Organic Compounds In Bowel Responsible For Longer Healthier Lives in Variety of Species

MedicalResearch.com Interview with:

Daniel Kalman, Ph.D. Department of Pathology and Laboratory Medicine Emory University

Dr. Kalman

Daniel Kalman, Ph.D.
Department of Pathology and Laboratory Medicine
Emory University

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

  1. We think a lot about living longer, but that means we will also have a longer period of frailty and infirmity, which isn’t optimal. Moreover, with geriatric populations projected to expand by 350 fold over the next 40 years, healthcare costs will be unsustainable.
  2. We were interested in understanding how health span of animals is regulated, and whether the microbiota plays a role. The microbiota, which is composed of bacteria inside and on us, when dysregulated (called dysbiosis) contributes to disease; the question we asked was whether it could also contribute to healthy aging, and how.
  3. We showed that animals of widely divergent phyla and separated by hundreds of millions of years of evolutionary time, all utilize indoles to regulate how well they age; in short indoles  make older animals look younger by various metrics, including motility, and fecundity.

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Targeting CD44s May Make Glioblastoma More Sensitive To Clinical Treatment

MedicalResearch.com Interview with:

Chonghui Cheng, M.D., Ph.D. Associate Professor Department of Molecular & Human Genetics Lester & Sue Smith Breast Center Baylor College of Medicine Houston, TX77030

Dr. Cheng

Chonghui Cheng, M.D., Ph.D.
Associate Professor
Department of Molecular & Human Genetics
Lester & Sue Smith Breast Center
Baylor College of Medicine
Houston, TX77030

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

Response: Understanding the mechanisms that give cancer cells the ability to survive and grow opens the possibility of developing improved treatments to control or cure disease. In the case of glioblastoma multiforme, the deadliest type of brain cancer, abnormal EGFR signaling is frequently observed.

Treatment with the EGFR inhibitor erlotinib attempts to kill cancer cells. However, the clinical benefit of treatment with this and other EGFR inhibitors has been limited by the development of drug resistance.

Scientists at Baylor College of Medicine discovered that the molecule CD44s seems to give cancer cells a survival advantage. Eliminating this advantage by reducing the amount of CD44s resulted in cancer cells being more sensitive to the deadly effects of the drug erlotinib.

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Neural Tube Defects in Infants Share Molecular Processes With Neurodegenerative Diseases

MedicalResearch.com Interview with:

Zhiyong Zhao, Ph.D. Associate Professor Department of Obstetrics, Gynecology & Reproductive Sciences University of Maryland School of Medicine Baltimore, MD

Dr. Zhiyong Zhao

Zhiyong Zhao, Ph.D.
Associate Professor
Department of Obstetrics, Gynecology & Reproductive Sciences
University of Maryland School of Medicine
Baltimore, MD

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

Response: Diabetes in early pregnancy can cause neural tube defects in fetus. The defects are a result of failure in neural tube closure, due to excess cell death. The aim of this study was to delineate molecular processes that induce cell death.

The main findings of this study are:
(1) Hyperglycemia disrupts protein folding. The misfolded proteins, including the ones that are associated with neurodegenerative diseases, form aggregates, indicating similar molecular processes in both fetal neural tube defects and adult neurodegenerative diseases.
(2) Protein aggregation leads to formation of a neurodegenerative disease-related cell death inducting mechanism.

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Human Placenta May Be Most Vulnerable To Zika In First Trimester

MedicalResearch.com Interview with:

R. Michael Roberts

Dr. R. Michael Roberts

R. Michael Roberts PhD
Curators’ Distinguished Professor
240b Bond Life Sciences Center
Columbia, Missouri 65211-7310

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

Response: My background in placental biology and in communication between the embryo and the mother in early pregnancy made me curious about how the zika virus (ZIKV) crossed the placenta in early pregnancy to cause microcephaly. My group had been working on a laboratory model for placental trophoblast for over 10 years. We generate trophoblast from human pluripotent cells (embryonic stem cells and induced pluripotent stem cells) by exposing them to the growth factor BMP4 and two pharmaceuticals that inhibit the signaling pathways necessary to maintain pluripotency. I was curious to determine whether or not ZIKV could infect these cells, replicate, and release infectious virus, because work from my collaborator Yoel Sadovsky at the University of Pittsburgh indicated that the mature placenta was likely to be resistant to infection.

MedicalResearch.com: What are the main findings?

Response: There are, I believe two striking outcomes from this work.

