MedicalResearch.com Interview with:
David S. Lopez, Dr.P.H., M.P.H.
Assistant professor
University of Texas Health School of Public Health
Medical Research: What is the background for this study? What are the main findings?
Dr. Lopez: Coffee, and its most studied component, caffeine, have been implicated in potential health benefits due to the rich sources of antioxidants and anti-inflammatory compounds contained in this beverage.
Caffeine intake reduced the odds of prevalent erectile dysfunction, especially an intake equivalent to approximately 2-3 daily cups of coffee (170-375 mg/day). This reduction was also observed among overweight/obese and hypertensive men, but not among diabetic men. These associations are warranted to be investigated in prospective studies.
Medical Research: What are the main findings?Dr. Lopez: Caffeine intake reduced the odds of prevalent erectile dysfunction, especially an intake equivalent to approximately 2-3 daily cups of coffee (170-375 mg/day). This reduction was also observed among overweight/obese and hypertensive men, but not among diabetic men. These associations are warranted to be investigated in prospective studies.
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MedicalResearch.com Interview with:
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?
Dr. Zhang: Epithelial ovarian cancer remains the most lethal gynecological malignancy. The 5-year survival rate for patients with advanced ovarian cancer is only 30-40%, and acquired resistance to platinum is considered a major factor in disease relapse. A major challenge in cancer treatment is the resilient ability of cancer cells to repair DNA damage caused by chemotherapy agents. In this study, we found that adding a molecule called miR-506 to standard chemotherapy can help cells overcome drug resistance, so that the chemotherapy drugs remain effective against ovarian cancer. This research supports a new combination approach, which may substantially benefit patients with this deadly disease.
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MedicalResearch.com Interview with:Perry N Halkitis, Ph.D., M.S., MPH
Professor of Applied Psychology
Global Public Health, and Population Health/Medicine
New York University.
Medical Research: What is the background for this study?
Dr. Halkitis: The P18 Cohort Study is a prospective cohort study of gay, bisexual and other young men who have sex with men (YMSM) which seeks to examine the development of health behaviors as these young men transition from adolescent to adulthood. Officially named “Syndemic Production among Emergent Adult Men”, this study was funded by the National Institute on Drug Abuse from 2009-2014 and renewed on March 1, 2014 for an additional five years.
The original aims of the study were as follows:
1) to develop and test theoretically informed measurement models of the covariance of illicit drug use, unprotected sexual behavior and mental health burden (multiple overlapping epidemics known as a syndemic) among emergent adult HIV-negative YMSM within and across time;
2) to delineate the risk and protective bases- physical factors (e.g., pubertal onset, HIV status, etc.), relational and structural factors (e.g., family history of psychopathology, current romantic relationships, peer support, neighborhood factors, etc.), and psychosocial factors (e.g., sexual identity, internalized homophobia, hyper-masculine conceptions, etc.) that predict the development of syndemics; and
3) to determine the extent to which the development of a syndemic varies by race/ethnicity, social class, and homelessness/housing instability.
In this current five year continuation we also seek
1) to describe the social and sexual networks of YMSM, and to examine the relationship between social and sexual network-level structural characteristics, social support and normative influences on syndemic production (illicit drug use, unprotected sexual behaviors, and mental health burden) in YMSM, singly and in combination with the physical, psychosocial, and relational predictors, both within and across time;
2) to describe the acquisition of sexually transmitted infections (STIs) in YMSM, specifically, urethral and rectal gonorrhea and chlamydia, pharyngeal gonorrhea as well as syphilis serology; and to determine the extent to which physical, relational, and psychosocial factors explain STI acquisition as part of the syndemic model within and across time.
A third exploratory aim was also added: 3) to describe HIV clinical treatment markers (i.e., HIV viral load, ART uptake and adherence, HIV care) among HIV+ YMSM, and to assess the extent to which physical, relational, and psychosocial factors are associated with differences in these clinical markers among HIV+ YMSM, both within and across time. The study is led by Drs. Perry N Halkitis and Farzana Kapadia at New York University’s Center for Health, Identity, Behavior & Prevention Studies.
Potential participants were recruited through both active (e.g., approaching individuals to solicit study participation) and passive (e.g., flyer posting, website advertisements) methods from June 2009 to May 2011. Eligibility criteria included being 18-19 years old, biologically male, residing in the NYC metropolitan area, having sex (any physical contact that could lead to orgasm) with a man in the last 6 months, and reporting a seronegative or unknown HIV status at baseline. We ensured the diversity of our sample by setting a fixed recruitment quota for participants in each targeted racial/ethnic group, such that African Americans, Latino (across race), Asian-Pacific Islander (API), and mixed race men comprised the majority of the sample. All participants provided written, informed consent before data was collected and were compensated for their time and effort upon completing the baseline assessment. The New York University’s Institutional Review Board (IRB) approved all study protocols and a federal Certificate of Confidentiality protects these data.
A total of 2,068 participants were screened for eligibility to participate in the study, and 600 participants completed the baseline assessment in the first wave of the study. In 2014, we began the second wave and opened to cohort to recruit a baseline sample of 650 YMSM who will now be between the ages of 22-23; recruitment of participants is still underway.
Medical Research: What are the main findings?
