Brain gene editing has tremendous therapeutic potential, and can be achieved with non-viral Cas9 RNP delivery...
Dr. Burgess[/caption]
Dr. Stephen Burgess PhD
Programme Leader at the Medical Research Council Biostatistics Unit
University of Cambridge
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Lipoprotein(a) is a lipoprotein subclass, and an important biomarker for coronary heart disease. As a clinical biomarker, it has a similar story to LDL-cholesterol (“bad” cholesterol), in that it is thought to be a causal risk factor for coronary heart disease, and so is a potential target for drug development. However, while drugs that lower LDL-cholesterol, such as statins, have been successful in reducing coronary heart disease risk, drugs that lower lipoprotein(a) have not as yet been successful. New drugs are currently in development that specifically target lipoprotein(a) and can lower lipoprotein(a) concentrations by 80-90%. We performed this study to investigate whether these drugs are likely to be successful in reducing coronary heart disease risk.
We compared individuals with naturally-occurring genetic variants that predispose them to a higher or lower lifetime concentration of lipoprotein(a) as a way of mimicking a randomized controlled trial. This approach has previously been undertaken for other biomarkers, including LDL-cholesterol. We found that having 10mg/dL lower genetically-predicted concentration of lipoprotein(a) was associated with a 5.8% reduction in coronary heart disease risk.
However, associations between genetically-predicted LDL-cholesterol and coronary heart disease risk are quantitatively much stronger than the proportional effect of LDL-cholesterol lowering on coronary heart disease risk as estimated by statin trials. This is because differences in genetic variants reflect lifelong changes in LDL-cholesterol, whereas statin trials only lower LDL-cholesterol for a few years. Hence, using the ratio between the genetic and trial estimates for LDL-cholesterol, we estimate that lowering lipoprotein(a) by 10mg/dL in a short-term clinical trial would only reduce coronary heart disease risk by 2.7%. To obtain the same reduction in coronary heart disease risk of around 20% as observed in statin trials, lipoprotein(a) would have to be lowered by around 100mg/dL. This explains why previous trials of less specific and less potent lipoprotein(a)-lowering drugs have failed to demonstrate benefit.
Dr. Rosenfeld[/caption]
Cheryl Rosenfeld PhD DVS
Professor of biomedical sciences in the College of Veterinary Medicine
investigator in the Bond Life Sciences Center, and
research faculty member for the Thompson Center for Autism and Neurobehavioral Disorders
University of Missouri
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: My laboratory has been examining the effects of developmental exposure to the endocrine disrupting chemical (EDC), bisphenol A (BPA) on later neurobehavioral responses in a variety of rodent models, including California mice. This species is unique in that both parents rear the pups and they have monogamous social structure, similar to most human societies.
We had previously found that developmental exposure to BPA or another EDC, ethinyl estradiol (EE), disrupted later maternal and paternal care by F1 offspringto their F2 pups. Rodent pups use vocalizations both in the range of human hearing (20,000 hertz or below) and outside of the range of human hearing (20,000 hertz) to communicate with each other and their parents, and for the latter, such communications serve as a trigger to provide additional parental care in the form of nutrition or warmth to the pups.
Thus, in the current studies we sought to determine if exposure of the grandparents to BPA or EE could lead to disruptions in their grandoffspring (F2 generation) pup communications that might then at least partially account for the parental neglect of their F1 parents.
We found that early on female BPA pups took longer to call to their parents but later during the neonatal period they vocalized more than pups whose grandparents were not exposed to either chemical. Such vocalization changes could be due to multigenerational exposure to BPA and/or indicate that the pups are perceiving and responding to the reduced parental care and attempting but failing to signal to their F1 parents that they need more attention.
Dr. Schumacher[/caption]
Fredrick R. Schumacher, PhD, MPH.
Associate Professor, Department of Population & Quantitative Health Sciences
Case Western Reserve University
Cleveland
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Our study examines the genetic underpinnings of prostate cancer initiation using technology to test variants across the genome. Our study focused on men of European ancestry and included over 80,000 men with prostate cancer and 60,000 men without disease. We discovered 63 novel genetic variants associated with prostate cancer risk, which increases our knowledge of prostate cancer genetic risk factors by more than 60%.