One is that the results indicate that the human placenta is likely most vulnerable to infection by Zika during the first trimester. We also suggest that women whose fetus is affected from an infection occurring later in pregnancy likely had a past dengue infection. The second striking result is that the African strain of Zika may have greater virulence towards early placenta than the Asian strains, such as the ones that have spread in the New World.

The work with the virus only began when we realized that term trophoblasts lacked expression of the genes that encode the protein factors that promote flavivirus infection (ZIKV is a flavivirus, like dengue, West Nile virus), e.g. TYRO3, AXL, MERTK, and also had a poised innate immune system that would counteract virus replication. Conversely, the trophoblasts we create from embryonic stem cells had the factors that would promote virus uptake, but seemed ill-prepared to counteract virus replication once infection occurred. In other words, the early placental trophoblasts were potentially more susceptible to infection. We confirmed this hypothesis with two strains of ZIKV (an Asian strain related to the one encountered in Brazil, and an African strain often considered to be relatively benign). What was unexpected was the African strain appeared to be more virulent than the Asian strain.

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

Response: Whether the early placenta could be protected by some sort of immune therapy or by prior vaccination of the mother is clearly uncertain at present. Vaccination programs have not been altogether successful when used to protect against Dengue, which is a virus related to ZIKV.

There is evidence that the early placenta is also permissive to other viruses, such as Rubella. Also there is a very interesting paper in the Journal of the American medical Association by Honein et al. that was published on December 15, 2016. In this study, the overall risk for microcephaly and other brain abnormalities in infants born to a large cohort of U.S. women exposed to ZIKV while traveling (n = 442) was 5.9 % (18), and, of these, there were no cases noted among the women known to have been infected during their second or third trimesters. In Brazil, women appear to be at risk for fetal infections by ZIKV throughout their pregnancies but this may be because they had experienced an earlier infection by Dengue. I have discussed this puzzle in the paper.

I have no disclosures to make, nor conflicts of interest regarding the research or this response to your queries.

Citation:

PNAS Plus – Biological Sciences – Applied Biological Sciences:
Megan A. Sheridan, Dinar Yunusov, Velmurugan Balaraman, Andrei P. Alexenko, Shinichiro Yabe, Sergio Verjovski-Almeida, Danny J. Schust, Alexander W. Franz, Yoel Sadovsky, Toshihiko Ezashi, and R. Michael Roberts
Vulnerability of primitive human placental trophoblast to Zika virus PNAS 2017 114 (9) E1587-E1596; published ahead of print February 13, 2017, doi:10.1073/pnas.1616097114

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

More Medical Research Interviews on MedicalResearch.com

Anti-Cancer Agent May Have Simultaneous Regenerative Properties

MedicalResearch.com Interview with:

Lawrence Lum, Ph.D. Associate Professor Virginia Murchison Linthicum Scholar in Medical Research UT Southwestern Medical Center

Dr. Lum

Lawrence Lum, Ph.D.
Associate Professor
Virginia Murchison Linthicum Scholar in Medical Research
UT Southwestern Medical Center

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

Response: Scarring of the adult heart due to excessive fibrotic responses is common after a heart attack, or following radiation therapy for the treatment of certain cancers. We have identified an anti-cancer agent currently in clinical development called WNT-974 that decreases fibrotic responses and improves heart function following myocardial infarction in mice. This unexpected observation was the outcome of a study focused on identifying unwanted adult tissue toxicities associated with this class of chemicals.

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Parents Can Encourage Children To Enter and Succeed in STEM Studies

MedicalResearch.com Interview with:

Janet Shibley Hyde Evjue-Bascom Professor Helen Thompson Woolley Professor of Psychology and Gender & Women’s Studies Director, Center for Research on Gender & Women University of Wisconsin Madison, WI

Dr. Janet Shibley Hyde

Janet Shibley Hyde
Evjue-Bascom Professor
Helen Thompson Woolley Professor of
Psychology and Gender & Women’s Studies
Director, Center for Research on Gender & Women
University of Wisconsin
Madison, WI

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

Response: The background is that, in the U.S. and many other Western nations, we don’t have enough people going into STEM fields (Science, Technology, Engineering, and Mathematics). Innovations in STEM fields are enormously important in 21st century economies. So, we need to encourage more people to go into STEM fields. To do that, they have to major in a STEM field in college, and to do that, they need to prepare in high school.

