Author Interviews, Infections, PNAS / 27.07.2016

MedicalResearch.com Interview with: Adam Hayward PhD Impact Research Fellow University of Stirling MedicalResearch.com: What is the background for this study? Response: Adult life expectancies in industrialized countries have increased dramatically in the last 150 years, even once we’ve accounted for the fact that previously common deaths in childhood and now very rare. One hypothesis seeking to explain this increase is that childhood infections cause chronic inflammation, which are then linked with heart disease and stroke in later life, reducing lifespan. Since such childhood infections were previously common but are now, thanks to vaccine and sanitation, much rarer, chronic inflammation should be lower and people should live longer and be less likely to die from early-onset heart disease. If this hypothesis is correct, we should see that higher exposure to infections in early life leads to increased adult mortality and deaths from heart disease and stroke. (more…)
Author Interviews, Heart Disease, PNAS, UT Southwestern / 28.06.2016

MedicalResearch.com Interview with: Dr. Audrey Chang, PhD Kamm-Stull Lab UT Southwestern Medical Center [email protected] MedicalResearch.com: What is the background for this study? What are the main findings? Response: The heart is a singular kind of muscle that contracts and relaxes continuously over a lifetime to pump blood to the body’s organs. Contractions depend on a motor protein myosin pulling on actin filaments in specialized structures. Heart contraction is improved when myosin has a phosphate molecule attached to it (phosphorylation), and a constant amount of phosphorylation is essential for normal heart function. The amount of phosphorylation necessary for optimal cardiac performance is maintained by a balance in the activities of myosin kinase enzymes that add the phosphate and an opposing phosphatase enzyme that removes the phosphate. If the amount of phosphorylation is too low, heart failure results. Animal models with increased myosin phosphorylation have enhanced cardiac performance that resist stresses that cause heart failure. In this recent study reported in PNAS, a new kinase that phosphorylates myosin in heart muscle, MLCK4, was discovered and its crystal structure reported, a first for any myosin kinase family member. Compared to distinct myosin kinases in other kinds of muscles (skeletal and smooth), this cardiac-specific kinase lacks a conserved regulatory segment that inhibits kinase activity consistent with biochemical studies that it is always turned on. Additionally, another related myosin kinase found only in heart muscle (MLCK3) contains a modified regulatory segment, allowing partial activity enhanced by the calcium modulator protein, calmodulin. Thus, both myosin kinases unique to cardiac muscle provide phosphate to myosin in normal beating hearts to optimize performance and prevent heart failure induced by stresses. (more…)
Author Interviews, Education, PNAS, Surgical Research / 23.06.2016

MedicalResearch.com Interview with: Sunita Sah MD PhD Management & Organizations Johnson Graduate School of Management Cornell University MedicalResearch.com: What is the background for this study? What are the main findings?  Dr. Sah: Physicians often recommend the treatment they specialize in, e.g., surgeons are more likely to recommend surgery than non-surgeons. Results from an observational study and a randomized controlled laboratory experiment found that when physicians revealed their bias toward their own specialty, patients were more likely to report increased trust in the physician’s expertise and take the treatment in accordance with the physician’s specialty.    (more…)
Author Interviews, Genetic Research, Mental Health Research, PNAS / 22.06.2016

MedicalResearch.com Interview with: Brian W. Haas PhD Department of Psychology Interdisciplinary Neuroscience Graduate Program University of Georgia, Athens, GA MedicalResearch.com: What is the background for this study? Response: A burgeoning body of evidence highlights the role of several key genes within the oxytocin signaling pathway linked to sociability. Although many studies strongly supports the role of OXTR in the phenotypic expression of sociability in humans, the roles of other oxytocin pathway genes, such asOXT, has received relatively little attention. (more…)
Addiction, Author Interviews, Genetic Research, PNAS / 29.04.2016

MedicalResearch.com Interview with: Shelly B. Flagel, PhD Molecular and Behavioral Neuroscience Institute Department of Psychiatry University of Michigan, Ann Arbor, MI 48109 MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Flagel: We used a unique genetic animal model to examine individual differences in addiction liability. This model of selectively bred rat lines allowed us to examine the brains of “addiction-prone” and “addiction-resilient” rats before and after they were exposed to cocaine. I mportantly, even though all rats were exposed to the same amount of drug, only a certain subset exhibited addiction-like behavior. We focused our neurobiological analyses on two molecules that have been previously implicated in response to drugs of abuse – the dopamine D2 receptor and fibroblast growth factor (FGF2). We examined gene expression and the epigenetic regulation of these molecules and found that low levels of FGF2 in the core of the nucleus accumbens, a brain region known for regulating motivated behavior, may protect individuals from becoming addicted; whereas low levels of D2 in this brain region may predispose individuals to addiction. Further, this is the first study to show that epigenetic modulation of these molecules may be a predisposing factor and that, the epigenetic regulation of D2 may be especially important in susceptibility to relapse. (more…)
Author Interviews, Education, Pediatrics, PNAS, Social Issues / 26.04.2016

MedicalResearch.com Interview with:

Joan L. Luby, MD Samuel and Mae S. Ludwig Professor of Child Psychiatry Director, Early Emotional Development Program Washington University School of Medicine St. Louis, Missouri

MedicalResearch.com: What is the background for this study? What are the main findings?  Dr. Luby: The study was designed to investigate brain development in early onset mental disorders. The main findings validate depression in preschoolers with brain change evident this young similar to that known in adults. We also found effects of maternal support on brain development in this process which is what the current paper focuses on . (more…)
Author Interviews, Multiple Sclerosis, PNAS / 12.04.2016