A genetic risk score created from the combination of 163 new and known prostate cancer risk variants revealed men with the highest genetic risk score are nearly seven times more likely to develop disease compared to the average man. Additionally, men with the lowest genetic risk score have a 85% risk reduction of developing prostate cancer compared to the average. Lastly, these new discoveries uncover several biological mechanisms involved in the initiation of prostate cancer.
David Haussler PhD
Investigator, Howard Hughes Medical Institute
Distinguished Professor, Biomolecular Engineering
Scientific Director, UC Santa Cruz Genomics Institute
Scientific Co-Director, California Institute for Quantitative Biosciences and
Sofie Salama, PhD
Research Scientist in BIomolecular Engineering
Howard Hughes Medical Institute Senior Scientist
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Haussler: Researchers specializing in this area are interested understanding which evolutionary changes in our genome underlie human-specific brain features including our large (3X greater than chimpanzee) brain.
It has been my personal dream to peer into human evolution at the level of individual genes and gene functions. 
Daniel de Boer
Founding Chief Executive Officer
ProQR
MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by dystrophic epidermolysis bullosa?
Response: Dystrophic epidermolysis bullosa (DEB) is caused by a mutation in the COL7A1 gene which is responsible for the formation of a protein called type VII collagen (C7). This protein helps bind the inner and outer layers of the skin together. Mutations in one part of COL7A1 gene, exon 73, are the most common cause of DEB resulting in a non-functional C7 protein. ProQR's QR-313 is designed to skip exon 73 of the COL7A1 gene, leading to a shortened C7 protein called C7Δ73. The current studies are intended to determine whether C7Δ73 functions the same as normal C7 protein. This mechanism can hopefully restore normal skin function for DEB patients.
DEB is a rare genetic skin disease characterized by easy blistering of the skin, poorly healing wounds and skin infections. DEB is present at birth and in severe cases leads to skin cancer, which can significantly reduce a patient’s lifespan. There are currently no treatments for DEB that target the underlying cause of the disease. The current standard of care consists of expensive time-consuming wound care, antibiotics to prevent infection and pain medications. As a result, this disease presents a huge burden to the patients themselves, as well as people who help with daily care.
Rebecca Somerville MB BCh BAO, BMedSci, MRCPI, MPH, PhD
School of Public Health, Physiotherapy and Sports Science
University College Dublin
Dublin, Ireland
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Rates of obesity in the Western world have increased dramatically over recent decades. The negative health consequences of obesity are well known and significant amounts of research have been conducted into the causes and possible solutions. While it is clear that there have been massive changes in diet and physical activity at a societal level that are primarily responsible for this 'obesity epidemic', it is less clear the extent to which obesity, once established, or risk factors for same, can be perpetuated down generations. Family studies lend opportunity to explore these questions, however there are few world wide which incorporate 3 generations.
We therefore sought to examine patterns of central adiposity, as measured by waist circumference, between grandparents and their grandchildren, separately in maternal and paternal lines. We were able to utilize prospectively collected data from the Lifeways Cross-Generation Cohort Study. This is a longitudinal birth cohort, established in Ireland in 2001, involving up to 7 members of the same family (mother, father, child and 4 grandparents). In the 589 families where a child had a waist circumference measurement we found that, at the age of both 5 and 9, there was a direct relationship between the waist circumference of the maternal grandmother and her grandchild (both male and female). This remained after adjustment for a wide range of confounding variables including mother's waist circumference. There was no relationship seen with any of the other grandparents.
Marianthi-Anna Kioumourtzoglou ScD
Assistant Professor
Environmental Health Sciences
Mailman School of Public Health
Columbia University
MedicalResearch.com: What is the background for this study?
Response: The prevalence of neurodevelopmental disorders, like attention deficit/hyperactivity disorder (ADHD) has been increasing. One of the hypothesized risk factors for increased risk for neurodevelopmental disorders is a class of chemicals known as endocrine disrupting chemicals (EDCs). These chemicals are known to interfere with the endocrine system, i.e. the system that uses hormones to control and coordinate metabolism, reproduction and development. Several high production volume chemicals, ubiquitously present in commercial products, are known or suspected endocrine disruptors. Because of their widespread use in consumer products, the population-wide exposure to known and suspected EDCs is very high.
Recently, there has been increased attention in the potential effects of EDCs on neurodevelopment that span multiple generations. Animal studies have provided evidence that exposure to EDCs, such as phthalates and bisphenol A (BPA), alter the behavior and social interactions in mice in three to five generations after exposure. However, evidence of such multi-generational impacts of EDC exposure on neurodevelopment in humans is unavailable, likely because of the lack of detailed information on exposures and outcomes across generations.