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Breast Cancer Cells Become Chemotherapy Resistant By Eating Surrounding Stem Cells

MedicalResearch.com Interview with:

Thomas Bartosh Jr, Ph.D. Assistant Professor Medical Physiology Texas A&M Health Science Center

Dr. Thomas Bartosh Jr,

Thomas Bartosh Jr, Ph.D.
Assistant Professor Medical Physiology
Texas A&M Health Science Center

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

Response: One mysterious and devastating aspect of breast cancer is that it can reemerge abruptly, often as metastatic disease, in patients many years after an apparent eradication of the primary tumor. The sudden reappearance of cancer has been termed relapse and is thought to occur because a minimal number of resilient tumor cells are able to evade frontline therapies and linger in an undetectable/dormant state somewhere in the body for an unpredictable amount of time. Then, for reasons that remain unclear, these same dormant cells awaken and rapidly grow, and produce almost invariably fatal cancerous lesions. The therapeutic challenges of tumor dormancy and need to decode the underlying mechanisms involved are apparent.

Cancer cell behavior is strongly influenced by various non-malignant cell types that are found within the tumor mass itself and that help make up the tumor microenvironment (TME). In particular, bone marrow-derived mesenchymal stem/stromal cells (MSCs), which are actively recruited into the tumor stroma, directly interact with carcinoma cells and significantly impact cancer progression, although the role of MSCs in tumor dormancy remains ill-defined.

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Early Use of Gene Therapy May Stop Plaques of Alzheimer’s Disease

MedicalResearch.com Interview with:

Dr. Magdalena Sastre PhD Faculty of Medicine, Department of Medicine Senior Lecturer Imperial College London

Dr. Magdalena Sastre

Dr. Magdalena Sastre PhD
Faculty of Medicine, Department of Medicine
Senior Lecturer
Imperial College London

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

Response: Alzheimer’s disease is the most common neurodegenerative disorder, affecting over 45 million people around the world. Currently, there are no therapies to cure or stop the progression of the disease. Here, we have developed a gene therapy approach whereby we delivered a factor called PGC-1α, which regulates the expression of genes involved in metabolism, inflammation and oxidative stress in the brain of transgenic mice. This factor is also involved in the regulation of energy in the cells, because it controls the genesis of mitochondria and in the generation of amyloid-β, the main component of the neuritic plaques present in the brains of Alzheimer’s disease patients.

We have found that the animals with Alzheimer’s pathology treated with PGC-1α develop less amyloid plaques in the brain, perform memory tasks as well as healthy mice and do not have neuronal loss in the brain areas affected by the disease.

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How Can Radiologists Detect Cancer In a Fraction of a Second?

MedicalResearch.com Interview with:

Karla K. Evans, Ph.D. Lecturer, Department of Psychology The University of York Heslington, York UK

Dr. Karla Evans

Karla K. Evans, Ph.D.
Lecturer, Department of Psychology
The University of York
Heslington, York UK

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

Response: This research started after initially talking to radiologists and pathologists about how they search a radiograph or micrograph for abnormalities. They talked about being able to tell at the first glance if the image had something bad about it. Jokingly, they talked about “having the force” to see the bad. We wanted to know whether this hunch after the brief initial viewing was real and to systematically test it. We collected radiographic and micrographic images, half of them that had signs of cancer in them and half of them that didn’t, and we briefly presented them (250 millisecond to 2000 milliseconds) to radiologists or pathologistsrespectively. They simply had to report whether they would recall the patient or not and try localize on the outline the location of the abnormality. We first reported these finding in the following paper.

Evans et al. (2013) The Gist of the Abnormal: Above chance medical decision making in the blink of an eye. Psychonomic Bulletin & Review (DOI) 10.3758/s13423-013-0459-3
In addition to finding that radiologists and pathologists can indeed detect subtle cancers in a quarter of a second we also found that they did not know where it was in the image leading us to conclude that the signal that they were picking up must be a global signal (i.e. the global image statistic or the texture of the breast as a whole) rather than the result of a local saliency. This led me to start further exploring this signal in order to characterize it when I moved to University or York, UK to establish my own lab.
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Step Closer To Treating Mitochondrial Diseases by Understanding How Embryos Digest Sperm

MedicalResearch.com Interview with:

Peter Sutovsky PhD Professor of Animal Science in the College of Agriculture, Food and Natural Resources University of Missouri Professor of Obstetrics, Gynecology and Women’s Health at the School of Medicine University of Missouri Health System

Dr. Peter Sutovsky

Peter Sutovsky PhD
Professor of Animal Science in the College of Agriculture, Food and Natural Resources
University of Missouri
Professor of Obstetrics, Gynecology and Women’s Health at the School of Medicine
University of Missouri Health System

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

Response: Strictly maternal inheritance of mitochondria, the cellular power stations, and mitochondrial genes that mitochondria harbor, is a major biological paradigm in mammals. Propagation of paternal, sperm-contributed mitochondrial genes, resulting in a condition called heteroplasmy, is seldom observed in mammals, due to post-fertilization elimination sperm mitochondria, referred to as “sperm mitophagy.” Our and others’ recent results suggest that this process is mediated by the synergy of ubiquitin–proteasome system (UPS) pathway that recycles outlived cellular proteins one molecule at a time, and autophagic pathway capable of engulfing and digesting an entire mitochondrion.

