AHA Journals, Author Interviews, Heart Disease, Outcomes & Safety, UT Southwestern / 04.12.2016

MedicalResearch.com Interview with: Rohan Khera, MD Cardiology Fellow, T32 Clinical-Investigator Pathway UT Southwestern Medical Center Dallas, TX MedicalResearch.com: What is the background for this study? What are the main findings? Response: Nearly 200 thousand people have an in-hospital cardiac arrest in the US each year. Of these, the vast majority have a non-shockable initial rhythm – either pulseless electric activity (PEA) or asystole. The survival of this type of arrest remains poor at around 12-14%. Moreover, even after accounting for differences in case mix, there is a wide variation in survival across hospitals – and this serves as a potential avenue for targeting quality improvement strategies at poor performing hospitals. Recent data suggest that a shorter time from the onset of cardiac arrest to the first dose of epinephrine is independently associated with higher survival. Against this background of wide hospital variation in cardiac arrest survival, and patient-level data suggesting an association between time to epinephrine and patient survival, we wanted to assess (A) if there were differences in time to epinephrine administration across hospitals, and (B) if a hospital’s rate of timely epinephrine use was associated with its cardiac arrest survival rate. Within Get With The Guidelines-Resuscitation, we identified nearly 104-thousand adult patients at 548 hospitals with an in-hospital cardiac arrest attributable to a non-shockable rhythms. delays to epinephrine, We found that (a) proportion of cardiac arrests with delayed epinephrine markedly across hospitals, ranging from no arrests with delay (or 0%) to more than half of arrests at a hospital (54%). There was an inverse correlation between a hospital’s rate of delayed epinephrine administration and its risk-standardized rate of survival to discharge and survival with functional recovery - compared to a low-performing hospitals, survival and recovery was 20% higher at hospitals that performed best on timely epinephrine use.
Author Interviews, Cannabis, Nature, UT Southwestern, Weight Research / 19.11.2016

MedicalResearch.com Interview with: [caption id="attachment_29787" align="alignleft" width="300"](l-r) Dr. Zhenhua Shao and Dr. Daniel Rosenbaum (l-r) Dr. Zhenhua Shao and Dr. Daniel Rosenbaum UT Southwestern[/caption] Dan Rosenbaum, Ph.D. Principal Investigator Department of Biophysics The University of Texas Southwestern Medical Center Dallas, Texas MedicalResearch.com: What is the background for this study? What are the main findings? Response: This study focuses on the structure of the human CB1 cannabinoid receptor. The CB1 protein is a membrane-embedded G protein-coupled receptor (GPCR) in the brain and peripheral tissues that responds to a variety of different compounds, including endogenous lipid messengers (‘endocannabinoids’), plant natural products (such as THC from the Cannabis sativa plant i.e. marijuana), and synthetic antagonists (such as the taranabant ligand used for this study). The CB1 receptor is involved in regulating neurotransmission in vertebrates, and is a potential therapeutic target for numerous conditions including obesity, pain, and epilepsy. The main findings of this study entailed the solution of the high-resolution crystal structure of human CB1 receptor bound to the inhibitor taranabant. This structure revealed the precise shape of the inhibitor binding pocket, which is also responsible for binding THC and endocannabinoids. In addition to helping explain the mechanism of inhibitor and THC binding, our structure provides a framework for computational studies of binding to a large diversity of cannabinoid modulators of therapeutic importance.
Author Interviews, Blood Pressure - Hypertension, Heart Disease, JACC, Race/Ethnic Diversity, UT Southwestern / 13.11.2016

MedicalResearch.com Interview with: [caption id="attachment_29589" align="alignleft" width="140"]Wanpen Vongpatanasin, M.D. Professor of Medicine Norman & Audrey Kaplan Chair in Hypertension Fredric L. Coe Professorship in Nephrolithiasis and Mineral Metabolism Research Director, Hypertension Section, Cardiology Division, UT Southwestern Medical Center Dallas, TX 75390-8586 Dr. Wanpen Vongpatanasin[/caption] Wanpen Vongpatanasin, M.D. Professor of Medicine Norman & Audrey Kaplan Chair in Hypertension Fredric L. Coe Professorship in Nephrolithiasis and Mineral Metabolism Research Director, Hypertension Section, Cardiology Division, UT Southwestern Medical Center Dallas, TX 75390-8586 MedicalResearch.com: What is the background for this study? What are the main findings? Response: Aortic stiffness is known to be associated with cardiovascular disease, including heart attack, stroke, and heart failure, possibly related to increase afterload to the left ventricle. Previous studies have not directly assessed proximal aortic function among ethnic minorities in the United States. We evaluated the multiethnic, population-based Dallas Heart Study participants (N=2544, 54.2% women, 49.7% Black) who underwent cardiovascular magnetic resonance imaging (CMR) at 1.5 Tesla. Aortic stiffness and characteristic impedance (Zc) were determined from aortic arch PWV and lumen area measurements. Linear regression was used to evaluate ethnic differences in proximal aortic wall stiffness using aortic arch PWV and Zc as dependent variables with and without adjustment for traditional cardiovascular risk factors.
Author Interviews, Biomarkers, Cancer, Prostate Cancer, UT Southwestern / 08.10.2016

