Genetic Defect in DNA Repair Enzyme Linked to Prostate Cancer

MedicalResearch.com Interview with:
G. Andrés Cisneros, Ph.D.

Associate Professor
Department of Chemistry Center for Advanced Scientific Computing and Modeling, University of North Texas

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

Response: The accurate maintenance of DNA is crucial, if DNA damage is not addressed it can lead to various diseases including cancer. Therefore, the question arises about what happens if enzymes in charge of DNA repair are themselves mutated. We previously developed a method to perform targeted searches for cancer-related SNPs on genes of interest called HyDn-SNP-S. This method was applied to find prostate-cancer SNPs on DNA dealkylases in the ALKB family of enzymes.

Our results uncovered a particular mutation on ALKBH7, R191Q, that is significantly associated with prostate cancer. Subsequent computer simulations and experiments indicate that this cancer mutation results in a decreased ability of ALKBH7 to bind its co-factor, thus impeding its ability to perform its native function.

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Brain–Computer Interface Allows Communication With Locked-In Patients

MedicalResearch.com Interview with:

Dr. Ujwal Chaudhary, PhD Institute of Medical Psychology and Behavioral Neurobiology University of Tübingen Tübingen, Germany

Dr. Ujwal Chaudhary

Dr. Ujwal Chaudhary, PhD
Institute of Medical Psychology and Behavioral Neurobiology
University of Tübingen
Tübingen, Germany

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

Response: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder which causes an Individual to be in Locked-in state (LIS), i.e. the patients have control of their vertical eye movement and blinking, and ultimately in Completely Locked-in state (CLIS), i.e, no control over their eye muscle. There are several assistive and augmentative (AAC) technology along with EEG based BCI which can be used be by the patients in LIS for communication but once they are in CLIS they do not have any means of communication.  Hence, there was a need to find an alternative learning paradigm and probably another neuroimaging technique to design a more effective BCI to help ALS patient in CLIS with communication.

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Executive Brain Function Predictive of Success on the Soccer Pitch

MedicalResearch.com Interview with:
soccer; creative commons imageTorbjörn Vestberg

Licensed Psychologist & Researcher
Department of Clinical Neuroscience, Karolinska Institutet
Stockholm, Sweden

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

Response: The aim of our research is to study the importance of executive functions for successful behaviour. In our first study published in 2012 (Executive Functions Predict the Success of Top-Soccer Players) we showed that the level of elite soccer players’ higher executive functions was in general 2 standard deviations above the normal population. It was the same for both men and women.

Moreover, we also found a strong correlation between the capacities of higher executive functions and the number of goals and assists the player made after two and a half year.

In our new study we were interested in how the situation is at a younger age, from twelve to nineteen years of age. Because of the maturation of the brain, higher executive functions do not reach their full capacity before nineteen years of age.

On basis of this, our question was whether there were other parts of the executive functions that correlated with success in soccer. In this new study, we focused on core executive functions like the working memory, as it reaches its full capacity in the early teens. We found that there was a moderate correlation with the accuracy of the working memory and the number of goals the junior elite players made during a period of two years. When we made a composite measurement of both the demanding working memory and the test for the capacity of the higher executive functions, we found a strong correlation between these results and the number of goals that the players made during the two years of time. When we measured IQ and physical features, like length, we found out that those did not influence the results.

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Cost Effectiveness of Lung Cancer Screening Requires Careful Patient Selection

MedicalResearch.com Interview with:
Kevin ten Haaf MSc

Scientific researcher, Public Health
Erasmus Medical Center
Rotterdam

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

Response: Lung cancer screening is currently recommended in the United States, for persons aged 55 through 80 who smoked at least 30 pack-years (the average number of cigarettes smoked per day multiplied by the number of years the person has smoked) and who currently smoke or have quit within the last 15 years. Other countries, such as Canada, are investigating the feasibility of implementing lung cancer screening policies.

However, the cost-effectiveness of lung cancer screening in a population-based setting is uncertain. Concerns have been raised on the feasibility of implementing lung cancer screening policies, especially with regards to the potential costs. In this study, the benefits, harms and costs of implementing lung cancer screening in the province of Ontario, Canada were assessed.

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Does Maternal BMI Affect Offspring’s Obesity Risk?

MedicalResearch.com Interview with:

Dr Rebecca Richmond PhD

Dr Rebecca Richmond

Dr Rebecca Richmond PhD
Senior Research Associate in the CRUK Integrative Cancer Epidemiology Programme
MRC Integrative Epidemiology Unit
School of Social and Community Medicine
University of Bristol

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

Response: We have been involved in earlier work which applied the same methods used here (using genetic variants to provide causal evidence) and showed that higher maternal pregnancy body mass index (BMI) causes greater infant birth weight. The paper here aimed to build on that earlier research and asked whether maternal BMI in pregnancy has a lasting effect, so that offspring of women who were more overweight in pregnancy are themselves likely to be fatter in childhood and adolescence. Our aim was to address this because an effect of an exposure in pregnancy on later life outcomes in the offspring could have detrimental health consequences for themselves and future generations. However, we did not find strong evidence for this in the context of the impact of maternal BMI in pregnancy on offspring fatness.