Dr. Halkitis: Numerous publications have been generated from the P18 Cohort Study and can be accessed at www.chibps.org. A recent publication, “Incidence of HIV infection in Young Gay, Bisexual, and other YMSM: The P18 Cohort Study” became available in the May 2015 of JAIDS, the Journal of Acquired Immune Deficiency Syndromes. This paper reports that over a 36 month follow-up period, during the first wave of the study, 7.2% of study participants seroconverted, with Black and Hispanic men much more likely to seroconvert over this time frame than White men. This finding aligns with epidemiological trends for HIV infection at the national and local, NYC, levels. Also, men reporting a lower familial socioeconomic status were more likely to seroconvert than men reporting high familial socioeconomic status, and Black men were more likely to report a lower socioeconomic status. Moreover, the Black young men who seroconverted were more likely to reside in neighborhoods with higher area-level poverty and higher area-level HIV prevalence. Additionally we found that men who reported anal sex without a condom in the 30 days prior to assessment were no more likely to seroconvert than those who reported sex with a condom. However, an earlier age of sexual debut was a predictor of HIV seroconversion.
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MedicalResearch.com Interview with:
Thomas M. Gill, M.DHumana Foundation Professor of Medicine (Geriatrics)
Professor of Epidemiology and of Investigative Medicine
Director Yale Program on Aging and Yale Center for Disability and Disabling Disorders
Director, Yale Training Program in Geriatric Clinical Epidemiology and Aging-Related Research
Medical Research: What is the background for this study? What are the main findings?h
Response: Understanding the disabling process at the end of life is essential for informed decision-making among older persons, their families, and their physicians.
We know from prior research that the course of disability at the end of life does not follow a predictable pattern for most older persons. This raises the question about what is driving the development and progression of disability at the end of life.
We identified six distinct trajectories of disability in the last year of life, ranging from the least disabled to most disabled. We found that the course of disability in the last year of life closely tracked the monthly prevalence of hospitalization for each of the six trajectories.
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MedicalResearch.com Interview with:Rik Ossenkoppele PhD.
Postdoctoral researcher
UCSF Memory and Aging Center
MedicalResearch: What is the background for this study? Dr. Ossenkoppele: Since 2004, several PET tracers have been developed that measure fibrillar amyloid-β plaques, a neuropathological hallmark of Alzheimer’s disease (AD). Through visual assessment by a nuclear medicine physician or quantitative cut-points, the presence or absence of amyloid-β pathology can be determined in the living human brain. The FDA, in support of the clinical application of amyloid imaging, has recently approved three of these PET tracers. A proportion of patients with other types of dementia then Alzheimer’s disease that harbor cerebral amyloid-β pathology, however, potentially limits the clinical utility of amyloid imaging. When ordering clinical amyloid PET scans and correctly interpreting the significance of amyloid PET results, clinicians need to understand the prevalence of amyloid-positivity across different types of dementia. It is also important to be aware of the relationships of amyloid-positivity prevalence and demographic (e.g. age and sex), cognitive and genetic (e.g. presence of the AD-risk allele apolipoprotein E [APOE] ε4) factors. Most amyloid PET studies to date come from single centers with modest sample sizes. We therefore conducted a meta-analysis with individual participant data from 29 cohorts worldwide, including 1359 patients with clinically diagnosed Alzheimer’s disease and 538 patients with non-AD dementia. We also included 1849 healthy controls with amyloid PET data, and an independent sample of 1369 AD patients with autopsy data from the NACC database.
MedicalResearch: What are the main findings?Dr. Ossenkoppele: In patients clinically diagnosed with Alzheimer’s disease, the prevalence of amyloid-positivity decreased from 93% at age 50 to 79% at age 90. The drop in amyloid-positivity was most prominent in older Alzheimer’s disease patients who did not carry an APOE ε4 allele (~1/3 of these patients had a negative amyloid PET scan). This most likely reflects a mix of
1) clinical misdiagnoses (i.e. non-AD pathology causing an AD phenotype),
2) false negative PET scans (i.e. abundance of cerebral amyloid pathology that is not detected by PET), and
3) possibly elder patients need less amyloid pathology (sub-threshold levels for PET) to reach the stage of dementia due to age-related reductions in cognitive resilience (“cognitive reserve theory”) or simultaneous presence of multiple pathologies (“double-hit theory”).
The relatively high rate of amyloid-negative Alzheimer’s disease patients highlights the necessity of biomarker-informed patient selection for Alzheimer’s disease clinical trials.
In most patients clinically diagnosed with non-AD, the prevalence of amyloid-positivity increased with aging and was ~18% higher in APOE ε4 carriers. Presence of amyloid pathology in non-AD dementia may reflect
1) clinical misdiagnosis (i.e. AD pathology is the causative pathology), or
2) comorbid pathologies, where amyloid may be secondary to other pathologies that are actually driving the clinical presentation. Interestingly, patients with a clinical diagnosis of non-AD dementia who harbored cerebral amyloid pathology showed lower Mini-Mental State Examination scores (measure of global cognition), suggesting that amyloid-β is not just an innocent bystander.
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MedicalResearch.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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MedicalResearch.com Interview with:
C. Munro Cullum, PhD, ABPP
Professor of Psychiatry and Neurology & Neurotherapeutics
Pamela Blumenthal Distinguished Professor of Clinical Psychology
Chief of Psychology , Director of Neuropsychology
Univ. of Texas Southwestern Medical Center Dallas, TX Medical Research: What is the background for this study? What are the main findings?
Dr. Cullum: My colleague and principal investigator of the study, Dr. John Hart and I have been interested in the acute and longer-term effects of traumatic brain injury for years, and because of my roles in the Alzheimer’s Disease Center and the Texas Institute for Brain Injury and Repair at the University of Texas Southwestern Medical Center, it seemed like a natural to begin studying older individuals with and without cognitive disorder who have a history of traumatic brain injury. Our main findings are two-fold:
First, we demonstrated that a history of concussion with loss of consciousness (which make up only about 10% of all concussions) was associated with smaller memory centers in the brain (the hippocampus) and lower memory results in our sample of retired professional football players. Concussions that did not result in loss of consciousness did not show that same strong association.