For this study we leveraged information from a nationwide cohort, the Nurses’ Health Study II (NHSII), to investigate the potential link between exposure to diethylstilbestrol (DES) and third generation ADHD, i.e. ADHD among the grandchildren of the women who used DES while pregnant. DES is a very potent endocrine disruptor that was prescribed between 1938 and 1971 to pregnant women thought to prevent pregnancy complications. In the United States, between 5 and 10 million women are estimated to have used DES, although the exact number is not known. DES was banned in 1971, when was linked to vaginal adenocarcinomas (a rare cancer of the reproductive system) in the daughters of the women who had used it during pregnancy. Since then, DES has been also linked to multiple other reproductive outcomes in DES daughters, as well as with some reproductive outcomes in the grandchildren of the women who used it, such as hypospadias and delated menstrual regularization. However, to our knowledge, no study to date has evaluated the association between DES, or any other EDC, and multigenerational neurodevelopment.
Prof. Munroe[/caption]
Prof. Patricia Munroe PhD
Professor of Molecular Medicine
William Harvey Research Institute
Barts and The London School of Medicine and Dentistry
Queen Mary University of London
MedicalResearch.com: What is the background for this study?
Response: Over the years, it has become increasingly evident that impaired capacity to increase heart rate during exercise and reduce heart rate following exercise are important predictors of all-cause and cardiovascular mortality. A person's capability to regulate their heart rate is the result of complex interactions of biological systems, including the autonomic nervous and hormonal systems. Prior work has demonstrated that genetic factors significantly contribute to variations in resting heart rate among different individuals, but less was known about the genetic factors modulating the response of heart rate to exercise and recovery.
Dr. Wei-Qi Wei[/caption]
Wei-Qi Wei, MD, PhD
Assistant Professor
Department of Biomedical Informatics
Vanderbilt University
Nashville, TN 37203
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The study was motived by the clinical observation that some patients develop coronary heart disease events despite taking statins, one of our most effective drugs to reduce cardiovascular risk. We collected data within the eMERGE network of people taking statins and monitored them for development of coronary heart disease events over time. We conducted a genome-wide association study of those with events compared to those without events.
Our results showed that single nucleotide polymorphisms (SNPs) on the LPA gene were associated with a significantly increased risk of coronary heart disease events. Individuals with the variant were 50% more likely to have an event. More importantly, even among patients who achieved ideal on-treatment LDL cholesterol levels (<70 mg/dL), the association remained statistically significant.
We then did a phenome-wide association study to see if other diseases or conditions were associated with these LPAvariants. The major associated conditions were all cardiovascular. This sort of study can highlight potential other indications for a drug targeting this pathway and suggest potential adverse events that might be experienced from targeting this pathway. Clearly, more and larger studies will be needed to truly understand the potential risks and benefits of a future drug targeting this pathway. 
Dr. Kaufmann[/caption]
Tobias Kaufmann PhD
Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine
University of Oslo, Oslo, Norway
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Over the past years, a lot of work has pointed toward impaired brain networks in schizophrenia. With this work we assessed brain network stability across different loads of a cognitive task using functional magnetic resonance imaging of the brain.
Based on our earlier work on adolescents with pre-clinical signs of mental illness who showed decreased stability of networks across different tasks and conditions, we hypothesized that brain networks in adults with schizophrenia show similar properties of decreased stability. Our results confirmed this hypothesis. Stability was reduced in several large-scale brain networks across the sampled age range from early adulthood to the sixties. Further, network stability was associated with polygenic risk for schizophrenia as well as cognitive task performance.
Dr. Kurian[/caption]
MedicalResearch.com Interview with:
Allison W. Kurian, M.D., M.Sc.
Associate Professor of Medicine (Oncology) and of Health Research and Policy
Director, Women’s Clinical Cancer Genetics Program
Stanford University School of Medicine
Stanford, CA 94305-5405
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Changes in genetic sequencing technology and regulation have allowed much cheaper testing of many more genes in recent years. We investigated how these changes have affected hereditary cancer risk evaluation in women newly diagnosed with breast cancer.
The main findings are that more comprehensive multiple-gene sequencing tests have rapidly replaced more limited tests of two genes (BRCA1 and BRCA2) only. This has helped patients by doubling the chance of finding an important gene mutation that can change their treatment options.