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Transcranial Stimulation Reduced Bulimia Symptoms

MedicalResearch.com Interview with:

Dr Maria Kekic PhD

Dr. Maria Kekic

Dr Maria Kekic PhD
Research Worker | The TIARA study:
Transcranial magnetic stimulation and imaging in anorexia nervosa
Section of Eating Disorders | Department of Psychological Medicine
Institute of Psychiatry, Psychology & Neuroscience | King’s College London

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

Response: Bulimia nervosa is an eating disorder characterised by repeated episodes of binge-eating and inappropriate compensatory behaviours. It is associated with multiple medical complications and with an increased risk of mortality. Although existing treatments for bulimia are effective for many patients, a sizeable proportion remain symptomatic following therapy and some do not respond at all.

Evidence shows that bulimia is underpinned by functional alterations in certain brain pathways, including those that underlie self-control processes. Neuroscience-based techniques with the ability to normalise these pathways may therefore hold promise as treatments for the disorder.

One such technique is called transcranial direct current stimulation (tDCS) – a form of non-invasive brain stimulation that delivers weak electrical currents to the brain through two electrodes placed on the head. It is safe and painless, and the most common side effect is a slight itching or tingling on the scalp.

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In-Bed Cycling Feasible for ICU Patients on Ventilation

MedicalResearch.com Interview with:

Michelle Kho, PT, PhD</strong> Canada Research Chair in Critical Care Rehabilitation and Knowledge Translation Assistant Professor School of Rehabilitation Science McMaster University

Dr. Michelle Kho

Michelle Kho, PT, PhD
Canada Research Chair in Critical Care Rehabilitation and Knowledge Translation
Assistant Professor
School of Rehabilitation Science
McMaster University

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

Response: Patients who survive the ICU are at risk for muscle weakness and can experience physical functional disability lasting 5 to 8 years after the ICU. From a study conducted in Belgium, patients who were randomized to receive cycling after being in ICU for 2 weeks walked farther at ICU discharge than those who did not. Other research supported physiotherapy starting within days of starting mechanical ventilation to improve functional outcomes. Our CYCLE research program combines these 2 concepts – Can we start cycling very early in a patient’s ICU stay, and will this improve functional outcomes post-ICU?

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Genetics Magnifies Health Effects of Discrimination

MedicalResearch.com Interview with:

Connie J. Mulligan, PhD Professor, Department of Anthropology University of Florida Gainesville, FL

Dr. Connie J. Mulligan

Connie J. Mulligan, PhD
Professor, Department of Anthropology
University of Florida
Gainesville, FL

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

Response: Lance Gravlee (UF Dept of Anthropology, UF Genetics Institute) started this research over 10 years ago. As a cultural anthropologist, Lance uses ethnographic (open-ended questions) interviews and discovered that over half of the participants in our study talked about experiences of discrimination that happened to people close to them.

As a geneticist (UF Dept of Anthropology, UF Genetics Institute), I came into the project because I was interested in seeing how genetics and sociocultural stressors, like discrimination, interact. In our project, we look at blood pressure because hypertension is a disease that shows racial disparities and also because it is a complex disease that is caused by both genetic and environmental factors (like discrimination).

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Predictors of Chemosensitivity in Triple Negative Breast Cancer

MedicalResearch.com Interview with:

Christos Hatzis, PhD Assistant Professor of Medicine Director of Bioinformatics, Breast Medical Oncology Yale Comprehensive Cancer Center Yale School of Medicine New Haven, CT

Dr. Christos Hatzis,

Christos Hatzis, PhD
Assistant Professor of Medicine
Director of Bioinformatics, Breast Medical Oncology
Yale Comprehensive Cancer Center
Yale School of Medicine
New Haven, CT

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

Response: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.

Identifying chemosensitive triple negative breast cancers could significantly impact
the survival of patients with these difficult to treat cancers until novel targeted
therapies become available. We hypothesized that genomic somatic aberrations may
provide important molecular clues about chemosensitivity in TNBC. Our study used
a carefully selected cohort of 29 uniformly treated TNBC patients who either achieved
pathologic complete response (pCR) or had extensive residual disease after neoadjuvant
anthracycline/taxane chemotherapy.

MedicalResearch.com: What are the main findings?

Response: We sequenced the coding genomic DNA of TNBC tumors and compared the somatic mutations found in the two groups at the two extremes of the chemosensitivity spectrum.

Our analysis revealed that, although mutations in single genes were not individually predictive, TNBC tumors bearing mutations in genes involved in the androgen receptor
(AR) and FOXA1 pathways were much more sensitive to chemotherapy.
We also found that mutations that lowered the levels of functional BRCA1 or BRCA2 RNA
were associated with significantly better survival outcomes; we derived a BRCA
deficiency signature to define this new, highly chemosensitive subtype of TNBC.
BRCA-deficient TNBC tumors have a higher rate of clonal mutation burden, defined as
more clonal tumors with a higher number of mutations per clone, and are also associated
with a higher level of immune activation, which may explain their greater chemosensitivity.