MedicalResearch.com Interview with: Dr. Christian W. Gruber PhD Assistant Professor tenure-track and ARC Future Fellow The University of Queensland, School of Biomedical Sciences, Australia Medical University of Vienna, Center for Physiology and Pharmacology, Vienna, Austria  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Gruber: We initially discovered that particular circular peptides (called cyclotides) isolated from an African traditional herbal medicine have promising immunosuppressive properties (Gründemann et al., 2012, J Nat Prod, 75(2):167-74). Cyclotides are considered a pharmacological ‘treasure trove’ (Koehbach et al., 2013, PNAS, 110(52):21183-8). Hence we aimed at testing the efficacy of these peptides to treat and ameliorate multiple sclerosis, and found that the new plant-derived drug (‘T20K’), in an animal model, can block the progression of the disease. We demonstrated in an animal model that T20K stopped progression of the normal clinical symptoms of multiple sclerosis (Thell et al., PNAS, doi: 10.1073/pnas.1519960113). (more…)
Author Interviews, Brain Cancer - Brain Tumors, Brigham & Women's - Harvard, PNAS / 06.04.2016

MedicalResearch.com Interview with: Rakesh K. Jain, Ph.D. A.W.Cook Professor of Radiation Oncology (Tumor Biology) Director, E.L. Steele Laboratory Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital Boston, MA    02114

MedicalResearch.com: What is glioblastoma and why is it difficult to treat?

Dr. Jain: Glioblastoma (GBM) is the most common malignant tumor of the brain, and remains highly lethal. The standard treatment consists of surgical removal followed by chemo-radiation and anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) antibody. Unfortunately, glioblastoma cells invade the brain far from the original tumor mass. Hence, even with the best surgical techniques it is not possible to remove all tumor cells, as they are embedded in vital parts of the brain at the time of the surgery. As a result, even after multimodal therapies, most  glioblastoma patients succumb to their disease within 2 years. New approaches are desperately needed.

MedicalResearch.com: What is anti-angiogenic therapy and why is it used for glioblastoma?

Dr. Jain: One key feature ofglioblastomas is their highly abnormal, leaky and ineffective vasculature. This leads to brain swelling around the tumor and poor tumor blood perfusion, which in turn can render the tumors more aggressive. These vascular abnormalities are due to the uncontrolled overproduction in GBMs of angiogenic factors such as VEGF. Anti-angiogenic therapies using anti-VEGF agents can transiently “normalize” the GBM vasculature structure and function and reduce brain swelling, increase blood perfusion, and impact morbidity and survival. Unfortunately, even when this therapy is added to the standard therapy with surgery and chemo-radiation, GBM patients typically do not survive on average more than 1.5 years. (more…)
Author Interviews, Education, NYU, Pediatrics, PNAS, Weight Research / 15.03.2016

MedicalResearch.com Interview with: Michele Leardo Assistant Director Institute for Education & Social Policy New York University New York, NY 10012 MedicalResearch.com: What is the background for this study? What are the main findings? Response: US school districts increasingly distribute annual fitness and body mass index (BMI) “report cards” to students and parents. Such personalized informational interventions have appeal in economics because they can inform parents about their children's obesity status at relatively low costs. Awareness of the weight status can lead to behavioral responses that can improve health. New York City public schools adopted Fitnessgram in 2007-2008, reporting each student’s BMI alongside categorical BMI designations. We examined how being classified as “overweight” for the previous academic year affected the students’ subsequent BMI and weight. Specifically, we compared female students whose BMI was close to their age-specific cutoff for being considered overweight with those whose BMI narrowly put them in the “healthy” category. We find that being labeled overweight had no beneficial effects on students’ subsequent BMI and weight. (more…)
Author Interviews, Cancer Research, Genetic Research, PNAS / 28.01.2016

MedicalResearch.com Interview with: Nina Bhardwaj, MD, PhD and Director of Immunotherapy and professor of Hematology and Medical Oncology Benjamin Greenbaum, PhD Assistant Professor The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai   Medical Research: How did the discovery of the group of non-coding RNA molecules in cancer cells that sets off an immune response come about? Dr. Greenbaum: Our work is a collaboration between my lab, which is computational, and the Bhardwaj lab, focused on cancer immunology. I had previously made the observation that certain RNA viruses were avoiding certain motifs, such as CpG dinucleotide containing motifs, and the Bhardwaj lab tested whether those motifs could set off an immune response. Recent work had shown that tumors transcribe unusual RNA with immunological consequences, so we investigated whether the same sort of approaches we had used for viral RNA worked here. Dr. Bhardwaj: It has recently become clear that, due to epigenetic alterations, tumors transcribe non-coding RNAs that are typically silenced. Often such RNA emanates from the “dark matter” genome. Many of these regions consist of repetitive elements and endogenous retroelements that are rarely transcribed in normal tissue. At the same time, due to immunotherapy, understanding the role of the immune system and immune activation in tumors has become critically important. The activation of specific elements of the innate immune system in a tumor may have either beneficial or detrimental effects for patients. Moreover, recent work has suggested that endogenous element activation can lead to improved immunotherapy outcomes. Therefore, it is critically important to understand the nature of innate immune activation in tumors and what triggers are responsible for these responses. We have been developing methods to detect abnormal patterns in viral RNA that may indicate activation of the innate immune system. We have found that patterns of motif usage avoided in the evolution of viruses, such as influenza, indicate RNA features that provoke an innate immune response. The innate immune system is capable of sensing motifs in viruses. We tested directly whether these avoided patterns are immunostimulatory. Medical Research: What are the main findings? Dr. Bhardwaj: We used a novel quantitative approach, derived from methods in statistical physics, to characterize all of the non-coding RNA transcribed by normal tissue and compared them to the non-coding RNA found in tumors. We found that while the non-coding RNA transcribed in normal tissue displays patterns of motif usage consisting with that of coding RNA, the RNA transcribed in tumors, yet rarely found in normal tissue, can have motif usage more typically associated with viral and bacterial genomes. We predicted a handful of such RNA are immunostimulatory and validated this prediction in antigen presenting cells. We then showed that this sensing may come from a subset of the innate immune system associated with pathogen RNA sensing. We called these RNA “i-ncRNA”, for immunostimulatory non-coding RNA. (more…)
Author Interviews, Cancer Research, PNAS / 21.01.2016