However, there are important gaps in how this new, more comprehensive sequencing is used: more testing delays and more uncertain results, particularly among racial/ethnic minority women. 
Dr Sian Taylor-Phillips MPhys, PhD
Associate Professor Screening and Test Evaluation /
NIHR Career Development Fellow
Division of Health Sciences
Warwick Medical School
University of Warwick Coventry
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: In newborn blood spot screening a small amount of blood is taken from newborn babies heels, and this is tested for a range of rare diseases. The idea is to detect each disease earlier when it is more treatable. However, it would be better not to test for some diseases, for example if the test is inaccurate so worries parents that their baby may have a serious illness when they do not. Some countries test for as few as 5 diseases and others as many as 50. In this study we investigated how different countries choose which diseases to test for.
We found that many national recommendations on whether to screen newborn babies for rare diseases do not assess the evidence on the key benefits and harms of screening. Evidence about the accuracy of the test was not considered in 42% of recommendations, evidence about whether early detection at screening has health benefits was not consulted in 30% of recommendations, and evidence around the potential harm of overdiagnosis where babies have variants of the disease that would never have caused any symptoms or ill effects was not considered in 76% of recommendations.
We also found through meta-analysis that when a systematic review was used to bring together the evidence then countries were less likely to recommend screening for the disease.
Dr. Ed Liu[/caption]
Ed Liu, M.D
President and CEO
The Jackson Laboratory (JAX)
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: A few years ago we and others identified a complex genomic instability profile commonly found in the genomes of breast, ovarian and endometrial carcinomas, which is characterized by hundreds of isolated head-to-tail duplications of DNA segments, called tandem duplications. We refer to this configuration as the tandem duplicator phenotype, or TDP.
In this study, we perform a meta-analysis of over 2,700 cancer genomes from over 30 different tumor types and provide a detailed description of six different types of TDP, distinguished by the presence of tandem duplications of different sizes. Collectively, these profiles are found in ~50% of breast, ovarian and endometrial carcinomas as well as 10-30% of adrenocortical, esophageal, stomach and lung adeno-carcinomas. We show that distinct genetic abnormalities associate with the distinct TDPs, clearly suggesting that distinct molecular mechanisms are driving TDP formation. In particular, we provide strong evidence of a casual relationship between joint abrogation of the BRCA1 and TP53 tumor suppressor genes and the emergence of a short-span (~11 Kb) TDP profile. We also observe a significant association between hyper-activation of the CCNE1 pathway and TDP with medium-span (~230 Kb) tandem duplications, and between mutation of the CDK12 gene and medium- and large-span TDP (coexisting 230 Kb and 1.7 Kb tandem duplications).
Importantly, we find that different forms of TDP result in the perturbation of alternative sets of cancer genes, with short-span TDP profiles leading to the loss of tumor suppressor genes via double transections, and larger-span TDP profiles resulting in the duplication (i.e. copy number gain) of oncogenes and gene regulatory elements, such as super-enhancers and disease-associated SNPs. 
Dr. Nino Barrera[/caption]
Gustavo Nino, M.D.
Children’s National Health System pulmonologist
Study senior autho
MedicalResearch.com: What is the background for this study?
Response: The epidemiology of respiratory disorders is largely influenced by the individual’s sex resulting in overall higher risk for males than females, particularly during early life. Hormonal, anatomical and behavioral differences are postulated to play a role, but these sex-based respiratory differences are already present at birth, suggesting a strong genetic component. However, the genetic differences in the airways of males and females during early life have been remarkably understudied and are largely unknown.
Dr Aideen Maguire[/caption]
Dr. Aideen Maguire
Centre of Excellence for Public Health
Queen's University Belfast
Institute of Clinical Sciences B
Royal Hospitals Site, Belfast
MedicalResearch.com: What is the background for this study?
Response: Consanguineous Marriage is the marriage between second or first cousins. Although not common practice in the Western world approximately 1 in 10 children worldwide are born to consanguineous parents. It is legal in all countries worldwide except the United States of America, North Korea and China. Cousin-marriage is associated with an increased risk of autosomal recessive genetic disorders in offspring but the association between cousin-marriage and the mental health of offspring has not been extensively studied.
MedicalResearch.com: What are the main findings?