Here we demonstrate that the co-inhibition of the ubiquitin-binding autophagy receptor proteins SQSTM1, GABARAP, and UPS, and the UPS protein VCP dependent pathways delayed the digestion of sperm mitochondria inside the fertilized pig egg. By manipulating said proteins, we created heteroplasmic pig embryos with both the paternal and maternal mitochondrial genes. Such animal embryos that could be used as a biomedical model to research and alleviate certain forms of mitochondrial disease.

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Fewer Childhood Infections Do Not Explain Marked Increase In Human Longevity

MedicalResearch.com Interview with:

Adam Hayward PhD Impact Research Fellow University of Stirling

Dr. Adam Hayward

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.

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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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Novel Therapeutic Target Identified For Treatment Of Proliferative Diabetic Retinopathy Identified

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.

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A Neuronal Protein Keeps Alcohol Binge Drinking In Check

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.

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Akt3 Protein Makes Brain Tumor Resistant To Treatment

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. Continue reading

Single Step Process May Speed Production of Statins

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.

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Optogenetics Pinpoint Neurons That Drive REM Sleep

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.

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Cancer Drug May Overcome Physiological Resistance To Tuberculosis Medications

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.

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Diverse Herpes Viruses Share Ability To Suppress Immune Response

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.

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Bilingualism Can Preserve White Matter in Brain

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.

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Your Mother Was Right! Cold Viruses Thrive At Cooler Temperatures

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.

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Study Links Red Meat To Inflammation and Tumor Formation

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.

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Huntington’s disease: New Drug Class May Benefit Patient and Offspring

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.

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Novel Vaccine Fights MRSA Infections

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.

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New Ionic Liquids May Disrupt Pathogenic Biofilms, Enhance Antibiotic Delivery

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.
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Metformin May Extend Lifespan By Increasing Reactive Oxygen Species

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.
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Fat and Hair Growth Synchronized By Same Signalling Pathway

Professor Rodney Sinclair University of Melbourne and Epworth Hospital Melbourne, VIC, AustraliaMedicalResearch.com Interview with:
Professor Rodney Sinclair
University of Melbourne and Epworth Hospital
Melbourne, VIC, Australia

 

MedicalResearch.com: What are the main findings of the study?

Answer: Activation of Wnt signalling promoted hair growth and fat growth.  Inhibition of Wnt signalling reduces fat growth and hair growth.  We looked at the fat layer on the scalp.  It was reduced by 50% over the bald areas of alopecia areata.  The patch of alopecia areata we looked at was new- only appeared a few days earlier and so the changes in fat thickness are rapid.

What is interesting is that the fat layer is dynamic, and significant fluctuations can occur in a rapid period of time in sync with the hair cycle.  It is also interesting that ligands for BMP6 and IGF2 are pro-adipogenic.

There are a couple of bigger questions that earlier media reports did not focus on- namely upstream factors regulating the hair cycle clock and the beauty of synchronization of fat and hair growth for seasonal thermal insulation.

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Alzheimer’s Disease: Repairing Golgi Structures May Reduce Toxic Plaques

Yanzhuang Wang, PhD Associate professor Dept. of Molecular, Cellular and Developmental Biology and Dept. of Neurology University of Michigan Ann Arbor, MI 48109-1048MedicalResearch.com Interview with:
Yanzhuang Wang, PhD
Associate professor
Dept. of Molecular, Cellular and Developmental Biology and Dept. of Neurology University of Michigan
Ann Arbor, MI 48109-1048

 MedicalResearch.com: What are the main findings of the study?

Dr. Wang: We learned how to repair a cellular structure called the Golgi apparatus that is broken in Alzheimer’s disease. This helps us understand how to reduce the formation of the toxic plaques that kill cells in the brain of Alzheimer’s patients. The formation of amyloid plaques is a hallmark of Alzheimer’s disease; but exactly how much the plaques contribute to the disease is still not known. Our study found that the broken Golgi in the disease may be a major source of the toxicity of amyloid plaques. We showed in this study that repairing the Golgi can reduce the formation of the toxic plaques and thus may delay the disease development.