MedicalResearch.com Interview with: Dr. Elizabeth Murchison Menzies Institute for Medical Research University of Tasmania Save the Tasmanian Devil Program Tasmanian Department of Primary Industries, Parks, Water and the Environment Hobart Australia Department of Veterinary Medicine University of Cambridge, Cambridge UK Medical Research: What is the background for this study? Dr. Murchison: Transmissible cancers are cancers that can be transmitted between individuals by the transfer of living cancer cells. Transmissible cancers emerge only very rarely in nature, and until now only three examples were known. One of the three known naturally occurring transmissible cancers affects Tasmanian devils, the world’s largest carnivorous marsupial. This disease, which causes disfiguring facial tumours, was first observed in the late 1990s, and since then the disease has spread widely through the Tasmanian devil population. This transmissible cancer first emerged as a cancer in a single individual Tasmanian devil that probably lived about 30 years ago; this devil’s cancer cells have continued to survive by transmitting between hosts by biting. Medical Research: What are the main findings? Dr. Murchison: In late 2014, routine monitoring of the Tasmanian devil population led to the discovery of a male devil with facial tumours that resembled the known Tasmanian devil transmissible facial cancer. However, genetic analysis of this tumour indicated that the tumour in this devil was derived from a second transmissible cancer that was genetically unrelated to the first transmissible cancer in this species. Indeed, the genetic profile of this second cancer indicated that it had originally emerged from a male animal. This second cancer has subsequently been found in nine additional devils in the same part of Tasmania. (more…)
Author Interviews, Exercise - Fitness, PNAS / 22.12.2015

MedicalResearch.com Interview with: Ekaterina Subbotina, Ph.D. Postdoctoral Research Scholar University of Iowa Carver College of Medicine Iowa City, IA 52242  Medical Research: What is the background for this study? Dr. Subbotina: Exercises represent the most natural and effective way to maintain physical and metabolic well-being. Lack of physical activity can contribute to many preventable diseases such as cardiovascular disease, stroke, cancer, diabetes and obesity. It is known that moderate exercise is beneficial for health but the mechanism of this effect is only partially understood. It becomes more and more evident that skeletal muscles function as an organ that produces and secretes biologically active molecules called myokines. Studies of the biological role and mechanism of action of myokines are important for understanding of muscle function under sedentary and exercise conditions. (more…)
Author Interviews, Autism, Pediatrics, PNAS / 21.11.2015

MedicalResearch.com Interview with: Lauren Kenworthy, PhD Associate professor of Neurology, Pediatrics, and Psychiatry George Washington University School of Medicine Director of the Center for Autism Spectrum Disorders Children’s National Health System Medical Research: What is the background for this study? What are the main findings? Dr. Kenworthy: Connectivity among brain regions may account for variability in autism outcomes not explained by age or behavioral measures, according to a study. We have previously shown that behavioral assessments of intelligence, baseline adaptive behavior and executive functions in people with autism can explain some of the variation in outcomes and function, but we have not been able to explain all of the variance in outcome (e.g. Pugliese et al 2015a, 2015b). In this study, we found that 44% of the study group experienced significant change in scores on adaptive behavior between the initial scan and follow-up. Connectivity between three resting-state networks, including the salience network, the default-mode network, and the frontoparietal task control network, was linked not only to future autistic behaviors but also to changes in autistic and adaptive behaviors over the post-scan period. Further, connectivity involving the salience network and associated brain regions was associated with improvement in adaptive behaviors, with 100% sensitivity and around 71% precision. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, PNAS / 12.11.2015

MedicalResearch.com Interview with: Lei Xu, MD, PhD Steele Laboratory of Tumor Biology Radiation Oncology Department Massachusetts General Hospital Medical Research: What is the background for this study? Dr. Lei Xu: Neurofibromatosis 2 is characterized by benign tumors that develop throughout the nervous system. The most common site of these tumors is the eighth cranial nerve, which carries hearing and balance information from the ears to the brain. Although these vestibular schwannomas grow slowly, they usually lead to a significant or total hearing loss by young adulthood or middle age. The tumors can also press on the brain stem, leading to headaches, difficulty swallowing and other serious neurologic symptoms. While the tumors can be surgically removed or destroyed with radiation treatment, both approaches can also damage hearing. Several previous investigations had suggested that – unlike other benign tumors – vestibular schwannomas induce the formation of new blood vessels, as malignant tumors do. A 2009 New England Journal of Medicine study led by Scott Plotkin, MD, PhD, at Massachusetts General Hospital reported that treatment with the antiangiogenesis drug bevacizumab caused shrinkage of NF2-schwannomas in most of the treated patients and improved hearing in more than half. But the limitations of that approach – the fact that not all patients responded, that the hearing improvement was often transient and that some patients could not tolerate long-term bevacizumab treatment – indicated the need to better understand the mechanisms of anti-angiogenesis on the function of tumor-bearing nerves. (more…)
Author Interviews, Depression, PNAS / 20.08.2015

