Two Kinases That Keep Heart Beating May Be Targets For Heart Failure Therapy

Dr-Audrey-Chang credit: UT Southwestern

Dr. Audrey Chang

MedicalResearch.com Interview with:
Dr. Audrey Chang, PhD
Kamm-Stull Lab
UT Southwestern Medical Center
AudreyN.Chang@UTSouthwestern.edu

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.

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Patients More Likely to Trust Physicians Who Disclose Bias

MedicalResearch.com Interview with:

Sunita Sah MD PhD Management & Organizations Johnson Graduate School of Management Cornell University

Dr. Sunita Sah

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.    Continue reading

Modifying One Gene For Oxytocin Changes Behavior in Humans

MedicalResearch.com Interview with:

Brian W. Haas PhD Department of Psychology Interdisciplinary Neuroscience Graduate Program University of Georgia, Athens, GA

Dr. Brian Haas

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.

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Study Provides More Evidence of Biologic Basis of Drug Addiction

MedicalResearch.com Interview with:

Shelly B. Flagel, PhD Molecular and Behavioral Neuroscience Institute Department of Psychiatry University of Michigan, Ann Arbor, MI 48109

Dr. Shelly B. Flagel

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.

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Early Maternal Influence Critical To Childhood Brain Development

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

Dr. Joan Luby

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 .

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New Class of Herbal Peptides May Ameliorate Multiple Sclerosis Symptoms

MedicalResearch.com Interview with:

Dr-Christian-Gruber.jpg

Dr. Christian Gruber

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).

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Dual Treatment Strategies Can Slow Glioblastoma Tumor Growth

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

Dr. Rakesh Jain

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.

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Obesity Reporting By Schools Did Not Improve Students’ BMI

MedicalResearch.com Interview with:

Michele Leardo Assistant Director Institute for Education & Social Policy New York University New York, NY 10012

Michele Leardo

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.

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Cancer Cells Use Genomic ‘Junk DNA’ To Influence Immune Reactions

MedicalResearch.com Interview with:

Nina Bhardwaj, MD, PhD and Director of Immunotherapy and professor of Hematology and Medical Oncology

Dr. Nina Bhardwaj

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

Dr. Benjamin Greenbaum

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.

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Tasmanian Devils Have Given Rise To Two Distinct Transmissible Cancers

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

Dr. Murchison

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.

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Musculin: A Muscle Produced Peptide That Promotes Physical Endurance

Ekaterina Subbotina

Dr. Subbotina

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.

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Brain Connectivity Predicts Traits and Functioning in Autism

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

Dr. Kenworthy

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.

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Anti-VEGF Treatment Plus Radiation For Schwannoma Control

Dr-Lei-Xu.jpg

Dr. Lei Xu

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.

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Fortunately, Good Moods Are Contagious But Depression Is Not

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.

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TNF Gene May Link Rheumatoid Arthritis and Heart Disease

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.

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