Second, our data suggest that patients with a clinical diagnosis of mild cognitive impairment (ie a memory disorder that does not grossly impair overall functioning but may lead to dementia) who also have a history of concussion with loss of consciousness show worse memory results and more brain atrophy than similar individuals diagnosed with mild cognitive impairment in the absence of a history of concussion.
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MedicalResearch.com Interview with:
Alexander W. Pastuszak, MD, PhD
Male Reproductive Medicine and Surgery
Scott Department of Urology
Jason Malcolm Scovell
Medical Student, Ofc SA-BCM StudentsBaylor College of MedicineHouston, TX
Medical Research: What is the background for this study? What are the main findings?
Response: Sleep quality is an important component of overall health, and can both exacerbate health issues and be impaired by health problems. Shift workers, primarily those who do not work standard daylight shifts, are prone to sleep problems, a significant concern in light of the fact that up to 25% of the U.S. workforce is comprised of shift workers. As men age, the prevalence of Lower Urinary Tract Symptoms (LUTS), which include urgency, frequency, waking up at night to urinate, and difficulties with urination, increases. Unsurprisingly, men with LUTS report poor sleep in part due to awakening repeatedly during the night. We studied a group of male shift workers, who we believe to be an ‘at-risk’ population, and found that not only do the men who report worse sleep quality have worse Lower Urinary Tract Symptoms, but also men who report difficulty falling asleep have more severe LUTS than those who do not. This latter point is significant, given that most men with LUTS can fall asleep without difficulty, but then awaken repeatedly throughout the night, and suggests that sleep difficulties in this population may be resulting in Lower Urinary Tract Symptoms rather than LUTS exclusively resulting in sleep difficulties.
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MedicalResearch.com Interview with:
Jennifer R. Rider, ScD, MPH
Assistant Professor of Medicine
Channing Division of Network Medicine
Brigham and Women's Hospital and Harvard Medical School
Department of Epidemiology
Harvard T.H. Chan School of Public Health
Boston, MA 02115
Medical Research: What is the background for this study? What are the main findings?
Dr. Rider: Numerous studies have investigated the potential role of sexual activity on the development of prostate cancer. However, most of these studies have been small and retrospective, making them more prone to bias. In addition, previous studies often relied on proxies of exposure for sexual activity (number of sexual partners, age at first marriage, etc.), which may not adequately measure the aspects of sexual activity that are most important for prostate health. The current study is the largest prospective study to date on ejaculation frequency and prostate cancer. It includes 18 years of follow up of almost 32,000 healthy men, 3839 of whom later were diagnosed with prostate cancer. We asked men about their average monthly frequency of ejaculation between the ages of 20-29, 40-49, and in the year prior to the questionnaire (1991). We find that frequency of ejaculation throughout life course is inversely associated with risk of prostate cancer at all three of these time points. For instance, men who have an average monthly ejaculation frequency of 21 or more times/moth at ages 40-49 have a statistically significant 22% reduction in risk of developing prostate cancer compared to men with a frequency of 4-7 times/month, adjusting for multiple dietary and lifestyle factors, and prostate cancer screening history.
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MedicalResearch.com Interview with:
Jim Dupree, MD, MPH
Assistant Professor
Department of Urology, Division of Andrology
University of MichiganMedical Research: What is the background for this study? What are the main findings?
Dr. Dupree: There are increasing discussions in the United States about testosterone therapy and men with clinical hypogonadism (or low testosterone). Yet, to date, there have not been any nationally-representative studies of the prevalence of low testosterone in the United States. Using a validated national health examination program from the CDC, we found that the national prevalence of low testosterone (serum testosterone ≤ 300 ng/dL) in adult males in the US was 28.9%. Among other factors, men who were older, had a higher body mass index (BMI), or had a larger waist circumference were at risk for having lower testosterone levels.
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MedicalResearch.com Interview with:
Timothy E Sweeney, MD PhD
Resident, General Surgery
Postdoc, Khatri Lab, Bioinformatics
Stanford University
Medical Research: What is the background for this study? What are the main findings?Dr. Sweeney: Sepsis is defined as the presence of systemic inflammation due to infection. Systemic inflammation can be caused from many things, such as trauma, surgery, thrombosis, autoimmunity, etc. It can also be caused by infection. On the other hand, infection does not necessarily cause systemic inflammation, either: a person can get a minor infection, like strep throat, and not have a systemic response. It's the intersection of severe inflammation (a syndrome called SIRS) with infection that defines sepsis.
In general surgery, we frequently see patients after traumatic injury or surgery who are having an inflammatory response (ie, fevers, fast heart rate, high white blood cell count, etc). But it's not clear whether this inflammatory response is a reaction to the trauma or surgery, or whether there might be an infection brewing that is causing the reaction. Identifying the inflammatory response doesn't require many special tests-- it's easy to spot. So we know which patients have inflammation and which do not. What is difficult is determining the root cause of the inflammation, and, in particular, whether there is an infection present that needs treatment with antibiotics.