Response: Children of consanguineous parents are over 3 times more likley to be in receipt of medications for common mood disorders (antidepressant and/or anxioltyic medication) compared to children of non-related parents and over twice as likley to be in receipt of antipsychotic medication compared to children of non-related parents.
Dr. Aslibekyan[/caption]
Stella Aslibekyan, PhD
Associate Professor
PhD Program Director
Department of Epidemiology
University of Alabama at Birmingham
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: When the human genome was sequenced in 2003, there were somewhat unrestrained expectations of unraveling all etiologic mysteries and discovering breakthrough treatments. Needless to say, that did not happen, in part because individual genetic variants can only account for a small fraction of trait variability. Since then, epigenetics-- the study of mitotically heritable changes in gene expression-- has emerged as another promising avenue for understanding disease risk. The best studied epigenetic process in humans is DNA methylation, and earlier studies (including some from our group) have shown interesting associations between changes in methylation in specific genomic regions and cardiovascular disease traits, e.g. plasma cholesterol levels.
In this project, we have combined DNA methylation data on thousands of individuals from multiple international cohorts and interrogated epigenetic contributions to circulating tumor necrosis factor alpha (TNFa), a marker of systemic inflammation. We identified and replicated several epigenomic markers of TNFa, linked them to variation in gene expression, and showed that these methylation changes (which were located in interferon pathway genes) were predictive of coronary heart disease later in life. Interestingly, the variants we discovered were not sequence-dependent (in other words, they were not associated with any genetic mutations), highlighting the role of the environment.
Heather Hampel[/caption]
Heather Hampel, MS, LGC
Associate Director, Division of Human Genetics
Associate Director, Biospecimen Research
Professor, Internal Medicine
Licensed Genetic Counselor
The Ohio State University Comprehensive Cancer Center
Columbus, OH 4322
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The background is that we had recently shown that some colorectal cancer patients who underwent traditional screening for Lynch syndrome were eventually found to have double somatic (two acquired) mutations in the MMR genes and they did not have Lynch syndrome at all. This was discovered after their tumor had already had MSI and/or IHC screening test, followed by MLH1 methylation and/or BRAF testing, followed by germline DNA testing on a blood sample from the patient for MMR gene mutations, then finally by sequencing their tumor. This gave us the idea to reverse the sequence and start with tumor sequencing since it might streamline testing, save time, and prevent several other tests.
In addition, we knew that all stage IV colorectal cancer are already supposed to have tumor sequencing of the KRAS, NRAS, and BRAF genes and MSI testing for treatment purposes. Our hypothesis was that an upfront tumor sequencing test could replace all these separate tests with similar sensitivity and specificity.
Dr. Fejzo[/caption]
Marlena Fejzo, PhD
Aassociate researche
David Geffen School of Medicine
UCLA.
MedicalResearch.com: What is the background for this study?
Response: Most women experience some nausea and vomiting of pregnancy, and the worst 2% are diagnosed with Hyperemesis Gravidarum which is associated with poor maternal and fetal outcomes. I had HG in 2 pregnancies. In my second pregnancy my HG was so severe that I could not move without vomiting and did not keep any food or water down for 10 weeks. I was put on a feeding tube, but ultimately lost the baby in the second trimester. I am a medical scientist by training so I looked into what was known about HG. At the time, very little was known, so I decided to study it. I partnered with the Hyperemesis Education and Research Foundation (HER) and we did a survey on family history of .Hyperemesis Gravidarum that provided evidence to support a role for genes. I collected saliva samples from HG patients and their unaffected acquaintances to do a DNA study. Then I partnered with the personal genetics company, 23andMe to do a genome scan and validation study, which identified 2 genes, GDF15 and IGFBP7, linked to HG.
Dr. Easwaran[/caption]
Hariharan Easwaran, PhD
Assistant Professor of Oncology
The Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins University School of Medicine
Bunting/Blaustein Cancer Research Building 1
Baltimore, MD 21287
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The interpretation of the information encoded in our DNA by the various cells in our body is mediated by a plethora of modifications of DNA and proteins that complex with DNA. DNA methylation is one such important modification, which is normally established in a very orchestrated fashion during development. All normal cells have a defined pattern of DNA methylation, which may vary by tissue type, but is consistent within tissues. This normal pattern is disrupted in all known cancers, and is considered a hallmark of cancers.