MedicalResearch.com Interview with: Dr Ryan Hutchinson MD and Yair Lotan MD Department of Urology University of Texas Southwestern Medical Center MedicalResearch.com: What is the background for this study? What are the main findings? Response: The United States Preventative Services Task Force recommendation against PSA screening generated significant controversy. Research since then has relied heavily on survey data to examine the impact of the recommendation on PSA screening practices. In a hotly charged issue such as this, such data can carry significant bias. We examined a large, whole-institution data in the years before and after the USPSTF recommendations reflecting actual practice and found that the changes in PSA use at our institution, if any, were small. This is more consistent with behavior seen after the vast majority of practice recommendations.
Author Interviews, Breast Cancer, Cancer, Genetic Research, UT Southwestern / 23.09.2016

MedicalResearch.com Interview with: [caption id="attachment_28272" align="alignleft" width="96"]Roshni Rao, M.D Breast Surgery University of Texas Southwestern Dr. Roshni Rao[/caption] Roshni Rao, M.D Breast Surgery University of Texas Southwestern MedicalResearch.com: What is the background for this study? What are the main findings? Response: Triple negative breast cancer (TNBC) is characterized by not having estrogen, progesterone, or Her2Neu receptors. Although a less common type, it is aggressive, and leads to a disproportionate number of deaths from breast cancer. TNBC is more common in young, African American women, but can be found in other ethnic groups as well. This study performed mitochondrial DNA (mtDNA) analysis, to evaluate for patient genetic ancestry, in 92 patients with TNBC. In regards to self-identified ethnicity, there were 31 African-Americans, 31 Whites, and 30 Hispanics. Utilizing mtDNA, 13% of patients had discordance between self identified ethnicity and mtDNA analysis. Discordance was highest in the Hispanic group. The Hispanic patients were also much younger at initial age of diagnosis, and less likely to have a family history of breast cancer. Ancestry from Nigeria, Cameroon, or Sierre Leone were most common in the African-Americans with triple negative breast cancer.
Author Interviews, Blood Pressure - Hypertension, Mineral Metabolism, UT Southwestern / 06.07.2016

MedicalResearch.com Interview with: [caption id="attachment_25830" align="alignleft" width="172"]Dr-Wanpen-Vongpatanasin.jpg Dr. Vongpatanasin[/caption] Wanpen Vongpatanasin, MD Professor of Medicine Norman & Audrey Kaplan Chair in Hypertension Research Director, Hypertension Section Cardiology Division UT Southwestern Medical Center MedicalResearch.com: What is the background for this study? What are the main findings? Response: Inorganic phosphate has been added to our processed food at an enormous amount as food preservatives and flavor enhancer such that typical American diet contains twice as much as the recommended daily allowance. A high phosphate (Pi) diet was recently shown to trigger blood pressure (BP) elevation in otherwise normal rats but the mechanisms are still unknown.We found that rats treated with high phosphate diet that mimics the excess Pi consumed by the general American population developed high BP related to increased sympathetic nerve activity (SNA), resulting in excessive peripheral vasoconstriction. This exaggerated increase in SNA and BP is evident particularly during exercise. This study is conducted in collaboration with Drs. Masaki Mizuno and Scott Smith, the two leading experts in neural control of circulation at UT Southwestern in the Department of Health Care Sciences.
Author Interviews, Diabetes, UT Southwestern / 05.07.2016

MedicalResearch.com Interview with: Dr. Eunhee Choi Research scientist in the Yu laboratory and lead author of the study UT SouthWestern Dr. Hongtao Yu, Professor of Pharmacology at UT Southwestern and Investigator with the Howard Hughes Medical Institute (HHMI). MedicalResearch.com: What is the background for this study? What are the main findings? Response: Diabetes is a metabolic disease. High blood sugar is a common symptom of diabetes, and over time it can lead to serious damage to multiple organs. Insulin, a hormone made by the pancreas, regulates blood sugar. Diabetes can occur either when the pancreas does not produce enough insulin (type 1 diabetes) or when the cells in our body cannot efficiently respond to insulin (type 2 diabetes). Diabetes is now a major global epidemic. The World Health Organization (WHO) estimates that more than 400 million people worldwide have diabetes. Insulin binds the insulin receptor (IR) at the cell surface. The insulin-bound IR can send signals inside the cell and instruct the cell to take up sugar from the blood, thus maintaining healthy blood sugar levels. After insulin has done its job, insulin-bound IR is packaged into small vesicles with a protein coat and dragged into the cell, thus terminating the signals. An adequate level of IR on the cell surface is crucial for insulin signaling and blood sugar metabolism. We have found a new mechanism that keeps IR at the cell surface. Without such a mechanism, IR is prematurely dragged inside the cell before it encounters insulin. Our discovery is quite unexpected. A main interest of our lab is to study the molecular control of cell division. During each cell division, the duplicated sister chromosomes are evenly separated into two daughter cells. A cellular surveillance system called the spindle checkpoint ensures the accuracy of sister-chromosome separation. Three checkpoint proteins, p31comet, MAD2 and BUBR1, are critical for accurate chromosome segregation. In the process of studying this checkpoint, we have unexpectedly discovered that mice lacking p31comet in the liver develop diabetes. Liver cells lacking p31comet do not have IR on the cell surface, and thus cannot respond to insulin. We have further shown that MAD2 directly binds to IR, and along with BUBR1, helps to drag IR inside the cell. p31comet prevents BUBR1 from interacting with IR-bound MAD2, thus keeping IR at the cell surface. In cells lacking p31comet, MAD2 and BUBR1 gain the upper hand and remove IR from the cell surface. Thus, the dynamic tug-of-war between p31comet and MAD2-BUBR1 determines the status of IR at the cell surface.
Author Interviews, Blood Pressure - Hypertension, Mineral Metabolism, Nutrition, UT Southwestern / 04.07.2016