Edward Hill PhD student Centre for Complexity Science Member of the Warwick Infectious Disease Epidemiology Research Centre (WIDER) at the University of WarwickMedicalResearch.com Interview with: Edward Hill PhD student Centre for Complexity Science Member of the Warwick Infectious Disease Epidemiology Research Centre (WIDER) at the University of Warwick Medical Research: What is the background for this study? Response: Depression is a major public health concern worldwide. We know social factors, such as living alone, can influence whether someone becomes depressed. We also know that social support (having people to talk to) is important for recovery from depression. Our study is slightly different as we looked at the effect of being friends with people on whether you are likely to develop depression or recover from being depressed. To do this, we looked at over 2,000 adolescents in a network of US high school students to see how their mood influenced each other. (more…)
Author Interviews, Genetic Research, Heart Disease, PNAS, Rheumatology / 27.07.2015

MedicalResearch.com Interview with: Philippe Bouillet, PhD Walter and Eliza Hall Institute Parkville, Vic Australia Medical Research: What is the background for this study? What are the main findings? Dr. Bouillet: This study was initiated when we discovered mice that developed rheumatoid arthritis as a result of what was obviously a spontaneous dominant genetic mutation. Using several approaches, we identified the mutation as the insertion of a mobile genetic element called retrotransposon into the regulatory sequences of the gene encoding tumor necrosis factor (TNF). The mutation caused excessive amounts of TNF to be produced, a known cause of rheumatoid arthritis. The surprise came when some mice with the mutation died prematurely and suddenly with from heart disease. We showed that excess TNF also led to inflammation of the aortic and mitral valves, causing aortic regurgitation. Depending on the genetic background of the mice, the disease could also culminate in aortic aneurysm and death. We also investigated the regulatory region of the TNF gene and identified novel regulators and a new genetic element that normally make sure that levels of serum TNF are kept within reasonable limits, high enough to ensure its numerous physiological functions, low enough to prevent its harmful effects such as those described here. (more…)
Author Interviews, Diabetes, Johns Hopkins, Macular Degeneration, Ophthalmology, PNAS / 29.05.2015

MedicalResearch.com Interview with: Akrit Sodhi, M.D., Ph.D. Assistant Professor of Ophthalmology Retina Division Wilmer Eye Institute Johns Hopkins Medical Institutions Medical Research: What is the background for this study? What are the main findings? Dr. Sodhi: Diabetic eye disease is the most common cause of severe vision loss in the working age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In proliferative diabetic retinopathy, retinal ischemia leads to the upregulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization, in some, but not all diabetic patients, implicating additional factor(s) in proliferative diabetic retinopathy pathogenesis. In our study, we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identified angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is upregulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from proliferative diabetic retinopathy patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of proliferative diabetic retinopathy and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease. (more…)
Alcohol, Author Interviews, PNAS, Scripps / 19.05.2015

Interview of Candice Contet, Ph.D. Assistant Professor The Scripps Research Institute, La Jolla, CAMedicalResearch.com Interview with: Interview of Candice Contet, Ph.D. Assistant Professor The Scripps Research Institute, La Jolla, CA MedicalResearch: What is the background for this study? Dr. Contet: Alcohol changes the activity of numerous proteins in the brain. One of them is an ion channel found in neurons, the G-protein activated inwardly rectifying potassium (GIRK) channel. It is however unknown whether the ability of alcohol to open GIRK channels matters for its effects in vivo, i.e. how tipsy we feel or how motivated we are to drink alcohol. To address this question, we studied mice that are lacking one of the components of GIRK channels, the GIRK3 subunit. These mice behave normally in the absence of alcohol, and we sought to determine whether they respond differently to alcohol. MedicalResearch: What are the main findings? Dr. Contet: We found that the absence of GIRK3 did not impact how fast the mice clear alcohol from their body nor how sensitive they are to alcohol intoxication. Alcohol reduced their motor coordination, made them sleepy and lowered their body temperature to the same extent as in normal mice. GIRK3-deficient mice also drank as much alcohol as normal mice when they were given continuous access to alcohol, a situation in which mice sporadically drink throughout the day but rarely get intoxicated. By contrast, when mice are given access to alcohol only for a couple hours per day at a specific time of the day, they drink to the point of intoxication. Under these conditions, which emulate “binge drinking”, the GIRK3-deficient mice drank more than normal mice. The next step was to locate the region of the brain responsible for the effect of GIRK3 on binge drinking. We turned our attention to the mesocorticolimbic dopaminergic pathway, a neural circuit that facilitates reward seeking. This pathway originates in an area of the midbrain called the ventral tegmental area (VTA) and releases the neurotransmitter dopamine in two forebrain areas: the ventral striatum and the prefrontal cortex. Alcohol, like other drugs of abuse, activates this pathway. When we reintroduced GIRK3 in the VTA of GIRK3-deficient mice, their alcohol intake dropped down to normal levels. Increasing the levels of GIRK3 in the VTA of normal mice reduced their alcohol consumption even further. We concluded that GIRK3 in the VTA keeps binge drinking in check: the more GIRK3, the less binge drinking. We then wanted to understand how GIRK3 controls binge drinking: do the GIRK3-deficient mice drink more because alcohol is more rewarding to them, or because more alcohol is needed for them to experience the same level of reward? To answer this question, we measured the activity of VTA neurons in brain slices. Alcohol usually make VTA neurons fire more – but in the absence of GIRK3, these neurons were completely insensitive to alcohol, even at a very high concentration. We also measured the levels of dopamine in the ventral striatum. Injecting mice with a moderate dose of alcohol usually causes a rise in dopamine levels – but again, GIRK3-deficient mice were completely unresponsive. These results may seem paradoxical. If the canonical “reward pathway” of the brain cannot be activated by alcohol, these mice should not have any motivation to drink alcohol. But the mesocorticolimbic dopaminergic pathway is not the only brain circuit responsible for the rewarding properties of alcohol, and we think that GIRK3-deficient mice end up drinking more alcohol to activate alternative circuits more strongly than normal mice would. (more…)
Author Interviews, Cancer Research, MD Anderson, PNAS / 04.03.2015