Current diagnostics for infection (not sepsis) are either slow (like blood cultures, which can take 24-72 hours to return) or not highly accurate (like procalcitonin). We sought to define a better test that could specifically differentiate between people with sterile inflammation, and people with inflammation due to infection (sepsis). By integrating gene expression data from multiple publicly available cohorts, we were able to find a set of 82 genes that are significantly differently expressed between these two groups. We then used an algorithm called a greedy forward search to find a subset of 11 genes that were most diagnostic for sepsis.
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MedicalResearch.com Interview with:
Katherine Aird, Ph.D.Gene Expression and Regulation Program
The Wistar Institute, Philadelphia, PA
MedicalResearch: What is the background for this study? What are the main findings?Dr. Aird: Senescence is considered an important tumor suppressor mechanism. In normal cells, activation of certain oncogenes decreases the levels of dNTPs (the building blocks of DNA), leading to replication stress. We previously found that loss of the rate-limiting enzyme in dNTP synthesis, ribonucleotide reductase M2 (RRM2), is the cause of this replication stress. Restoration of RRM2 expression could rescue the loss of dNTPs and replication stress, which overcame the senescence-associated growth arrest. Indeed, RRM2 is highly expressed in many cancer types, including melanoma and ovarian cancer. Therefore, we found that increased dNTP levels can overcome senescence and potentially lead to transformation of cells and cancer.
We next wanted to further our understanding of replication stress in the context of senescence. In the current study, we suppressed nucleotide metabolism by decreasing RRM2 expression as a model for replication stress and then determined what proteins are necessary for the induction of senescence. We found that loss of ATM could overcome replication stress-induced senescence. This was due to increased dNTP levels. dNTPs were increased due to a coordinated inactivation of p53 and activation of c-MYC by loss of ATM. These changes at the molecular level correlate with reprogramming of cellular metabolism by generating dNTPs. Thus, loss of ATM in the context of replication stress can change cellular metabolism to a more cancer-like phenotype.
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MedicalResearch.com Interview with:
Melinda L. Telli, M.D. Assistant Professor of Medicine Stanford University Division of Medical Oncology Stanford, CA 94305-5826Medical Research: What is the background for this study? What are the main findings?
Response: A major goal of this study was to explore a DNA damaging chemotherapy regimen in patients with newly diagnosed early-stage triple-negative or BRCA1/2 mutation-associated breast cancer. This was based on the hypothesis that these types of tumors are more responsive to DNA damaging therapeutics. A second major goal was to identify predictors of response to this platinum-based therapy among patients with sporadic triple-negative breast cancer (TNBC).
Overall, this study demonstrated that the non-anthracycline and non-taxane neoadjuvant regimen of gemcitabine, carboplatin and iniparib resulted in a 36% pathologic complete response rate (pCR). This compares favorably to pCR rates commonly observed with anthracycline and taxane-based regimens in this group of patients. The response rate was higher among triple-negative breast cancer patients with a germline BRCA1 or BRCA2 mutation (56%).
Given the hypothesis of underlying DNA repair defects in sporadic triple-negative breast cancer, we also evaluated a novel measure of genomic instability to detect the accumulation of changes in the genomic landscape of a tumor attributable to defective homologous recombination DNA repair. Homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies. Very importantly, we found that the HRD-LOH assay was able to identify patients with sporadic TNBC lacking a BRCA1 or BRCA2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. (more…)
MedicalResearch.com Interview with:
Humphrey Yao, Ph.D.
Lead Researcher
Reproductive and Developmental Biology Laboratory
National Institute of Environmental Health Sciences (NIEHS)
National Institutes of Health (NIH)
Research Triangle Park, North Carolina
Medical Research: What is the background for this study? What are the main findings?
Dr. Yao: We wanted to understand how an organ forms, and what basic cell types were needed to form an organ. So, we used a mouse ovary model system to understand the process. The functional unit of the ovary is called the follicle, and it is made up of three types of cells — the maturing egg, granulosa cells, and theca cells. Scientists knew where the egg and the granulosa cells came from, but no one knew where theca cells came from. Theca cells are important, because they allow females to produce the hormones that sustain follicle growth. Researchers also lacked information about how the egg, granulosa cells, and theca cells talked to each other to promote growth and maintain a healthy ovary.
We made two discoveries. First, we answered the long-standing question of theca cell origin by determining that they have two sources, both inside and outside of the ovary. We don’t yet know why theca cells have two sources.
Second, we uncovered the molecular signaling system that the egg, granulosa cells, and theca cells use to communicate. We didn’t expect to find this three-way cellular crosstalk, but now that we know how they signal each other, I believe we are closer to understanding how an ovary develops and what happens when something goes wrong. Ovarian disorders, such as premature ovarian failure and polycystic ovarian syndrome, may start when cellular communication is altered or if the various cells fail to develop properly.
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MedicalResearch.com Interview with:
Joanne Brady, PhD candidate
Department of Anesthesiology, College of Physicians and Surgeons
Department of Epidemiology, Mailman School of Public Health
Columbia University, New York, NY
Medical Research: What is the background for this study? What are the main findings?
Response: Prescription drug overdose is a major public health problem in the United States. Prescription drug overdose mortality has increased dramatically over the past twenty five years. Frequent emergency department utilization may be a marker for risk of prescription drug overdose death. The current study assessed how frequency of emergency department visits in the past year related to risk of subsequent prescription drug overdose death. In a cohort of patients visiting the emergency department, patients with four or more visits to the emergency department in the past year were at substantially higher risk for prescription drug overdose death than patients who visited the emergency department one or fewer times. As the number of visits to the emergency department increased from 0 - 1 to 4 or more for any reason the risk of dying from prescription drug overdose also increased.