This transmission electron microscopic (TEM) image depicts a number of round, Dengue virus particles that were revealed in this tissue specimen. CDC image[/caption]
Luisa Pereira PhD
Institute for Research and Innovation in Health
University of Porto
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: By using admixture mapping along the genome in Thai cohorts, we were able to identify new candidate genes conferring protection/susceptibility to dengue fever. A very interesting result was that the set of genes differed with the dengue phenotype: genes coding proteins that may link to the virus, conditioning its entrance in the host cells and mobility therein were associated with the less severe phenotype; genes related with blood vessels permeability were associated with the dengue shock syndrome. 
Tyler Seibert, MD, PhD
Radiation Oncology
Center for Multimodal Imaging & Genetics
UC San Diego
MedicalResearch.com: What is the background for this study?
Response: Prostate cancer is an extremely common condition in men. Many die from it each year, and many others live with debilitating pain caused by prostate cancer. Screening for prostate cancer with prostate-specific antigen (PSA) testing can be effective, but there are concerns with the test.
MedicalResearch.com Interview with:
Bruno Sauce, PhD and
Louis D. Matzel, PhD
Department of Psychology, Program in Behavioral and Systems Neuroscience
Rutgers University
New Jersey, USA
MedicalResearch.com: What is the background for this study?
Response: Scientists have known for decades that intelligence has a high heritability, which means that much of the individual differences in IQ we see in people are due to genetic differences. Heritability is a value that ranges from 0.0 (meaning no genetic component) to 1.0 (meaning that the trait is completely heritable). For example, the heritability of breast cancer is estimated at 0.27; the heritability of body mass index is 0.59; and the heritability of major depression is 0.40. In comparison, the heritability of IQ is estimated to be as high as 0.8 – quite a high value!
More recently, however, there have been studies showing that intelligence has a high malleability: the studies cover cognitive gains consequent to adoption/immigration, changes in IQ’s heritability across life span and socioeconomic status, gains in IQ over time from societal and scientific progress, the slowdown of age-related cognitive decline, the gains in intelligence from early education, differences in average IQ between countries due to wealth and development, and gains in intelligence that seem to happen from working memory training.
Intelligence being both highly heritable and highly malleable is seemingly paradoxical, and this paradox has been the source of continuous controversy among scientists.
Why does it matter? Because IQ predicts many important outcomes in life, such as academic grades, income, social mobility, happiness, marital stability and satisfaction, general health, longevity, reduced risk of accidents, and reduced risk of drug addiction (among many other outcomes). A clear understanding of the genetic and environmental causes of variation in intelligence is critical for future research, and its potential implications (and applications) for society are immense.
Dag Alnaes, PhD
Norwegian Centre for Mental Disorders Research
KG Jebsen Centre for Psychosis Research
Division of Mental Health and Addiction, Oslo University Hospital
Oslo, Norway
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The transition from childhood to adulthood is characterized by swift and dramatic changes, both in our environment and in our brains. This period of life also coincides with the onset of many mental disorders.
To gain a better understanding of why, the clinical neurosciences must attempt to disentangle the complex and dynamic interactions between genes and the environment and how they shape our brains. The ultimate goal is to be able to predict which individuals are at risk before clinical symptoms appear. Advanced brain imaging has been proposed to represent one promising approach for such early detection, but there is currently no robust imaging marker that allows us to identify individuals at risk with any clinically relevant degree of certainty.
Our study shows that self-reported early signs of mental illness are associated with specific patterns of brain fiber pathways in young people, even if they may not fulfill criteria for a formal diagnosis or are currently in need of treatment. 
Dr. Saunders-Pullman[/caption]
Rachel Saunders-Pullman, MD, MPH
Associate Professor of Neurology
Icahn School of Medicine at Mount Sinai
Chief, Movement Disorders, Mount Sinai Beth Israel
Co-Director Clinical/Translational Research and Research Mentoring
Movement Disorders, Department of Neurology,
Mount Sinai Beth Israel
New York, NY 10003
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: There is a diversity in causes of Parkinson’s Disease (PD), and this may lead to heterogeneity in drug response. While LRRK2 PD due to G2019S mutations may fully mimic idiopathic PD (IPD), cross-sectional study suggests that the course may be slightly milder than IPD. Further, the pathology is heterogeneous with a minority not demonstrating Lewy bodies, and this may also correspond to less severe non-motor features.