MedicalResearch.com Interview with: Kristen Turner PhD. (first author) and Wei Zhang, Ph.D. Professor Department of Pathology Director, Cancer Genomics Core Lab University of Texas MD Anderson Cancer Center Houston, Texas 77030 Medical Research: What is the background for this study? What are the main findings? Response: Glioblastoma (GBM) is the most commonly diagnosed type of brain tumor and is among the most aggressive and challenging cancer types to treat. The traditional approaches to combat this pervasive cancer include surgery combined with radiation and chemotherapy (temozolomide); yet, most will succumb to the disease in just over one year. In this study, we investigated the Akt family of proteins that are known to be highly active in the majority of Glioblastoma cases. We compared each Akt family member and its ability to initiate glioma progression. We discovered that activation of the third Akt member (Akt3) led to glioma progression and very aggressive tumors. We then studied these tumors to compare their molecular attributes and found evidence of increased DNA repair. Finally, we discovered that the Akt3-induced DNA repair function led to increased survival of Glioblastoma cells after treatment with the DNA damaging agents, radiation and temozolomide. (more…)
Author Interviews, PNAS, Statins / 04.03.2015

Professor Andrew W. Munro FRSC FSB Professor of Molecular Enzymology Manchester Institute of Biotechnology Faculty of Life Sciences University of Manchester Manchester UKMedicalResearch.com Interview with: Professor Andrew W. Munro FRSC FSB Professor of Molecular Enzymology Manchester Institute of Biotechnology Faculty of Life Sciences University of Manchester Manchester UK MedicalResearch: What is the background for this study? What are the main findings? Dr. Munro: Statins are blockbuster drugs that inhibit the key enzyme in cholesterol synthesis: 3-beta-hydroxymethylglutaryl CoA reductase (HMG-CoA reductase), which catalyzes the rate-limiting step in the biosynthesis of cholesterol. As a consequence, statin drugs reduce levels of low-density lipoprotein (LDL-) cholesterol, are effective against hypercholesterolemia and reduce the risk of atherosclerosis and heart attack. One of the major statin drugs is pravastatin, which is derived from a fungal natural product called compactin. The process of conversion of compactin into pravastatin involves the use of an oxygen-inserting enzyme called a cytochrome P450 (or P450), which catalyzes the hydroxylation of compactin to form pravastatin. In order to produce a more cost-efficient and streamlined route to pravastatin production, our teams from the University of Manchester (UK) and DSM (Delft, The Netherlands) developed a single-step process for pravastatin production. This process involved harnessing the productive efficiency of an industrial strain of the beta-lactam (penicillin-type) antibiotic producing fungus Penicillium chrysogenum. The beta-lactam antibiotic genes were deleted from this organism, and replaced by those encoding for compactin biosynthesis (transferred from a different Penicillium species). This led to high level production of compactin, but also to substantial formation of a partially degraded (deacylated) form. To get around this problem and in order to further improve compactin production, the enzyme responsible for the deacylation (an esterase) was identified and the gene encoding this activity was deleted from the production strain. The final stages of development of the novel, one-step pravastatin production process involved the identification of a suitable P450 enzyme that could catalyze the required hydroxylation of compactin. A bacterial P450 was identified that catalyzed hydroxylation at the correct position on the compactin molecule. However, the stereoselectivity of the reaction was in favour of the incorrect isomer – forming predominantly epi-pravastatin over the desired pravastatin. This was addressed by mutagenesis of the P450 – ultimately leading to a variant (named P450Prava) that hydroxylated compactin with the required stereoselectivity to make pravastatin in large amounts. Determination of the structure of P450Prava in both the substrate-free and compactin-bound forms revealed the conformational changes that underpinned the conversion of the P450 enzyme to a pravastatin synthase. The expression of P450Prava in a compactin-producing strain of P. chrysogenum enabled pravastatin production at over 6 g/L in a fed-batch fermentation process, facilitating an efficient, single-step route to high yield generation of pravastatin. (more…)
Author Interviews, Brigham & Women's - Harvard, PNAS, Sleep Disorders / 06.02.2015