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MedicalResearch.com Interview with:Kristina Bečanovič Ph.D.
Department of Clinical Neuroscience
Karolinska Institutet, Stockholm, Sweden
Medical Research: What is the background for this study?
Dr. Bečanović: While the symptoms normally debut in middle-age, there is wide individual variation in how Huntington disease manifests itself, and even though two people carry the exact same genetic mutation that codes for the huntingtin protein, there can be up to a 20-year difference in onset of motor symptoms. This suggests that genetic variants, transcription factors and environmental factors could contribute to the observed differences in disease expressivity. As the identification of regulatory factors of the huntingtin gene would be targets for therapeutic intervention, we set out to study the regulation of the huntingtin gene as it has not been well-known which factors regulate the expression levels. We were interested in identifying both genetic variants and transcription factors that are of importance for gene regulation. We therefore used DNA from Huntington disease patients to study the regulation of the huntingtin gene promoter in cells.
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MedicalResearch.com Interview with:Dr. David Goldberg MD, MSCE
Assistant Professor of Medicine
LDI Fellow, Leonard Davis Institute, University of Pennsylvania
Medical Director for Living Donor Liver Transplantation, Hospital of the University of Pennsylvania
Senior Scholar, Center for Clinical Epidemiology and Biostatistics
MedicalResearch: What is the background for this study? What are the main findings?Dr. Goldberg: While there are data that demonstrate differences in authorization (consent) rates for deceased donation among racial and ethnic minorities, it is unknown how these differences contribute to geographic differences in the number of deceased organ donors. It has been postulated that geographic differences in the distribution of racial and ethnic minorities may contribute to differences in the deceased organ supply, yet there have been no empiric data to support this. Using data on “eligible deaths,” defined as potential brain-dead organ donors <=70 years of age, we demonstrated that even after accounting for differences in the racial/ethnic demographics of the potential donor population, there are dramatic differences in authorization (consent) rates across geographic areas that are not explained by demographics alone. If the source of these differences could be identified, then there could be large increases in the number of organ donors, and lifesaving transplants, in areas with lower authorization rates.
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MedicalResearch.com Interview with: Manoj Duraisingh Ph.D.
John LaPorte Given Professor of Immunology and Infectious Diseases
Harvard T.H. Chan School of Public Health
Department of Immunology and Infectious Diseases
Boston, Massachusetts
MedicalResearch: What is the background for this study? What are the main findings?Dr. Duraisingh: The malaria parasite P. falciparum is one of the most important pathogens of humans, with enormous mortality resulting from blood-stage infections, when parasites replicate exponentially in red blood cells. Although anti-Plasmodial drugs are in clinical use, widespread and increasing parasite drug-resistance has contributed to an ongoing public health crisis, and we urgently need to find novel approaches to prevent and treat disease.
Targeting host red blood cell molecules presents an unexploited alternative. However, the highly differentiated and enucleated red blood cell poses a significant technical hurdle for genetic experimentation, due to the lack of a nucleus.
Here we have developed a novel, forward genetic screen to identify critical factors of malaria infection of red blood cells in an unbiased fashion. Our screen takes advantage of recent advances in human stem cell biology that enable the ex vivo culture of red blood cells from nucleated hematopoietic precursors which are amenable to in vitro genetics.
We have now identified a surface molecule CD55 (alias Decay-Accelerating Factor, DAF) as an essential host factor required for the invasion of red blood cells by P. falciparum. We demonstrate that this protein is required by all P. falciparum strains tested (laboratory and field) for invasion. Furthermore, we demonstrate that CD55 acts at the initial stage of invasion when the P. falciparum parasite attaches to the surface of the red blood cell.
Collectively, our findings indicate that CD55 is an ideal target for the development of new host-directed and vaccine therapeutics for malaria.
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MedicalResearch.com Interview with:
Karen E. Joynt, MD MPH
Cardiovascular Division,
Brigham and Women's Hospital and VA Boston Healthcare System
Department of Health Policy and Management
Harvard T.H. Chan School of Public Health
MedicalResearch: What is the background for this study? What are the main findings?Dr. Joynt: While there is a great deal of optimism about the potential of Electronic Health Records (EHRs) to improve health care, there is little national data examining whether hospitals that have implemented EHRs have higher-quality care or better patient outcomes. We used national data on 626,473 patients with ischemic stroke to compare quality and outcomes between hospitals with versus without EHRs. We found no difference in quality of care, discharge home (a marker of good functional status), or in-hospital mortality between hospital with versus without EHRs. We did find that the chances of having a long length of stay were slightly lower in hospitals with EHRs than those without them.
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MedicalResearch.com Interview with:
Alan H.B. Wu, PhD, DABCC
Professor Laboratory Medicine
Chief, Clinical Chemistry Laboratory
University of California San Francisco, CA
Medical Research: What is the background for this study? What are the main findings?
Response: Clinical trials are conducted for validation of novel biomarkers. There is considerable heterogeniety in the quality design and documentation of findings. This can have a major impact on the conclusions rendered.
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MedicalResearch.com Interview with: Ishak Mansi, MD
Staff Internist, VA North Texas Health System.
Professor in Department of Medicine &
Department of Clinical Sciences, Division of Outcomes and Health services Research, University of Texas Southwestern, Dallas, TX
MedicalResearch: What is the background for this study? What are the main findings?Dr. Mansi: Statin use is associated with increased incidence of diabetes, and possibly increased body weight, and less exercise capacity. Data on the long-term effects of these associations in healthy adults are very limited. Additionally, the effects of these associations on diabetic complications have not been adequately studied.
