Breast Cancer Chemotherapy Advice

MedicalResearch.com Interview with:
Anne Kuijer, MD

Departments of Surgery and Radiology
University Medical Center Utrecht and
Thijs van Dalen, PhD
Department of Surgery
Netherlands Cancer Institute, Amsterdam

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In recent years it has become evident that clinicopathological factors fail to accurately determine prognosis in hormone receptor positive early stage breast cancer patients at intermediate risk of developing metastases. Gene-expression profiles, such as the 70-gene signature (MammaPrint) are therefore increasingly used for chemotherapy decision-making. In the current multicentre study we assessed the impact of 70-gene signature use on chemotherapy decisions in these patients. We demonstrated that, without the use of the 70-gene signature, half of patients was advised chemotherapy, which reflects the current controversy regarding chemotherapy benefit. Use of the 70-gene signature changed the chemotherapy advice in half of all patients and adherence to the 70-gene signature result was high.

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Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy

MedicalResearch.com Interview with:

Sara Saberi, MD Assistant Professor Inherited Cardiomyopathy Program Frankel Cardiovascular Center University of Michigan Hospital and Health Systems

Dr. Sara Saberi

Sara Saberi, MD
Assistant Professor
Inherited Cardiomyopathy Program
Frankel Cardiovascular Center
University of Michigan Hospital and Health Systems 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Patients with hypertrophic cardiomyopathy are often told not to exercise or to significantly curb their exercise due to concern over the potential risk of increased ventricular arrhythmias and sudden cardiac death. There is no data regarding risks/benefits of exercise in HCM though. There is, however, data that shows that patients with HCM are less active and more obese than the general population AND a majority feel that exercise restrictions negatively impact their emotional well-being.

So, we devised a randomized clinical trial of a 16-week moderate-intensity aerobic exercise program versus usual activity with the primary outcome being change in peak VO2 (oxygen consumption). This exercise intervention resulted in a 1.27 mL/kg/min improvement in peak VO2 over the usual activity group, a statistically significant finding. There were no major adverse events (no death, aborted sudden cardiac death, appropriate ICD therapies, or sustained ventricular tachycardia). There was also a 10% improvement in quality of life as measured by the Physical Functioning scale of the SF-36v2.

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Racial Disparities in Genetic Testing of Women With Breast Cancer

MedicalResearch.com Interview with:

Cary P. Gross, MD Section of General Internal Medicine Yale University School of Medicine New Haven, CT

Dr. Cary Gross

Cary P. Gross, MD
Section of General Internal Medicine
Yale University School of Medicine
New Haven, CT

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Prior work has demonstrated racial and socioeconomic disparities in breast cancer diagnosis, treatment, and outcomes.  As the oncology field has progressed over the past decade, the use of genetic testing to guide treatment decisions is one of the most exciting new developments.

Our team was concerned that these new gene tests, which can offer important benefits, may have the potential to exacerbate disparities further.  That is, if there is unequal access to gene testing among patients for whom it is recommended, then our progress against cancer will not be equitably shared among people of all races and ethnicities.

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Genotypes Can Increase or Decrease Young Adult Financial Outcomes, Depending on Parental Income

MedicalResearch.com Interview with:

Emily Rauscher PhD Assistant Professor Department of Sociology University of Kansas

Dr. Rausher

Emily Rauscher PhD
Assistant Professor
Department of Sociology
University of Kansas  

MedicalResearch.com: What is the background for this study?

Response: A lot of previous research has identified genotypes that increase sensitivity to context.  Much of this research, however, looks at particular aspects of health and is not able to address the methodological challenges of investigating gene-environment interactions.  To gain a better sense of the potential outcomes that may be susceptible to gene-environment interactions, I examine financial standing in young adulthood.  Testing this type of interaction is challenging because genotype and social environment are not randomly distributed throughout the population. Given this non-random distribution, unobserved confounders (such as parental behaviors, education, ethnicity, or social capital) could influence both parent and child financial standing.

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Gene “Decorations” Can Serve as Blood Biomarkers To Detect Cancer

MedicalResearch.com Interview with:

Kun Zhang, PhD Professor UCSD Department of Bioengineering La Jolla, CA 92093-0412

Dr. Kun Zhang

Kun Zhang, PhD
Professor
UCSD Department of Bioengineering
La Jolla, CA 92093-0412

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We have been interested in a type of chemical modification on the DNA, called CpG methylation, for years. This is like a decoration of DNA molecules that is specific to the cell type or tissue type. We were particularly interested in studying how such decoration spread along the DNA molecules. In this study, we did a very comprehensive search of the entire human genome for various human cell types and tissue types, and found close to 150,000 regions (called MHB in this study) in which adjacent CpG share the same decoration. We then went on to find out how many of such regions are unique to each normal cell/tissue type, and how many are specific to cancers. Then we took some of these highly informative regions as “biomarkers”, and showed that we can detect the absence or presence of cancer, and, in the latter case, where the tumor grow, in a patient’s blood.

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Genetic Variants Tied To Kidney Disease in African Americans

MedicalResearch.com Interview with:

Katalin Susztak MD, PhD Associate Professor of Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, PA 19104

Dr. Susztak

Katalin Susztak MD, PhD
Associate Professor of Medicine
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA 19104

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previous studies showed an association between genetic variants in the APOL1 gene and kidney disease development, but it has not been confidently shown that this genetic variant is actually causal for kidney disease. For this reason we developed a mouse model that recapitulates the human phenotype.

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Genetic Variant of p53 Gene May Explain Increased Breast Cancer Risk in African American Women

MedicalResearch.com Interview with:

Maureen E. Murphy, Ph.D. Professor and Program Leader, Molecular and Cellular Oncogenesis Program Associate Vice President for Faculty Affairs Associate Director for Education and Career Development The Wistar Institute Philadelphia, PA 19104

Dr. Murphy

Maureen E. Murphy, Ph.D.
Professor and Program Leader, Molecular and Cellular Oncogenesis Program
Associate Vice President for Faculty Affairs
Associate Director for Education and Career Development
The Wistar Institute
Philadelphia, PA 19104

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The Murphy group discovered a coding-region variant of the p53 tumor suppressor gene, called Pro47Ser, that exists in individuals of African descent. In previous studies this group reported that this amino acid change reduces the ability of p53 to function as a tumor suppressor.

In this study, African American women from two different large cohorts were assessed for the incidence of the Pro47Ser variant in pre-menopausal breast cancer. A modest but statistically significant association was found between Pro47Ser and pre-menopausal breast cancer.

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