MedicalResearch.com Interview with: [caption id="attachment_25830" align="alignleft" width="172"]Dr-Wanpen-Vongpatanasin.jpg Dr. Vongpatanasin[/caption] Dr. Wanpen Vongpatanasin MD The Norman and Audrey Kaplan Chair in Hypertension UT Southwestern Medical Center MedicalResearch.com: What is the background for this study? What are the main findings? Response: Diet rich in fruits, vegetables, and dairy products, known as the DASH diet, is known to reduce blood pressure in hypertensive patients. More recently, the DASH diet was shown to reduce oxidative stress in people with and without high blood pressure . However, the main nutritional ingredient responsible for these beneficial effects of the DASH diet remain unknown. Because the DASH diet is rich in potassium (K), magnesium (Mg), and alkali, we performed a randomized, double-blinded, placebo-controlled study to compare effects of KMg Citrate (KMgCit), K Chloride (KCl), and K Citrate (KCit) to allow dissociation of the three in hypertensive and prehypertensive individuals. This study was conducted in collaboration with Drs. Charles Pak and Orson Moe at UT Southwestern, the two leading experts in the field of Mineral Metabolism. We found that oxidative stress was markedly reduced by KMgCit powder compared to placebo, K Chloride, and K Citrate. On the hand, KMgCit has no significant effects on blood pressure . MedicalResearch.com Editor's note:  DO NOT Take Potassium supplements unless under the direction of your health care provider.
Author Interviews, Heart Disease, PNAS, UT Southwestern / 28.06.2016

[caption id="attachment_25439" align="alignleft" width="200"]Dr-Audrey-Chang credit: UT Southwestern Dr. Audrey Chang[/caption] 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.
Author Interviews, Cost of Health Care, Hospital Readmissions, Outcomes & Safety, UT Southwestern / 04.04.2016

MedicalResearch.com Interview with: Oanh Kieu Nguyen, MD, MAS | Assistant Professor UT Southwestern Medical Center Divisions of General Internal Medicine and Outcomes and Health Services Research Dallas, TXOanh Kieu Nguyen, MD, MAS | Assistant Professor UT Southwestern Medical Center Divisions of General Internal Medicine and Outcomes and Health Services Research Dallas, TX MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Nguyen: The impetus for this study was Steven Brill’s 2013 Time magazine award-winning article, “Bitter Pill: Why Medical Bills Are Killing Us.” This report investigated inflated charges for hospital bills, and and suggested that a major driver of irrationally high charges was the disproportionate negotiating power of hospitals, as evidenced through their high profit margins. As hospital physicians, our reaction was “But what if hospitals that make more money are delivering more value and better outcomes to patients? If that’s the case, wouldn’t most people say that their profits justifiably earned?” Surprisingly, we found that no one had really looked at this issue in a systematic way. We set out to answer this question using hospital financial data from California’s Office of Statewide Health Planning and Development (OSHPD) and outcomes data on 30-day readmissions and mortality for congestive heart failure, acute myocardial infarction (‘heart attacks’), and pneumonia from the Centers for Medicare and Medicaid Services (CMS) Hospital Compare website. California has more hospitals than any other state other than Texas, and also has a wide diversity of hospital types. The OSHPD financial data are also audited, so we thought these would be more reliable than using data from other sources. Because the outcomes reported on Hospital Compare are viewable by the general public, we thought hospitals would be most motivated to target improvements in these outcomes. We found that there was almost no association between how much money a hospital made and its subsequent performance on outcomes. The exception to this was we found that hospitals that had better finances reported higher rates of 30-day mortality for congestive heart failure, which was counterintuitive. We’re not sure why this was the case but speculate that it is possible that hospitals with better finances take care of sicker heart failure patients because they have more advanced (and more expensive) treatments available. Additionally, we looked to see if hospitals with lower readmissions rates subsequently made less money. This is a specific area of policy concern given federal penalties in the U.S. for excessive hospital readmissions. Many critics of these penalties have argued that reducing readmissions makes no financial sense for hospitals, since readmissions still generate hospital revenue despite the penalties. Thus, reducing readmissions would reduce a key source of hospital revenue and lead to poorer hospital finances. However, our analysis showed that lower readmissions rates were not associated with poorer hospital finances, as has been feared. 
Author Interviews, Genetic Research, UT Southwestern / 09.01.2016