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

Response: Mutations in the AR/FOXA1 pathway provide a novel marker for identifying chemosensitive TNBC patients who may benefit from current standard-of-care chemotherapy regimens.

The newly defined RNA-based BRCA-deficient subtype includes up to 50% of the
Triple negative breast cancer tumors that appear to be immune primed, and it would be of interest to investigate combinations of chemotherapy with immunotherapies, which could provide clinical benefit for these patients. Although our study showed concordant results in three different datasets, our key findings need to be further validated in a larger, prospectively designed study with archival samples.

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

Response: The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in Triple negative breast cancer and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC. Our results suggest that the combination of immunotherapies with ACT chemotherapy or PARP inhibitors might be an effective strategy for treating BRCA-D tumors.

The strong connection of ACT chemosensitivity and immune activity with a new transcriptionally defined BRCA-D phenotype could help inform future therapeutic strategies for TNBC patients.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic AnalysisTingting Jiang,Weiwei Shi,Vikram B. Wali,Lőrinc S. Pongor,Charles Li,Rosanna Lau,Balázs Győrffy,Richard P. Lifton,William F. Symmans,Lajos Pusztai,Christos Hatzis

PLOS Medicine Published: December 13, 2016http://dx.doi.org/10.1371/journal.pmed.1002193

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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Mental and Physical Disorders Linked at Early Age

MedicalResearch.com Interview with:

Dr-Gunther-Meinlschmidt.jpg

Prof. Dr. Gunther Meinlschmidt, Psych
University of Basel, Department of Psychology, Division of Clinical Psychology and Epidemiology
Faculty of Medicine
Switzerland

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

Response: Physical diseases and mental disorders affect a person’s quality of life. Further, they present a huge challenge for the healthcare system. It has been reported that physical and mental disorders systematically co-occur already early in life. What we wanted to know is whether there are certain temporal patterns between mental disorders and physical diseases during childhood and adolescence. A better understanding of such patterns may help to reveal processes that could be relevant both to the origins of physical diseases and mental disorders and to their treatment.

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Some Prions Can Be Cleared By Infected Organism

MedicalResearch.com Interview with:
Romolo Nonno, DVM, PhD
Istituto Superiore di Sanità
Dipartimento di Sanità Pubblica Veterinaria e Sicurezza Alimentare
Roma Italy

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

Response: Previous studies have suggested that prion populations are composed of a variety of conformational variants subjected to Darwinian evolution driven by selective regimes. However, the exact molecular mechanisms that make prions able to self-replicate and mutate are still poorly understood.

A major technical advance in this field has been the discovery of techniques that allow to replicate prions in vitro, outside live organisms. One of these techniques, Protein Misfolding Cyclic Amplification (PMCA), allows to grow prion populations for a very high number of replications in a relatively short time period.

Furthermore it is conceivable that the in vitro environment offers less constraint to prion replication than live animals or cells, due to the absence of active clearance and cell division, which are key players of conformers selection in ex vivo models. These features make PMCA an attractive tool to investigate prion replication, mutation and evolution. By using PMCA, we investigated the in vitro evolution of prion populations derived from natural scrapie. Unexpectedly, we found that the cloud of conformational variants which compose a natural scrapie isolate also includes “defective” variants which, once isolated, are unable to self-sustain in vivo.

Importantly, we found that the defective prion mutant that we have isolated possesses unique biochemical properties in that its prion domain lacks the central region of prion protein, which is invariably present in known infectious mammalian prions.

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Low Carb Meals Reduce Insulin Resistance

MedicalResearch.com Interview with>
Katarina Borer, Ph.D. Professor
Po-Ju Lin,PhD
School of Kinesiology
The University of Michigan
Ann Arbor, MI

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

Response: This study was part of the doctoral dissertation of Po-Ju Lin, who is now a post-doctoral fellow at the University of Rochester. With this study, we wanted to answer three questions:

(1) Is daily carbohydrate load responsible for evening glucose intolerance and post-meal insulin resistance. (Evening glucose intolerance represents well-documented higher glucose and insulin responses in the evening than in the morning when the same quantity of glucose is eaten or infused intravenously) To answer this question we offered two daily meals containing about 800 Kcal and either 30% or 60% of carbohydrates.

(2) Will exercise before the meals improve glucose tolerance (glucose clearance from the blood and insulin response) after eating? (Exercise is a well-known means of increasing glucose uptake by the muscle and of increasing muscle sensitivity to insulin action for a number of hours after exercise). To answer this question we had the subjects exercise for two hours walking on a treadmill at 45% of their maximal aerobic effort one hour before each meal.

(3) Is the upper-intestinal hormone GIP involved in any effects associated with variation in dietary carbohydrate? (GIP or glucose-dependent insulinotropic peptide, stimulates insulin secretion in advance of absorbed glucose).

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