Dr. Mansi at VA North Texas Health System, Dallas and Professor of Medicine and Clinical Sciences at the University of Texas Southwestern, Dallas, TX and his colleagues found that among generally healthy individuals, statin-users in comparison to non-users had a higher odds of being diagnosed with new onset diabetes, diabetes with complications, and overweight/obesity.
The researchers examined the records of tens of thousands of Tricare beneficiaries, during the period from 10/1/2003 to 3/1/2012. After excluding patients who had at baseline a preexisting cardiovascular diseases or severe chronic diseases that may be life-limiting (including diabetes mellitus), they identified a cohort of 25,970 patients as “healthy cohort”. They, further, matched 3,351 statins-users and 3,351 nonusers on several baseline characteristics to ensure comparability.
There are 3 main important findings for our study:
Statin use was associated with significantly higher risk of new onset diabetes even in a very healthy population. Whereas the risk of diabetes with statins is known, it was thought that this may be due to the overall multiple risks of statin-users (that caused them to receive statins as a therapy).
Statin use was associated with very high risk of diabetes complications in this healthy population: this was never shown before.
Statin use is associated with higher risk of obesity: this also is widely unknown. However, few studies have noted this (one study using patient survey noted this, another study using Mendelian randomization showed it, and post-hoc analysis of a clinical trial showed that statin user gained more weight). Our study, which used a different methodology (retrospective cohort study) add another piece of evidence. Obesity is at endemic level in the US and treatment options are limited.
High-intensity statins was associated with greater risks of all outcomes.
This article is published in the Journal of General Internal Medicine (JGIM). JGIM is the official journal of the Society of General Internal Medicine.
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MedicalResearch.com Interview
Dr. Ludovic Desvignes PhD.
Assistant Professor, Departments of Medicine and Pathology
NYU Langone Medical Center
MedicalResearch: What is the background for this study? Dr. Desvignes: This study is the result of a collaboration at NYU Langone Medical Center, between the laboratories of Dr. Stefan Feske and Dr. Joel Ernst, my mentor. Dr. Feske and colleagues had developed a mouse model of rare, inherited mutations he had identified in infants. These mutations occur in the genes for STIM1 and ORAI1, which are crucial for calcium flux in cells of the immune system. The young patients affected by these mutations suffer from severe, recurrent and chronic infections that often cause death before their first birthday. In particular, some of these patients cannot control infection with BCG, which is a normally innocuous strain of mycobacteria administered to protect against tuberculosis (TB). TB is a chronic infection and one of the leading causes of infection-related death worldwide. Going into this study, Dr. Feske and colleagues knew that without functional calcium channels, immune cells do not function properly. However, they did not fully understand how these channels contribute to immune responses to infectious pathogens in a living organism and in particular, for pathogens that cause chronic infections such as TB. This is why Dr. Ernst and I collaborated with Dr. Feske and provided him with our clinical and research expertise in TB.
MedicalResearch: What are the main findings?Dr. Desvignes: Dr. Feske’s mice are genetically engineered to lack STIM1 in a certain type of immune cells, known as T cells or T lymphocytes. We infected these mice with Mycobacterium tuberculosis, the bacterium causing TB. Mycobacterium tuberculosis causes chronic infection by manipulating the immune system even in healthy people. The first very surprising result of our study was that mice lacking calcium flux in T cells handled acute TB fairly well. Only during the chronic phase of infection did they become unable to control mycobacterial growth and developed a strong inflammation in their lungs, which was due to an infiltration by different types of immune cells, including T cells. We discovered that the accumulation of STIM1-deficient T cells in the lungs resulted from the cells’ inability to die, which is a normal mechanism to limit an immune response and prevent excessive inflammation.
Another immune control mechanism that failed in the absence of STIM1 is mediated by a subset of T cells called induced regulatory T cells, or iTreg cells. These cells are essential to prevent normal immune responses from going “overboard” by suppressing the functions of other immune cells, including T cells. We found that calcium signals are required for the development of iTreg cells and that their numbers were strongly reduced in the lungs of infected STIM1-deficient mice. We therefore think that the lack of iTreg cells in the absence of STIM1 contributes to the severe lung inflammation in chronic TB.
The third finding that really surprised us was that T cells accumulating in the lungs of STIM1-deficient mice produced large amounts of a protein called interferon gamma. While interferon gamma is required to control Mycobacterium tuberculosis, it is also a very potent promoter of inflammation and too much of it can lead to tissue damage. Dr. Feske and colleagues had previously observed that calcium fluxes promote the production of interferon gamma in T cells cultured in vitro and we expected the STIM1-deficient T cells to be defective in the production of that protein. During chronic TB, however, calcium signaling turned out to be not only dispensable for the production of interferon gamma by T cells but it was actually required to limit its production and thus, to control inflammation.
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MedicalResearch.com Interview with:
Ahmad M. Khalil, PhD
Assistant professor, Department of Genetics and Genome Sciences
Case Western Reserve University School of Medicine
MedicalResearch: What is the background for this study? What are the main findings?Dr. Khalil: This study aimed to identify other genes that work synergistically with the oncogene HER2 in HER2positive (HER+) breast cancer. The gene HER2 is amplified in those patients, which results in excess activities that promote uncontrolled cell growth. There are drugs that target HER2 and diminish its activity. However, these drugs can work initially, but patients relapse; or sometimes, the drugs don't work at all in some patients.