MedicalResearch.com Interview with: Rhonda Bassel-Duby, Ph.D. and Dr. Chengzu Long, PhD Department of Molecular Biology UT Southwestern Medical Center Dallas, TX 75390-9148 Medical Research: What is the background for this study? What are the main findings? Response: Duchenne muscular dystrophy (DMD), which was first described by Duchenne de Boulogne (1806-1875) in 1860s, is one of the most severe and common type of muscular dystrophy. DMD is caused by mutations in the gene for dystrophin (DMD) on the X chromosome and affects approximately 1 in 3500 to 5000 boys. Without dystrophin, a large cytoskeletal protein, muscles degenerate, causing myopathy. Symptoms can be visible between 1 to 6 years old. Most Duchenne muscular dystrophy patients are confined to a wheelchair by age 12. Death of DMD patients usually occurs by age 25, typically from breathing complications and cardiomyopathy. Hence, therapy for  Duchenne muscular dystrophy necessitates sustained rescue of skeletal, respiratory and cardiac muscle structure and function. Although several gene therapies have been tested, there is no curative treatment so far. Duchenne muscular dystrophy arises from a monogenic mutations in dystrophin gene. This makes DMD an ideal disease model for CRISPR-mediated gene editing therapeutics, a major breakthrough in gene engineering in the past three years. This system can remove the defect within the gene. In 2014, in a first proof of concept study, Olson’s team used CRISPR-mediated gene editing to correct the dystrophin gene mutation in the germline of DMD mouse model. In this new paper, we advanced the same technology to postnatal muscle tissues by delivery gene editing components via a harmless adeno-associated virus. Skeletal and cardiac muscle showed progressive rescue of dystrophin protein.
Author Interviews, Heart Disease, JAMA, UT Southwestern / 25.11.2015

[caption id="attachment_19634" align="alignleft" width="200"]Ambarish Pandey M.D. Division of Cardiology University of Texas Southwestern Medical Center Dallas, TX Dr. Ambarish Pandey[/caption] Ambarish  MedicalResearch.com Interview with: Ambarish Pandey M.D. Division of Cardiology University of Texas Southwestern Medical Center Dallas, TX Medical Research: What is the background for this study? What are the main findings? Dr. Pandey: Pulmonary artery (PA) catheters have been used for invasive bedside hemodynamic monitoring for past four decades. The ESCAPE trial, published in October 2005, demonstrated that use of  Pulmonary Artery catheter was not associated with a significant improvement in clinical outcomes of patients with heart failure. Accordingly, the current ACC/AHA guidelines discourage the routine use of PA catheter for routine management of acute heart failure in absence of cardiogenic shock or respiratory failure (Class III). Despite the significant evolution of available evidence base and guideline recommendations regarding use of  Pulmonary Artery catheters, national patterns of PA catheter utilization in hospitalized heart failure patients remain unknown. In this study, we observed that use of PA catheter among patients with heart failure decline significantly in the Pre-ESCAPE era (2001 – 2006) followed by a consistent increase in its use in the Post-ESCAPE era (2007-2012). We also observed that the increase in use of  Pulmonary Artery catheters is most significant among heart failure patients without underlying cardiogenic shock or respiratory failure.
Author Interviews, Chemotherapy, Lung Cancer, NEJM, UT Southwestern / 11.10.2015

David E. Gerber, MD Associate Professor Division of Hematology-Oncology Associate Director for Clinical Research Co-Leader, Experimental Therapeutics Program Co-Director, Lung Disease Oriented Team Harold C. Simmons Cancer Center University of Texas Southwestern Medical Center Dallas, TXMedicalResearch.com Interview with: David E. Gerber, MD Associate Professor Division of Hematology-Oncology Associate Director for Clinical Research Co-Leader, Experimental Therapeutics Program Co-Director, Lung Disease Oriented Team Harold C. Simmons Cancer Center University of Texas Southwestern Medical Center Dallas, TX Medical Research: What is the background for this study? What are the main findings? Dr. Gerber: In this trial, we compared an immunotherapy and a chemotherapy drug in patients with non-squamous non-small cell lung cancer (NSCLC) whose disease continued to progress after first-line chemotherapy. We found that nivolumab immunotherapy improved overall survival compared to docetaxel chemotherapy and was generally well tolerated. These results are significant because options for patients whose lung cancer progresses after initial treatment are limited. Nivolumab is an immunotherapy drug that works by inhibiting the cellular pathway known as PD-1 protein on cells that block the body’s immune system from attacking cancerous cells.  The idea behind nivolumab and other immunotherapy drugs is to kick-start the body’s natural immune response to a cancer. Cancer develops and grows in part because it has put the brakes on the immune response. These drugs take the foot off the brake, allowing the immune system to accelerate and attack the cancer. The phase 3 clinical trial followed more than 500 patients who had non-squamous non-small cell lung cancer (NSCLC): 287 received nivolumab and 268 received the chemotherapy drug docetaxel. The one-year survival rate was 51 percent in the nivolumab arm versus 39 percent in the docetaxel arm. The most common reported side effects with nivolumab were fatigue, nausea, decreased appetite, and weakness, and they were less severe than with docetaxel treatment. In a minority of cases, patients treated with nivolumab also developed autoimmune toxicities affecting various organs. In addition to studying safety and efficacy, the trial examined the protein biomarker PD-L1, which is believed to play a role in suppressing the immune system. The study results suggested that patients with a higher level of PD-L1 in their cancers may experience the greatest benefit from nivolumab, which targets the related molecule PD1. Using a biomarker helps oncologists predict which patients will do best on which treatment, and plan their treatment accordingly. Other promising predictive biomarkers for cancer immunotherapies include the degree of immune cell infiltration within a tumor and the number of mutations a tumor has. Specifically, the more mutations a cancer has, the more foreign it appears to the body, thus marking it for immune attack. With lung cancer, we see the greatest number of tumor mutations – and perhaps the greatest benefit from immunotherapy – among individuals with the heaviest smoking history.
AHA Journals, Author Interviews, Exercise - Fitness, Heart Disease, JACC, University Texas, UT Southwestern / 07.10.2015