Christa Van Dort PhD Department of Anesthesia, Critical Care, and Pain Medicine, Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts General Hospital, Harvard Medical School Boston, MA, 02114MedicalResearch.com Interview with: Christa Van Dort PhD Department of Anesthesia, Critical Care, and Pain Medicine, Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts General Hospital, Harvard Medical School Boston, MA, 02114 Medical Research: What is the background for this study? What are the main findings? Dr. Van Dort:  Sleep is crucial for survival and maintenance of health.  Inadequate sleep and sleep disorders impair many brain and body functions such as executive function, the immune system and memory consolidation. The benefits of sleep are dependent on normal sleep physiology and patterns. Natural sleep is composed of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep alternating every 90 min in humans.  Each stage provides different benefits, for example deep NREM sleep is associated with feeling rested and REM sleep is important for learning. Current sleep aids do not effectively restore normal sleep physiology or timing and as a result do not fulfill the important functions of natural sleep.  To develop new strategies for reproducing natural sleep, we aimed to understand each component of sleep (NREM and REM sleep) individually and then in combination. Cholinergic neurons have been hypothesized to control REM sleep for many years but no one had been able to test this directly due to limited methodology. Optogenetics solved this problem by giving us the ability to activate selectively the cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT). The primary finding of this study was that cholinergic neurons in the PPT and LDT are sufficient to drive REM sleep from NREM sleep. These cholinergic neurons were important for initiation of REM sleep but not the duration of REM sleep. Understanding REM sleep control is an important first step in reproducing normal sleep patterns and by itself could enhance learning and memory. (more…)
Author Interviews, Brigham & Women's - Harvard, Infections, PNAS / 28.01.2015

Rakesh K. Jain, Ph.D. A.W.Cook Professor of Tumor Biology Director, E.L. Steele Laboratory Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital Boston, MA    02114MedicalResearch.com Interview with: Rakesh K. Jain, Ph.D. A.W.Cook Professor of Tumor Biology Director, E.L. Steele Laboratory Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital Boston, MA    02114 Medical Research: What are the primary findings of this study and why are they important? Dr. Jain: Pulmonary granulomas are the hallmark of the Tuberculosis (TB) infection, yet it is not fully understood how these structures contribute to disease progression and treatment resistance. In this study, we applied our insight in tumor biology – gained over three decades – to explore and exploit the similarities between vasculature (blood vessel network) in solid cancerous tumors and TB pulmonary granulomas. We demonstrate for the first time that TB granulomas have abnormal vasculature. This abnormality provides a mechanism for the observation that TB granulomas are often hypoxic (have low oxygen conditions) and have differential distribution of anti-TB drugs. We showed that bevacizumab, a widely prescribed anti-VEGF antibody for cancer and eye diseases, is able to create more structurally and functionally normal granuloma vasculature and improve small molecule delivery. This study suggests that vasculature normalization in combination with anti-TB drugs has the potential to enhance treatment in patients with TB. Tuberculosis (TB) is a global scourge that is responsible for nearly 2 million deaths annually. Due to the inability of currently available treatment regimens to eradicate this devastating disease, it is clear that new treatment strategies are urgently needed. Unlike many researchers in the TB field, we do not seek to discover new therapeutics that target bacterial resistance; instead, we strive to overcome physiological resistance to treatment resulting from abnormalities in the granuloma vasculature that impair drug delivery and create hypoxia that impairs efficacy of drugs and immune system. By using an FDA-approved drug, our study has the potential to be rapidly translated into the clinic. Medical Research: Has any association previously been made between the vascular structure of TB granulomas and the challenges of treating TB – both the fact that treatment takes so long and the development of multidrug resistance? Dr. Jain: Our study is the first to implicate a specific facet of the granuloma – the abnormal vasculature – as a potential contributor to disease progression and treatment resistance. Granuloma hypoxia is known to negatively affect the local immune system while conferring resistance to some of the TB drugs. Our collaborators have shown that different anti-TB drugs have differential abilities to penetrate the granuloma structure, especially to the interior granuloma regions where the TB bacteria are found in greatest numbers. Our study is the first to provide evidence that by modulating the granuloma vasculature, hypoxia can be alleviated and drug delivery can be improved. (more…)
Author Interviews, Infections, PNAS, University Texas / 28.01.2015

Christopher S. Sullivan, Ph.D. Associate Professor Dept. Molecular Biosciences The University of Texas at Austin anMedicalResearch.com Interview with: Christopher S. Sullivan, Ph.D. Associate Professor Dept. Molecular Biosciences The University of Texas at Austin and Jennifer Cox, lead author Graduate student in Dr. Sullivan’s laboratory. Jennifer Cox, lead author Graduate student in Dr. Sullivan’s laboratory. Jennifer Cox's Replies: MedicalResearch: What is the background for this study? What are the main findings? Jennifer Cox: In the last decade, researchers have identified that many viruses encode small regulatory molecules known as microRNAs. Some viral microRNAs are able to manipulate host processes including stress responses, proliferation, and cell death. However, there are many viral microRNAs with unknown functions. Many of the viruses that encode microRNAs are associated with severe pathologies including various cancers so understanding the role of viral microRNAs can shed light on virus biology. For this study, we focused on identifying viral microRNAs that can regulate innate immune signaling for several reasons. First, all viruses have proteins to combat interferon signaling. Second, we have identified microRNAs from two diverse viruses (retro and annello) that can inhibit interferon signaling so we hypothesized that additional viral microRNAs will perform this same function. We screened ~70 viral microRNAs for the ability to regulate innate immune signaling and identified three herpesviruses, Epstein-Barr Virus, Kaposi’s Sarcoma Associated Virus, and Human Cytomegalovirus, that inhibit the interferon response. Epstein-Barr Virus, causes an estimated 200,000 cancers every year, including lymphomas, nasopharyngeal cancers and some stomach cancers. Interestingly, most of these cancers harbor latent EBV – a state of limited gene expression that produces no virus. microRNAs are one of the few viral gene product expressed during latency. Our further work identified that Epstein-Barr Virus, KSHV, and Human Cytomegalovirus have converged to inhibit interferon signaling in the same manner – through decreasing expression of a central hub of innate immune signaling, CREB binding protein (CBP). We show that this regulation conveys partial resistance to the negative effects of interferon treatment on an EBV+ lymphoma cell line. Additionally, removing the microRNA from a similar cell line increases the sensitivity to interferon. Interferon can be used in combination with other chemotherapies to treat lymphomas but varies in success. Our results may partially explain the variability seen in patients with EBV-associated cancers. (more…)
Author Interviews, Cognitive Issues, PNAS / 14.01.2015