To better understand the course of PD associated with the G2019S LRRK2 mutation (the most common LRRK2 mutation), we evaluated motor and cognitive progression in individuals enrolled in the LRRK2 Ashkenazi Jewish Consortium. Subjects were recruited from a Center in Tel Aviv, Israel, Sourasky Medical Center, and from two centers in New York, Columbia University and Mount Sinai Beth Israel. 144 participants were LRRK2 mutation carriers and 401 were not. We utilized all study visits, and constructed linear mixed-effects models to estimate the association between harboring the LRRK2 mutation and rate of change of both motor features- as assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS), and cognition, as measured by the Montreal Cognitive Assessment Scale (MoCA). Models adjusted for sex, site, age, disease duration and (for the motor models) cognitive score.
We found a small but significant difference in rate of progression, with LRRK2 PD progressing at 0.69 points/year, and IPD at 1.06 points/year. While the cognitive decline was also less in the LRRK2 PD (-0.10 vs. -0.19 in the IPD, this difference was not statistically different (p=0.08).
Dr. Geisert[/caption]
Eldon E. Geisert, PhD
Professor of Ophthalmology
Emory School of Medicine
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: In the late 1990s a group of doctors began a study of glaucoma patients to determine if there were phenotypes that are predictive for developing glaucoma.
In this Ocular Hypertension Treatment Study (OHTS) one of the highly correlated ocular traits was central corneal thickness (CCT). The early clinical studies found that people with thinner corneas were at a higher risk of developing glaucoma. In two large studies, examining thousands of people a number of genes were identified that were risk factors for glaucoma or that controlled CCT in humans. In both cases the identified genes accounted for less than 10% of the genetic risk for glaucoma and less than for 10% of the genetic control for CCT. There was little data linking the genetic control of CCT to the glaucoma risk.
Our group has taken an indirect approach to the question, using well-defined mouse genetic system to identify genes modulating CCT and then interrogating human glaucoma data to determine if these genes are associated with glaucoma risk. 
Dr. Kopetz[/caption]
Scott Kopetz, M.D., Ph.D., FACP
Associate Professor Department of Gastrointestinal Medical Oncology
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The BRAF mutation carries a very poor prognosis for patients with advanced colo-rectal cancer (CRC), and is particularly unresponsive after first-line therapy, so additional treatment options for these patients are needed. While treatment with a BRAF inhibitor alone has not been effective in treating this disease, combination therapies have shown promise and lead to the initiation of the BEACON study. The safety lead-in phase of the BEACON CRC trial was designed to assess the safety and tolerability of encorafenib, binimetinib and cetuximab triplet combination prior to the Phase 3 randomized portion of the study. Thirty patients were treated in the safety lead-in and received the triplet combination (encorafenib 300 mg daily, binimetinib 45 mg twice daily, and cetuximab per label). Out of the 30 patients, 29 had a BRAFV600E mutation. Microsatellite instability-high (MSI-H) (resulting from defective DNA mismatch repair) was detected in only 1 patient. The triplet demonstrated good tolerability, supporting initiation of the randomized portion of the study. In addition, promising initial clinical activity was observed.
In patients with the BRAFV600E mutation, the estimated median progression-free survival (mPFS) at the time of analysis was 8 months. The confirmed overall response rate (ORR) in patients with the BRAFV600E mutation was 48%, and 3 patients achieved complete responses (CR). Further, the ORR was 62% in the 16 patients (10/16) who received only one prior line of therapy.
Additionally, the triplet combination was generally well-tolerated. Two patients discontinued treatment due to AEs with only one of these considered related to treatment. The most common grade 3 or 4 AEs seen in at least 10% of patients were fatigue (4/30), urinary tract infection (3/30), increased aspartate aminotransferase (AST; 3/30) and increased blood creatine kinase (CK; 3/30).
Alexander Hauser[/caption]
Alexander S Hauser, PhD student
MRC Laboratory of Molecular Biology
Cambridge UK
Department of Drug Design and Pharmacology, University of Copenhagen
Copenhagen, Denmark
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The prevalence and impact of genetic variation among all human G protein coupled receptors (GPCRs) that are targeted by FDA-approved drugs remain unknown. In this study, we present a comprehensive analysis and map of the pharmacogenomics
landscape of GPCR drug targets. The key highlights are:
- GPCRs targeted by drugs show extensive genetic variation in the human population
- Variation occurs in functional sites and may result in altered drug response
- Understanding GPCR genetic variation may help reduce global healthcare expenses