Ambarish Pandey, MD Cardiology Fellow, PGY5 University of Texas Southwestern Medical Center, Dallas, Texas 75390MedicalResearch.com Interview with: Ambarish Pandey, MD Cardiology Fellow, PGY5 University of Texas Southwestern Medical Center, Dallas, Texas 75390 Medical Research: What is the background for this study? What are the main findings? Dr. Berry: Physical inactivity is considered a major modifiable risk factor for coronary artery disease and the current guidelines recommend atleast 150 min/week (~ 500 MET-min/week) of moderate intensity physical activity to reduce the burden of coronary artery disease. In contrast, the role of physical activity in reducing risk of heart failure is not emphasized in the current guidelines. This is particularly relevant considering the increasing burden of heart failure in the community. Against this background, we performed this study to the dose-response relationship between physical activity levels and risk of heart failure. We observed a dose dependent inverse association between physical activity levels and heart failure risk. Furthermore, we observed that the current guideline recommended physical activity levels (500 MET-min/week) are associated with only modest reduction in HF risk (< 10%). In contrast, a substantial reduction in heart failure risk was observed at twice and four times the recommended physical activity levels (19% and 35% risk reduction respectively)
Author Interviews, Brain Injury, JAMA, UT Southwestern / 18.05.2015

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 75390-9044 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.
Author Interviews, Diabetes, General Medicine, Statins, UT Southwestern / 08.05.2015

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, TXMedicalResearch.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:
  1. 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).
  2. Statin use was associated with very high risk of diabetes complications in this healthy population: this was never shown before.
  3. 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.
Author Interviews, Cancer Research, Nature, UT Southwestern / 03.05.2015

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 CenterMedicalResearch.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.
Author Interviews, Genetic Research, Nature, Pancreatic, UT Southwestern / 10.04.2015

Dr. Agnieszka Witkiewicz MD Associate Professor of Pathology Harold C. Simmons Comprehensive Cancer Center UT SouthwesternMedicalResearch.com Interview with: Dr. Agnieszka Witkiewicz MD Associate Professor of Pathology Harold C. Simmons Comprehensive Cancer Center UT Southwestern MedicalResearch: What is the background for this study? Dr. Witkiewicz: Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis, with a five year survival rate of approximately 6%. This poor outcome is related to multiple factors, including the relatively late stage of diagnosis, many patients presenting with unresectable disease, and therapy recalcitrance resulting in disease recurrence in spite of operable disease and systemic therapy. Thus far, insights into how to target the treatment of Pancreatic ductal adenocarcinoma have remained unclear in spite of prior sequencing efforts. MedicalResearch: What are the main findings? Dr. Witkiewicz: The underlying critical finding of the study was that Pancreatic ductal adenocarcinoma is genetically diverse and that, in principle, this diversity could be exploited for the treatment of disease.   Specifically, many cases harbored deregulation in pathways that are the target for drug development.   For example, we identified cases that were driven by BRAF V600E and that were sensitive to the FDA approved drug Vemurafenib.   Similarly, multiple cases harbored defects in DNA repair processes that impart sensitivity to select chemotherapeutic agents and PARP inhibitors.  Common pathway deregulation was observed in reference to beta-catenin, notch, hedgehog, chromatin remodeling, and cell cycle regulatory pathways that are all targets for therapeutic intervention.
Author Interviews, Endocrinology, Metabolic Syndrome, Nutrition, Pediatrics, UT Southwestern / 06.03.2015