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Menopause: Effects of Sex Hormones on Cognition and Mood

Dr. Victor W. Henderson MD Professor of Health Research and Policy and of Neurology and Neurological Sciences Stanford University, Stanford, CA 94305MedicalResearch.com Interview with:
Dr. Victor W. Henderson MD
Professor of Health Research and Policy and of Neurology and Neurological Sciences
Stanford University, Stanford, CA 94305


MedicalResearch.com: What are the main findings of the study?

Dr. Henderson: Estrogen or hormone therapy effects on some health outcomes differ by age, harmful at one age and beneficial at another.

This difference is sometimes referred to as the “critical window” or “timing” theory. It is controversial whether the so-called critical-window applies to memory or other cognitive skills.

In assessing the critical window hypothesis, we found that the relation between blood levels of estrogen and memory or reasoning skills is the same in younger postmenopausal women as in older postmenopausal women.  Essentially, there is no association at either age.
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Cognitive Function and Decision Making: Age-Related Changes

Agnieszka Anna Tymula Lecturer (Assistant Professor) School of Economics The University of Sydney NSW 2006, AustraliaMedicalResearch.com Interview with:
Agnieszka Anna Tymula
Lecturer (Assistant Professor)
School of Economics
The University of Sydney
NSW 2006, Australia

MedicalResearch.com: What are the main findings of the study?

Answer: We found that individual risk preferences as well as consistency and rationality in choice change with age. Just like cognitive abilities, the ability to make consistent and rational decisions considerably declines in older adulthood. Tolerance to risk in the domain of gains follows an inverted U-shaped pattern along the life span, with older adults (65+ y. o.) and adolescents being more risk averse than young or midlife adults. Interestingly, in the domain of losses, older adults are willing to accept significantly more risks than adolescents, young and midlife adults.

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Intestinal Virus Populations Huge and Rapidly Changing

MedicalResearch.com Interview with Frederic D. Bushman, Ph.D.  Professor, Department of Microbiology Department of Microbiology Perelman School of Medicine University of Pennsylvania 426A Johnson Pavilion 3610 Hamilton Walk Philadelphia, PA 19104MedicalResearch.com Interview with Frederic D. Bushman, Ph.D.

Professor, Department of Microbiology
Department of Microbiology
Perelman School of Medicine
University of Pennsylvania
426A Johnson Pavilion 3610 Hamilton Walk
Philadelphia, PA 19104

 

MedicalResearch.com: What are the main findings of the study?

Dr. Bushman: Viral populations in the human gut are huge, and some of the viruses change rapidly over time.
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Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

MedicalResearch.com eInterview with Dr. Mathieu Lupien PhD

Dr. Mathieu Lupien PhD  Princess Margaret Cancer Centre, University Health Network Ontario Cancer Institute (OCI)  Assistant Professor Department of Medical Biophysics University of Toronto Princess Margaret Cancer Centre, University Health Network
Ontario Cancer Institute (OCI)
Assistant Professor
Department of Medical Biophysics
University of Toronto

MedicalResearch.com: What are the main findings of the study?

Dr. Lupien: Approximately 50% of breast cancer patients fail to respond to the standard of care based on endocrine (hormonal) therapy. Our research identifies a mechanism that accounts for this resistance. Drugs against this mechanism are already tested for other diseases. Hence, our discovery should rapidly help reposition these drugs against endocrine therapy resistant breast cancer.
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Interpolated memory tests reduce mind wandering and improve learning of online lectures


Karl K. Szpunar PhD Department of Psychology, Harvard University, Cambridge, MA 02138MedicalResearch.com Interview with Karl K. Szpunar PhD

Department of Psychology,
Harvard University, Cambridge, MA 02138

MedicalResearch.com:   What are the main findings of the study?

Dr. Szpunar: The results of our experiments demonstrate that students can have difficulty paying attention to online lectures, and that including brief quizzes during lectures can help to alleviate this problem. Specifically, we found that students who were tested throughout a 21-minute long Statistics lecture were half as likely to mind wander during the lecture, three times as likely to take additional notes, and much better able to retain the contents of the lecture at a later time.
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Pathway-based personalized analysis of cancer

MedicalResearch.com Author Interview:
Prof. Eytan Domany

Department of Physics of Complex Systems and Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 76100, IsraelDepartment of Physics of Complex Systems and Department of Biological Regulation, Weizmann Institute of Science, Rehovot, 76100, Israel

MedicalResearch.com: What are the main findings of the study?