Dr Christos Pliatsikas PhD Lecturer in Cognitive Psychology School of Psychology University of Kent Canterbury KentMedicalResearch.com Interview with: Dr Christos Pliatsikas PhD Lecturer in Cognitive Psychology School of Psychology University of Kent Canterbury Kent Medical Research: What is the background for this study? What are the main findings? Response: It has been proposed that lifelong bilingualism preserves the white matter structure of older bilinguals because of the increased cognitive demands that come with handling two languages for their entire life. We wanted to extend this by investigating whether active (or "immersive") bilingualism in younger late bilinguals would give similar results. We showed increased white matter integrity (or myelination) in several white matter tracts that have also been shown to be better preserved in older lifelong bilinguals, compared to monolinguals.  Based on our findings, we propose that any benefit of bilingualism to the brain structure is simply an effect of actively handling two languages without presupposing lifelong usage- our participants were only about 30 years old and had been active bilinguals for only about 7-8 years. In other words, immersive bilingualism, even in late bilinguals, leads to structural changes that can bring about benefits in older age, by assisting in the preservation of the white matter structure in the brain. (more…)
Author Interviews, PNAS / 06.01.2015

Akiko Iwasaki PhD Departments of Immunobiology and Laboratory Medicine, Yale University School of Medicine New Haven, CT 06520 MedicalResearch.com Interview with: Akiko Iwasaki PhD Departments of Immunobiology and Laboratory Medicine, Yale University School of Medicine New Haven, CT 06520 Medical Research: What is the background for this study? What are the main findings? Dr. Iwasaki: Since the 1960's, scientists have known that the rhinovirus, the common cold virus, replicates preferably at the cooler temperature found in the nose (33C) but not at the core body temperature found in the lungs (37C). However, the underlying mechanisms were not known. We focused on the host immune response as a possible factor that enables rhinovirus to replicate in the cooler temperature. Indeed, we found that by incubating airway cells isolated from mice at the cooler temperature, immune response to the virus was impaired. By using airway cells from knockout mice from which key innate sensor pathway or interferon receptor is deleted, we found that the virus now replicates even at the core body temperature of 37C. These experiments showed us that the rhinovirus replication is blocked at the higher temperature because of a more efficient immune defense at the core body temperature. (more…)
Author Interviews, Cancer Research, PNAS, UCSD / 31.12.2014

MedicalResearch.com Interview with: Annie Samraj and  Ajit Varki MDDr. Annie Samraj MD Postdoc Fellow Varki Lab and Ajit VAjit Varki MD Distinguished Professor of Medicine and Cellular & Molecular Medicine Co-Director, Center for Academic Research and Training in Anthropogeny (CARTA) Co-Director, Glycobiology Research and Training Center (GRTC)  University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0687.arki MD Distinguished Professor of Medicine and Cellular & Molecular Medicine , Co-Director, Center for Academic Research and Training in Anthropogeny, Co-Director, Glycobiology Research and Training Center University of California, San Diego, La Jolla, CA Medical Research: What is the background for this study? What are the main findings? Dr. Varki: For the past decade, there has been increasing evidence that people who consume red meat (beef, pork, lamb) are at a higher risk for certain kinds of cancers. Although red meat is a high quality source of protein, iron and vitamins, too much consumption may be harmful to humans. While there are other hypotheses under consideration, we focused on a non-human sugar molecule called Neu5Gc in red meat that could explain the link to cancer risk. We extensively studied various foods and concluded that red meat (particularly beef) is rich in Neu5Gc. In contrast poultry, fish steaks and hen eggs have little or no Neu5Gc. From previous studies, we knew that animal-derived Neu5Gc could be incorporated into human tissues. In this study, we hypothesized that eating red meat could lead to inflammation if the body’s immune system targets the foreign Neu5Gc. Chronic inflammation is also known to instigate or promote tumor progression. To test this hypothesis, we used mice engineered to be similar to humans in that they lacked Neu5Gc, and also produced antibodies against it. When these mice were fed Neu5Gc, they developed systemic inflammation. Tumor formation increased fivefold and Neu5Gc accumulated in the tumors, proving the hypothesis. None of the various control groups of mice showed this effect. (more…)
Author Interviews, Genetic Research, Neurological Disorders, PNAS, Scripps / 26.12.2014