Thus, by identifying other genes that work synergistically with the HER2 gene, we now have more genes to target by various drugs or compounds to destroy the tumor. The challenge was how to identify the key genes that work synergistically with HER2, especially in human subjects. To that end, we used clinical samples from a clinical trial of a drug that is known to inhibit HER2 activity to identify those genes. To further refine our list, we used cell culture models of the disease to also inhibit HER2. By combining those data sets, we identified 44 protein-coding genes.
Next, we wanted to make sure that those genes stand a third independent filter. For that part, we interrogated those 44 genes in HER2+ tumors vs matched normal tissues from The Cancer Genome Atlas database — a collection of hundreds of tumors and normal tissues. Of the 44 genes, 35 genes passed this third filter. By examining the known functions of those genes, we can deduce that those genes work cooperatively with HER2 to promote carcinogenesis.
There are currently known drugs that target some of those genes. We will use these drugs in combination with a drug that target HER2 to determine if the combination works better at destroying the tumor entirely.
Lastly, we found that a special type of genes that we previously discovered, called lincRNAs, could also affect the oncogenic activity of HER2. These lincRNAs can also be targeted with HER2 to eliminate the tumor. (more…)
MedicalResearch.com Interview with:
Anita L. Nelson, MDProfessor, Department of Obstetrics and Gynecology at Harbor-UCLA Medical Center
Los Angeles BioMedical Research Institute
Harbor-UCLA Medical Center
Torrance, California
Medical Research: What is the background for this study? What are the main findings?
Dr. Nelson: The clinical impact heavy menstrual bleeding has often been expressed in terms of quality of life issues, but many women have heavy and prolonged bleeding that can lead to serious medical problems. The frequency with which women were treated at Harbor-UCLA Medical Center with profoundly low hemoglobin levels prompted us to do a comprehensive review of such women during a recent five year period to remind readers that even in the 21st century, this is not an uncommon problem. Overall 149 woman were treated 168 times for severe anemia (hemoglobin < 5.0 g/dL); 40% had previously been transfused (but not effectively treated). Over a quarter had reactive thrombocytosis which placed them at high risk for thrombosis (DVT, PE, and stroke). Over a third were discharged without therapy to prevent recurrence.
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MedicalResearch.com Interview with:
Candace McNaughton, MD MPH
Assistant Professor
Department of Emergency Medicine
Vanderbilt University, Nashville, TN
Medical Research: What is the background for this study?
Dr. McNaughton: Heart failure affects more than 5 million Americans, is a frequent cause of hospitalization, and by 2030 is projected to cost as much $70 billion, so there is a lot of interest in helping patients with heart failure manage their condition. Health literacy, or the ability to use and understand healthcare information, is important for all patients, but the stakes are very high for patients with heart failure. Some people who are highly literate or highly educated in other areas may have difficulty reading and understanding healthcare information. Patients with lower health literacy skills may have difficulty communicating with healthcare providers, navigating the healthcare system, recognizing signs of health decline, and knowing when and who to contact when they do become ill.
Medical Research: What are the main findings?
Dr. McNaughton: To our knowledge, this is the first study in which health literacy was measured by nurses when patients were admitted to the hospital for heart failure. Nurses asked patients three questions about whether they have problems learning about their medical condition, their confidence filling out medical forms, and how often they have someone help them read hospital materials. With these three questions, information about the health literacy level of individual patients can be made easily available their healthcare providers.
We found that among 1,379 patients hospitalized for acute heart failure, those with low health literacy had 32% greater risk of death compared to patients with a literacy score of 10 or higher, even after adjusting age, sex, race, insurance status, education, other medical conditions, and how long they were in the hospital. (more…)
MedicalResearch.com Interview with:
Robert J Canter MD
Associate Professor of Clinical Surgery
Division of Surgical Oncology
University of California at Davis
Medical Research: What is the background for this study?
Dr. Canter: Our data suggest that surgeons are improving in their ability to select patients for surgical intervention in cancer patients near their end of life. Our research suggests that surgeons may be operating on healthier patients who are anticipated to have a better recover from a palliative operation. These are patients who can perform activities of daily living without assistance, for example.
Our interest in the appropriate surgical care of people with late-stage cancer grew from observing terminally ill patients whose acute problems were addressed through surgery, and who then suffered complications resulting in lengthy stays in intensive care units, and even in death.
Unfortunately, it is quite common that this group of disseminated malignancy patients end up dying in the intensive care unit instead of being managed with less invasive interventions with hopes of returning home with their families, including with hospice care.
(more…)
MedicalResearch.com Interview with:
Andre Paixao, MD
Division of Cardiology
Emory University
Atlanta, GA, 30322.
Medical Research: What is the background for this study?
Dr. Paixao: Despite advances in cardiovascular prevention, coronary heart disease remains a major cause of morbidity and mortality. Understanding risk factor burden and control as well as perceived risk prior to acute myocardial infarction (MI) presentation may identify opportunities for system-based interventions to promote adherence to evidence based recommendations and improve overall cardiovascular health.
Medical Research: What are the main findings?Dr. Paixao: Our study assessed predicted risk and risk factor control prior to Myocardial Infarction (MI) presentation in 443,117 patients included in the NCDR ACTION Registry-GWTG. Only 36.1% of patients met all assessed risk factor control metrics (i.e. LDL cholesterol, non-HDL cholesterol, nonsmoking status and aspirin use among those with prior cardiovascular disease). Risk factor control was suboptimal in the primary and secondary prevention groups.