Dr. Roy Kim, MD Depts. Endocrinology and Pediatrics UT Southwestern Medical CenterMedicalResearch.com Interview with: Dr. Roy Kim, MD Depts. Endocrinology and Pediatrics UT Southwestern Medical Center Medical Research: What was the problem you were focused on? Dr. Kim: We were focused on the problem of adolescent metabolic syndrome, a major public health problem. Our objective was to determine whether nut intake is linked with any difference in odds for metabolic syndrome in US adolescents. Medical Research: How is metabolic syndrome defined? Dr. Kim: In general it is diagnosed when there are 3 or more of the following things: increased belly fat, high blood pressure, high fasting glucose, elevated triglycerides, and low HDL cholesterol. Medical Research: How did you do your study? Dr. Kim: We used data from the National Health and Nutrition Examination Survey (NHANES), years 2003-2010, to examine health status and the diet history for 2,322 US adolescents age 12 to 19 years. Dr. Kim: Our first major finding was that adolescents who ate at least 12.9 grams of nuts per day - this is the equivalent of about 1 ounce of nuts 3 times per week – had a dramatically lower odds for metabolic syndrome compared to adolescents who ate less than that amount. The odds for nut-consumers was only about 43% of the odds for non-consumers. This remained true after controlling for age, gender, race, income, and dietary factors including sugar, fruit, and vegetable intake. Our second major finding was that average nut intake is very low among US adolescents – only about 5 grams per day - and more than 75% of US adolescents eat no nuts at all on a typical day.
Author Interviews, Journal Clinical Oncology, Lung Cancer, Radiation Therapy, UT Southwestern / 03.01.2015

[caption id="attachment_10398" align="alignleft" width="200"]Dr. Puneeth Iyengar (left) and Dr. Robert Timmerman Dr. Puneeth Iyengar (left) and Dr. Robert Timmerman[/caption] MedicalResearch.com Interview with: Dr. Puneeth Iyengar, MD, PhD. Assistant Professor Director of Clinical Research Dept of Radiation Oncology Co-leader, Thoracic Disease Oriented Team Harold Simmons Cancer Center UT Southwestern Medical Center  Dallas, TX Medical Research: What is the background for this study? What are the main findings? Response: Stage IV Non-small cell lung cancer (NSCLC) remains a disease of limited survival, in the range of one year for a majority of patients who historically have gone on to receive systemic therapy only. Disease in this patient population most often recurs in the sites of original gross disease. With greater understanding of the biology and patterns of failure that occur in stage IV NSCLC, it is becomingly increasingly obvious that there are subsets of patients, those with limited sites of metastatic disease, who may benefit with more aggressive local therapy in addition to systemic agents to effectuate longer progression free survival (PFS) and potentially overall survival (OS). Since failures of treatment occur most commonly in original gross deposits, local non-invasive therapy in the form of stereotactic body radiation therapy (SBRT) may offer a means to curtail the recurrences, perhaps as a way to shift the time to and patterns of failure. To address these concepts, a multi institutional single arm phase II study was conducted at UT Southwestern Medical Center in Dallas and University of Colorado Medical Center. Twenty-four patients with limited metastatic NSCLC (fewer than or equal to six sites of disease including the primary) who had progressed through at least one systemic therapy regimen were treated with SBRT to all sites of gross disease and the EGFR inhibitor erlotinib with progression free survival the primary end point. The results of the study were very significant, with a PFS in this study cohort of 14.7 months, compared to historical ranges of 2-4 months, and an OS of 20.4 months, compared to historical ranges of 6-9 months for this same patient population. The SBRT treatments were found to be very safe and efficacious – only 3 out of 47 measurable lesions irradiated recurred with a concomitant shift in failure patterns from local to distant sites. As importantly, EGFR status was evaluated in 13 patient tumors, with none harboring the most common mutations. One could, therefore, predict that with a mutation enriched population, the combination of EGFR inhibitor and SBRT may have offered even greater PFS and OS benefits. Our observations also suggest that the SBRT treatments probably contributed the most to the dramatic PFS and OS outcomes. These findings were published in the Journal of Clinical Oncology in the December 1, 2014 print issue with an accompanying editorial.
Author Interviews, JAMA, Obstructive Sleep Apnea, Pediatrics, University Texas, UT Southwestern / 26.12.2014

Ron B. Mitchell, MD Professor of Otolaryngology and Pediatrics William Beckner Distinguished Chair in Otolaryngology Chief of Pediatric Otolaryngology UT Southwestern and Children's Medical Center Dallas ENT Clinic Dallas, TX 75207MedicalResearch.com Interview with: Ron B. Mitchell, MD Professor of Otolaryngology and Pediatrics William Beckner Distinguished Chair in Otolaryngology Chief of Pediatric Otolaryngology UT Southwestern and Children's Medical Center Dallas ENT Clinic Dallas, TX 75207 Medical Research: What is the background for this study? What are the main findings? Dr. Mitchell: The “gold standard” for the diagnosis of and quantification of obstructive sleep apnea (OSA) is polysomnography (PSG or a ‘sleep study’). However, the majorities of T&A procedures are done without PSG and are based on a clinical diagnosis. This is because PSG is expensive, requires overnight observation and is often unavailable. It is important to diagnose and quantify OSA as it allows for surgical planning and predicts the need and type of treatment after surgery. We used data from the Childhood Adenotonsillectomy (CHAT) study; a large multicenter trial (RCT), to look at the ability of clinical parameters to predict the severity of obstructive sleep apnea in children scheduled for a T&A. The main findings of the study are that certain clinical parameters such as obesity and African American race as well as high scores on certain validated questionnaires (such as the pediatric sleep questionnaire- PSQ) are associated, but cannot predict OSA severity. PSG remains the only way to measure objectively the severity of OSA.
Author Interviews, Cancer Research, JNCI, Lung Cancer, UT Southwestern / 02.10.2014