Elizabeth A. Thomas, Ph.D. Associate Professor Department of Molecular and Cellular Neuroscience The Scripps Research InstituteMedicalResearch.com Interview with: Elizabeth A. Thomas, Ph.D. Associate Professor Department of Molecular and Cellular Neuroscience The Scripps Research Institute   Medical Research: What is the background for this study? What are the main findings? Response: Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression, and in turn, influence resistance or susceptibility to disease.  Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, and are being proposed for therapeutic use in several neurological disorders.  Our previous studies have shown that selective HDAC inhibitors can cause beneficial effects in mouse models of Huntington’s disease, improving symptoms, and reducing severity of the disease.  Our current studies show that one such compound can alter DNA methylation, an epigenetic mark that can be inherited, leading to changes in gene expression that are seen in the parent mouse exposed directly to the drug, as well as in offspring from the drug-treated male mice.  Concurrent with these changes, we observed that offspring from drug-treated males shown improved disease symptoms, showing a delay in disease onset and a reduction of motor and cognitive symptoms that included improved performance in tests of balance, speed and memory. These finding have significant implications for human health as they enforce the concept that ancestral drug exposure may be a major molecular factor that can affect disease outcome in a subsequent generation.  One exciting aspect of our study is that the parental drug treatment made the offspring better, not worse, like other compounds known to cause transgenerational effects. (more…)
Author Interviews, MRSA, PNAS, UCLA, Vaccine Studies / 14.12.2014

Dr. Michael Yeaman Ph.D. Professor of Medicine, Infectious Disease Specialist Chief, Division of Molecular Medicine David Geffen School of Medicine at UCLA Los Angeles Biomedical Research Institute at Harbor-UCLA Medical CenterMedicalResearch.com Interview with: Dr. Michael Yeaman Ph.D. Professor of Medicine, Infectious Disease Specialist Chief, Division of Molecular Medicine David Geffen School of Medicine at UCLA Los Angeles Biomedical Research Institute Harbor-UCLA Medical Center Medical Research: What is the background for this study? What are the main findings? Dr. Yeaman: In the U.S. and around the globe, skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA) continue to endanger the health and lives of patients and otherwise healthy individuals. Treatment is difficult because MRSA is resistant to many antibiotics, and the infections can recur, placing family members and other close contacts at risk of infection. Infectious disease specialists at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) tested a new investigational vaccine, NDV-3, and found it holds new hope for preventing or reducing the severity of infections caused by the "superbug" MRSA. In the study, which was published Dec. 8 in the Proceedings of the National Academy of Sciences USA, the researchers reported that NDV-3, employing the recombinant protein Als3, can mobilize the immune system to fight off MRSA skin infections in an experimental model. The researchers found the vaccine works by enhancing molecular and cellular immune defenses of the skin in response to MRSA and other S. aureus bacteria in disease models. This is the first published study to demonstrate the effectiveness of a cross-kingdom recombinant vaccine against MRSA skin infections. NDV-3 is unique as it is the first vaccine to demonstrate it can be effective in protecting against infections caused by both S. aureus and the fungus Candida albicans. NDV-3 represents a novel approach to vaccine design that pioneers an approach termed convergent immunity. (more…)
Antibiotic Resistance, Author Interviews, PNAS / 05.09.2014

MedicalResearch.com Interview with: David T. Fox, Ph.D. Scientist 3 Los Alamos National Laboratory andDavid T. Fox, Ph.D. Scientist 3 Los Alamos National Laboratory and Prof. Samir Mitragotri Center for Bioengineering and Department of Chemical Engineering University of California, Santa Barbara, CA 93106Prof. Samir Mitragotri Center for Bioengineering and Department of Chemical Engineering University of California, Santa Barbara, CA 93106 Medical Research: What are the main findings of this study? Answer: Our research team identified a molten salt, choline-geranate, that possessed multiple beneficial biological traits. Specifically, when mixed in a 1:2 ratio (choline:geranate) this solvent is able to effectively disrupt and neutralize 72-hour biofilms formed by both Pseudomonas aeruginosa and Salmonella enterica. Further, our studies demonstrated the same solvent exhibited minimal cytotoxicity effects to normal human bronchial epithelial (NHBE) cells and was able to deliver an antibiotic, cefadroxil, through the stratum corneum into the epidermis and dermis. Most importantly, the research culminated in demonstrating the molten salt was able to neutralize ~95% of the bacteria found within a 24-hour P. aeruginosa biofilm when grown on a skin wound model (MatTek)  and ~98% of the bacteria when formulated with the antibiotic, ceftazidime. When the biofilm was treated with only antibiotic in a saline solution, less than 20% of the bacteria were neutralized. (more…)
Author Interviews, Diabetes, PNAS / 07.06.2014

Wouter De Haes Functional Genomics and Proteomics (Schoofs lab) Zoological Institute Leuven BelgiumMedicalResearch.com Interview with: Wouter De Haes Functional Genomics and Proteomics (Schoofs lab) Zoological Institute Leuven Belgium MedicalResearch: What are the main findings of the study? Answer: We discovered that the lifespan-extending effect of metformin is dependent on the increased production of reactive oxygen species in the roundworm Caenorhabditis elegans. Antioxidants, compounds that remove these reactive oxygen species, abolished the lifespan-extending effect of metformin, adding to the growing body of evidence that anti-oxidants are not as beneficial for health as generally assumed. We also identified the protein, belonging to the group of peroxiredoxins, that seems responsible for translating this increase in reactive oxygen species production into longevity. (more…)