Prior cardiovascular disease was present in 41.6% of patients presenting with an acute MI. Among those without prior cardiovascular disease or diabetes, only 13.4% were classified as high risk based on the Framingham Risk Score. (more…)
MedicalResearch.com interview with
Dr. Victoria L. Chiou, MD
Medical Oncology Fellow
Women’s Malignancies Branch
National Cancer Institute
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Chiou: We studied the effects of different treatments in ovarian and breast cancer cell lines with and without BRCA1 mutation in the laboratory. Our discovery that olaparib pretreatment before carboplatin led to decreased carboplatin-induced DNA damage in tumor cells carrying BRCA1 mutation led us to a novel clinical question. We wanted to further understand whether there was an optimal way to deliver a combination of the new tablet formulation of olaparib with carboplatin chemotherapy in women with gynecologic and breast cancers.
We launched our clinical trial to test this important question. Overall, we are pleased that the drug combination of olaparib and carboplatin chemotherapy can be given safely together, with preliminary activity in women with breast and ovarian cancer associated with germline BRCA mutations. We are excited to report the findings of this study, which is the first to report preclinical and clinical data on sequence specificity for this drug combination in this patient population. (more…)
MedicalResearch.com Interview with:
Dr. Alec (Chengcheng) Zhang
Michael L. Rosenberg Scholar in Medical Research
Associate Professor of Physiology and Developmental Biology, Member of the Harold C. Simmons Comprehensive Cancer Center
UT Southwestern Medical Center
Medical Research: What is the background for this study? What are the main findings?
Response:Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. Treatments for AML yield poor outcomes, especially for the typical senior patients. The medical need for new therapies for AML is underscored by the fact that no new therapies for AML have been approved in over 30 years. There are over 50 experimental agents in clinical trials for the treatment of AML today, although only a few agents have promising data to date. New molecular targets and therapeutic strategies are needed for AML treatment.
In 2012, we published a paper showing that we cloned the human leukocyte immunoglobulin-like receptor B2 (LILRB2) as a receptor for several angiopoietin-like proteins (Angptls) (Zheng et al 2012 Nature 485:656-660). The LILRB family receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and are classified as inhibitory receptors because ITIM motifs can recruit phosphatases SHP-1, SHP-2, or SHIP to negatively regulate immune cell activation. Surprisingly, in that work, we showed that PirB, the mouse ortholog of LILRB2, is expressed by AML stem cells (AML-SCs) and supports AML development. Although counterintuitive, this result is consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system.
In the current paper, we continued the research and report that a number of receptors containing the ITIMs are crucial for the development of AML. We mainly focus on studying the function and downstream signaling of LAIR1 as a representative ITIM-containing receptor. We found that the deletion of LAIR1 does not affect normal hematopoiesis but abolishes leukemia development in several different mouse leukemia models. We also identified a mechanism by which LAIR1 supports AML development, showing that the LAIR1/SHP-1/CAMK1/CREB pathway sustains the survival and self-renewal of AML cells. Importantly, our findings are well supported by bioinformatics analysis of AML patient databases and experimental results of human leukemia cells. Since certain ITIM-containing receptors are essential for AML cells but not critical for normal hematopoiesis, and blocking their signaling can boost immunity, these ITIM-containing receptors including LAIR1 represent ideal targets for treating AML.
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MedicalResearch.com Interview with:
Shannon M. Dunlay, M.D. M.S.
Advanced Heart Failure and Cardiac Transplantation
Assistant Professor of Medicine and Health Care Policy and Research
Mayo Clinic Rochester
MedicalResearch: What is the background for this study? What are the main findings? Dr. Dunlay: Left ventricular assist devices (LVAD) are increasingly utilized as destination therapy (DT) in patients that are not candidates for heart transplantation. Optimal patient selection is essential in improving outcomes, but many of the factors associated with favorable outcomes remain poorly understood. It is important for us to better understand the role that psychosocial factors may play in outcomes after DT LVAD. Unlike transplant, where the limited organ supply requires choosing candidates with optimal psychosocial characteristics, DT LVAD therapy is more readily available as it does not rely on organ donors. There are no clear guidelines on what constitutes an acceptable psychosocial risk prior to DT LVAD. As a result, many programs will offer DT LVAD to candidates despite psychosocial concerns if it is felt they will otherwise benefit. Data are needed to inform programs about whether such candidates are truly at elevated risk of adverse outcomes.
In our single-center study including 131 patients, we found that several psychosocial characteristics are predictive of readmission after DT LVAD. A history of illegal drug use and depression are associated with a higher risk of readmission, while tobacco use is associated with lower readmission risk. Psychosocial characteristics were not significant predictors of death after DT LVAD.
(more…)
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MedicalResearch.com Interview with:
David S. Lopez, Dr.P.H., M.P.H.
Assistant professor
University of Texas Health School of Public Health
Medical Research: What is the background for this study? What are the main findings?
Dr. Lopez: Coffee, and its most studied component, caffeine, have been implicated in potential health benefits due to the rich sources of antioxidants and anti-inflammatory compounds contained in this beverage.
Caffeine intake reduced the odds of prevalent erectile dysfunction, especially an intake equivalent to approximately 2-3 daily cups of coffee (170-375 mg/day). This reduction was also observed among overweight/obese and hypertensive men, but not among diabetic men. These associations are warranted to be investigated in prospective studies.
Medical Research: What are the main findings?
Dr. Lopez: Caffeine intake reduced the odds of prevalent erectile dysfunction, especially an intake equivalent to approximately 2-3 daily cups of coffee (170-375 mg/day). This reduction was also observed among overweight/obese and hypertensive men, but not among diabetic men. These associations are warranted to be investigated in prospective studies.
(more…)