Dr. David Gerber MD Associate Professor of Internal Medicine Division of Hematology and Oncology Harold C. Simmons Cancer Center at UT Southwestern Medical CenterMedicalResearch.com Interview with: Dr. David Gerber MD Associate Professor of Internal Medicine Division of Hematology and Oncology Harold C. Simmons Cancer Center at UT Southwestern Medical Center Medical Research: What are the main findings of the study? Dr. Gerber: Fewer than 3% of adult cancer patients in the United States are enrolled in clinical trials.  Increasingly numerous and stringent eligibility criteria are a major factor limiting participation in clinical trials.  We examined the longstanding and widespread practice of excluding patients with prior cancer from oncology clinical trials.  This policy presumably reflects concerns that a prior cancer would interfere with the conduct, outcomes, or interpretation of a clinical trial, although there is no clear evidence supporting that assumption. We examined more than 50 National Cancer Institute (NCI)-sponsored lung cancer clinical trials.  We found that 80% excluded patients with prior cancers.  This exclusion criterion was applied broadly, including to more than two-thirds of trials with non-survival endpoints.  We then examined national Surveillance Epidemiology and End Results (SEER)-Medicare linked data to estimate the proportion of patients who would be excluded from these trials due to prior cancer.  We found that up to 18% of potential patients are excluded for this reason alone.  In large phase 3 clinical trials, that corresponds to more than 200 patients.
AHA Journals, Author Interviews, Heart Disease, UT Southwestern / 13.08.2014

MedicalResearch.com Interview with: Hurst M. Hall, MD and Sandeep Das, MD, MPH Division of Cardiology University of Texas Southwestern Medical Center Dallas, TX Medical Research: What are the main findings of the study? Answer: Most patients treated for a heart attack in the United States during this study period were discharged home on 325 mg of aspirin a day.  This was true even among subgroups expected to be at high bleeding risk. In addition, there was tremendous variability in the proportional use of this higher dose aspirin across hospitals, suggesting a prominent local influence on prescribing patterns.
Author Interviews, JAMA, Respiratory, UT Southwestern / 04.06.2014

Dr. Eric M. Mortensen, M.D., M.Sc. VA North Texas Health Care System and University of Texas Southwestern Medical Center, DallasMedicalResearch.com Interview with: Dr. Eric M. Mortensen, M.D., M.Sc. VA North Texas Health Care System and University of Texas Southwestern Medical Center, Dallas   MedicalResearch: What are the main findings of the study? Dr. Mortensen: The main findings of our study was that for older patients hospitalized with pneumonia that with the use of azithromycin although there is a small increase in the number of non-fatal heart attacks there was a much lower decrease in mortality.   In addition there were no other significant increases in cardiac events.  So the overall risk:benefit ratio was that for each non-fatal heart attack there were 7 deaths that were prevented.
Author Interviews, Cancer Research, Hepatitis - Liver Disease, UT Southwestern / 07.05.2014

Amit Singal MD MS Assistant Professor of Medicine Medical Director, Liver Tumor Program Dedman Scholar of Clinical Care Division of Digestive and Liver Diseases University of Texas Southwestern Dallas TX 75201 - 8887MedicalResearch.com Interview with: Amit Singal MD MS Assistant Professor of Medicine Medical Director, Liver Tumor Program Dedman Scholar of Clinical Care Division of Digestive and Liver Diseases University of Texas Southwestern Dallas TX 75201 - 8887 MedicalResearch: What are the main findings of the study? Dr. Singal: We conducted a meta-analysis of current studies to characterize the association between hepatocellular carcinoma surveillance and early detection, curative treatment rates, and overall survival in patients with cirrhosis.  We identified 47 studies with 15,158 patients, of whom 6,284 (41.4%) had hepatocellular carcinoma  detected by surveillance. Hepatocellular carcinoma  surveillance was associated with improved early stage detection (OR 2.08, 95% CI 1.80–2.37) and curative treatment rates (OR 2.24, 95% CI 1.99–2.52). These associations were robust to several sensitivity analyses, including study design, study location, and study period. Hepatocellular carcinoma  surveillance was associated with significantly prolonged survival (OR 1.90, 95% CI 1.67–2.17), which remained significant in the subset of studies adjusting for lead-time bias. Three-year survival rates were 50.8% among patients who underwent surveillance, compared to only 28.2% among hepatocellular carcinoma  patients with tumors detected outside of a surveillance program.
Author Interviews, Case Western, Chemotherapy, Genetic Research, Lung Cancer, UT Southwestern / 22.03.2014