Prof. Domany: The findings are two-fold: methodological and clinical.  A novel method was introduced for personalized analysis of cancer, and was applied on large colon cancer and glioblastoma datasets.

The method uses high throughput (gene expression) data to infer a pathway deregulation score (PDS) for individual tumors, for hundreds of pathways and biological processes. The method is knowledge-based in that it uses well known information about the assignment of genes to biologically relevant pathways. No detailed knowledge of the underlying networks of interactions and activations is necessary. Each tumor is represented by a few hundred of these PDSs, and further analysis uses this representation.

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Cellular origin of a rare form of breast cancer identified

BOSTON (September 22, 2011) — Identifying the cellular origins of breast cancer might lead to earlier diagnosis and more efficient management of the disease. New research led by Charlotte Kuperwasser of Tufts University School of Medicine (TUSM) has determined that common forms of breast cancer originate from breast cells known as luminal epithelial cells while rarer forms of breast cancer, such as metaplastic carcinomas, originate from basal epithelial cell types. The study was published online ahead of print this week in PNAS Early Edition as part of its breast cancer special feature.

Clinicians and researchers classify breast cancers into subtypes based on both clinical features and molecular features, including expression of certain genes and proteins. These classifications help determine diagnosis, treatment decisions, and patient prognosis. The most common form of breast cancer, called invasive ductal carcinoma, is classified broadly into two types based on molecular features of the tumor cells: luminal-like cancers, which are sensitive to hormones, and the more aggressive basal-like cancers, which are not sensitive to hormones and tend to have a poorer prognosis.

However, there are also rare forms of breast cancer, some of which are called metaplastic carcinomas, where the cancer cells no longer resemble cells of the breast. Scientists do not yet fully understand how and why these different types of breast cancers form but one theory is that they originate from adult breast tissue stem cells.

“For the past several decades, most research efforts have been focused on discovering cancer-causing genes in hope that this information might help us discover better treatments for breast cancer. While these efforts have led to successes in treating some common forms of breast cancer, they have not provided us with information regarding where breast cancer originates and in particular, the origins of rare forms of metaplastic breast cancers for which the best course of treatment has not yet been determined,” said Kuperwasser, PhD, associate professor in the department of anatomy and cellular biology, Tufts University School of Medicine, and a member of the genetics and cell, molecular & developmental program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts and the Molecular Oncology Research Institute (MORI) at Tufts Medical Center.

In light of this, the research team chose to study the two major types of cells in the human breast, those that line the ducts and produce milk (luminal cells) and those that surround the ductal cells and contract to move the milk from the ducts (basal/myoepithelial cells) to determine whether they might form different types of breast cancers.

“We found that when basal/myoepithelial breast cells become cancerous they no longer resemble breast tissue; instead they look more like cells of the skin and form rare metaplastic breast cancers. In contrast, when luminal breast cells become cancerous, they retain the structure and molecular features of more common types of breast cancers,” said first author Patricia Keller, PhD, post-doctoral associate in the anatomy and cellular biology department at TUSM and a member of the Kuperwasser lab and MORI.

The researchers introduced cancer-causing genes into healthy breast cells obtained from breast reduction surgeries. Using specialized markers, they were able to isolate different types of normal breast cells and evaluate how they behaved as they became cancerous in a mouse model.

“By understanding more about the cellular beginnings of cancer, we can direct our research toward investigating preventive methods and possibly even developing new therapies,” said Kuperwasser.

This study adds to Kuperwasser’s growing body of work in breast cancer research. Earlier work identified a mechanism behind the preferential formation of aggressive breast cancers in people carrying a mutated BRCA1 gene. A team co-led by Kuperwasser and Philip Hinds, of Tufts Medical Center, also proposed and supported a model for breast cell differentiation that identified two distinct populations of progenitor cells for breast cancer. Her work has been published in Cell Stem Cell, Breast Cancer Research, Cancer Cell, and Nature Protocols.

Keller PJ, Arendt LM, Skibinski A, Logvinenko T, Klebba I, Dong S, Smith AE, Prat A, Perou CM, Gilmore H, Schnitt S, Naber SP, Garlick JA, Kuperwasser C. PNAS Early Edition, “Defining the cellular precursors to human breast cancer.” Published ahead of print, September 21, 2011, doi:10.1073/pnas.1017626108