Dr. Azi Gazdar, MD UT Southwestern Medical Center W. Ray Wallace Distinguished Chair in Molecular Oncology Research Hamon Center for Therapeutic Oncology, PathologyMedicalResearch.com Interview with: Dr. Azi  Gazdar, MD UT Southwestern Medical Center W. Ray Wallace Distinguished Chair in Molecular Oncology Research Hamon Center for Therapeutic Oncology, Pathology MedicalResearch.com: What are the main findings of the study? Dr. Gazdar: We describe the characteristics of lung cancers arising in subjects who inherited a germline mutation that predisposes to lung cancer.  The mutation is rare in the general populations, and is inherited equally by both sexes.  However it is a potent predisposing gene, and one third of the never smoking carriers will develop lung cancer.  Thus, about 1% of patients who develop lung cancer carry the germline mutation.  This figure may rise as awareness of the condition and its link to lung cancer is raised among doctors diagnosing lung cancer. However, lung cancers mainly develop in women who are lifetime never smokers.  Lung cancer development is much less common among smokers and men, although accurate figures are not yet available. So the risk among carriers is somewhat similar to the BRCA genes predisposing to breast cancer, where a female carrier has about a 50% lifetime chance of developing breast cancer. The specific germline mutation (known as T790M) occurs in a gene known as epidermal growth factor receptor (EGFR) gene.  Sporadic mutations in this gene usually predict for effective responses to a class of drugs known as tyrosine kinase inhibitors (TKIs), which are widely used in the treatment of lung cancer.  However, the T790M mutation, when it occurs in sporadic tumors not associated with germline inheritance are resistant to TKI therapy.  Thus the prediction is that lung cancers arising in carriers with the germline mutation would also be resistant to TKI therapy.
Author Interviews, Ophthalmology, Transplantation, UT Southwestern / 31.12.2013

Dr. Jerry Y. Niederkorn, Ph.D. George A. and Nancy P. Shutt Professorship in Medical Sciences Royal C. Miller Chair in Age-Related Macular Degeneration Research Professor of Ophthalmology and Microbiology Vice Chair, Research (Department of Ophthalmology) Department of Ophthalmology, University of Texas Southwestern Medical Center Dallas, TXMedicalResearch.com Interview with: Dr. Jerry Y. Niederkorn, Ph.D. George A. and Nancy P. Shutt Professorship in Medical Sciences Royal C. Miller Chair in Age-Related Macular Degeneration Research Professor of Ophthalmology and Microbiology Vice Chair, Research (Department of Ophthalmology) Department of Ophthalmology, University of Texas Southwestern Medical Center Dallas, TX FN-γ Blocks CD4+CD25+ Tregs and Abolishes Immune Privilege of Minor Histocompatibility Mismatched Corneal Allografts MedicalResearch.com: What are the main findings of the study? Dr. Niederkorn: These findings indicate that a combination of two simple maneuvers increases the acceptance of corneal transplants. In the past, there was no clear benefit in performing tissue matching of the cornea donor’s major histocompatibility complex (MHC) with the recipient of the corneal transplant. However, our study in experimental animals revealed that blocking a single immune system molecule called interferon-gamma (IFN-γ) combined with matching the corneal transplant donor with the transplant recipient’s MHC gene complex reduced the risk of rejection to less than 10% in the total absence of anti-rejection drugs. This study revealed that blocking this single immune system molecule promoted the development of immune system cells called T regulatory cells (Tregs) that suppressed the lymphocytes that are responsible for attacking organ transplants.
Author Interviews, Blood Pressure - Hypertension, Compliance, JACC, Outcomes & Safety, UT Southwestern / 10.12.2013

Dr. Wanpen Vongpatanasin, MD Professor of Medicine Director, Hypertension Section Cardiology Division UT Southwestern Medical CenteMedicalResearch.com Interview with; Dr. Wanpen Vongpatanasin, MD Professor of Medicine Director, Hypertension Section, Cardiology Division UT Southwestern Medical Center MedicalResearch.com: What are the main findings of the study? Dr. Vongpatanasin: We found that more than 50% of patients with resistant hypertension were non-adherent to at least one drug prescribed by their primary care physicians for blood pressure control. When we provided this information back to the patients, as part of care in our hypertension specialty clinic, we found that many patients report difficulty taking prescribed medications due to either associated side effects or cost of the medication. When we adjusted patient's medications to fit their needs, BP levels were substantially improved during subsequent visits without increasing the number of medications.
Author Interviews, JAMA, UT Southwestern / 08.10.2013

Roshni Rao, MD Division of Surgical Oncology, Department of Surgery University of Texas Southwestern Medical Center, DallasMedicalResearch.com Interview with: Roshni Rao, MD Division of Surgical Oncology, Department of Surgery University of Texas Southwestern Medical Center, Dallas MedicalResearch.com: What are the main findings of the study?  Dr. Rao: That in most women with small breast cancer (<3.0cm in size), it is not necessary to removal all the lymph nodes underneath the arm, even if those nodes do have cancer. Radiation therapy, which is required after a partial mastectomy for breast cancer, can prevent these nodes from growing or becoming clinically significant.
Author Interviews, Nature, UT Southwestern, Weight Research / 01.10.2013

Philipp E. Scherer, PhD Professor, Department of Internal Medicine Gifford O. Touchstone Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research Director, Touchstone Diabetes Center The University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas, TX 75390-8549MedicalResearch.com Interview with: Philipp E. Scherer, PhD Professor, Department of Internal Medicine Director, Touchstone Diabetes Center The University of Texas Southwestern Medical Center Dallas, TX 75390-8549 MedicalResearch.com: What are the main findings of the study? Dr. Scherer: This is the first study that tracks the emergence of new fat cells in response to various physiological stimuli, such as high fat diet and cold exposure.