Author Interviews, Breast Cancer, Genetic Research, NYU/NYMC / 16.01.2016
Functional Genomics Identifies Genes Essential To Breast Cancer Cell Survival
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Dr. Benjamin Neel[/caption]
More on Breast Cancer Research on MedicalResearch.com
MedicalResearch.com Interview with:
Dr. Benjamin Neel MD PhD
Professor, Department of Medicine
Director Perlmutter Cancer Center
NYU Langone Medical Center
Medical Research: What is the background for this study? What are the main findings?
Dr. Neel: Over the past 10 years, there have been major advances in cancer genomics--i.e., defining what changes in genes are found in different types of cancer cells. Sometimes, such studies have resulted in the identification of new drug targets, such as EGF receptor mutations or EML-ALK translocations in lung cancer, RAF mutations in melanoma and hairy cell leukemia, and KIT or PDGFR mutations in GIST. More often, though, either the genetic changes that genomic studies reveal are difficult to target by conventional small molecule drugs or we dont know which of the many mutations found in a given tumor are critical to its proliferation/survival.
"Functional genomics" is a parallel approach to tumor genomics, that aims to use large scale screening technology to identify which genes are essential to cancer cell survival/proliferation. This approach can reveal which genetic changes in cancer cells "drive" the cancer--but it also can find genes on which the cancer becomes dependent because of the other "driver" genes. One major approach to functional genomics uses short hairpin RNAs (a type of RNAinterference/RNAi) to "knock down" the expression of each gene in a cell. Scientists can generate a "library" of designer virus particles, each of which expresses a different hairpin that can "knockdown" a different gene. A large population of tumor cells is then infected with the virus, and scientists use gene sequencing or array based approaches to see which shRNAs become depleted from the starting population of shRNAs; this type of screen is called a "dropout screen".
Earlier studies, including by our group, performed dropout screens on smaller numbers of cancer cell lines. Yet because these screens involved only a few cell lines, they could not represent the large number of sub-types knownt to occur in, for example, breast cancer. Our study, by using 77 breast cancer lines, has adequate power to survey the landscape of breast cancer. Furthermore, by obtaining parallel genomic information, as well as some information on the breast cancer cell "proteome" (the proteins in these cells), we can couple genomic analysis with functional genomics. In addition, we had drug response information for a large number of these lines, and so were able to make some predictions for drugs that might prove additive for breast cancer therapy.
The result is a large number of potential new targets linked to genetic information, as well as new insights into how the different sub-types of breast cancer "rewire" their respective signaling diagrams compared with normal cells.
Dr. Benjamin Neel[/caption]
More on Breast Cancer Research on MedicalResearch.com
MedicalResearch.com Interview with:
Dr. Benjamin Neel MD PhD
Professor, Department of Medicine
Director Perlmutter Cancer Center
NYU Langone Medical Center
Medical Research: What is the background for this study? What are the main findings?
Dr. Neel: Over the past 10 years, there have been major advances in cancer genomics--i.e., defining what changes in genes are found in different types of cancer cells. Sometimes, such studies have resulted in the identification of new drug targets, such as EGF receptor mutations or EML-ALK translocations in lung cancer, RAF mutations in melanoma and hairy cell leukemia, and KIT or PDGFR mutations in GIST. More often, though, either the genetic changes that genomic studies reveal are difficult to target by conventional small molecule drugs or we dont know which of the many mutations found in a given tumor are critical to its proliferation/survival.
"Functional genomics" is a parallel approach to tumor genomics, that aims to use large scale screening technology to identify which genes are essential to cancer cell survival/proliferation. This approach can reveal which genetic changes in cancer cells "drive" the cancer--but it also can find genes on which the cancer becomes dependent because of the other "driver" genes. One major approach to functional genomics uses short hairpin RNAs (a type of RNAinterference/RNAi) to "knock down" the expression of each gene in a cell. Scientists can generate a "library" of designer virus particles, each of which expresses a different hairpin that can "knockdown" a different gene. A large population of tumor cells is then infected with the virus, and scientists use gene sequencing or array based approaches to see which shRNAs become depleted from the starting population of shRNAs; this type of screen is called a "dropout screen".
Earlier studies, including by our group, performed dropout screens on smaller numbers of cancer cell lines. Yet because these screens involved only a few cell lines, they could not represent the large number of sub-types knownt to occur in, for example, breast cancer. Our study, by using 77 breast cancer lines, has adequate power to survey the landscape of breast cancer. Furthermore, by obtaining parallel genomic information, as well as some information on the breast cancer cell "proteome" (the proteins in these cells), we can couple genomic analysis with functional genomics. In addition, we had drug response information for a large number of these lines, and so were able to make some predictions for drugs that might prove additive for breast cancer therapy.
The result is a large number of potential new targets linked to genetic information, as well as new insights into how the different sub-types of breast cancer "rewire" their respective signaling diagrams compared with normal cells.
Dr. Elena Batrakova[/caption]
Dr. Mia T. Minen[/caption]
Dr. Dai Fukumura[/caption]
MedicalResearch.com Interview with:
Dai Fukumura, M.D., Ph.D.
Joao Incio, M.D.
and Rakesh K. Jain, Ph.D
Edwin L. Steele Laboratory
Department of Radiation Oncology
Massachusetts General Hospital
Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Dr. Fukumura: This study focused on pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, which accounts for almost 40,000 cancer death in the U.S. ever year. Half of those diagnosed with this form of pancreatic cancer are overweight or obese, and up to 80 percent have type 2 diabetes or are insulin resistant. Diabetic patients taking metformin – a commonly used generic medication for type 2 diabetes – are known to have a reduced risk of developing pancreatic cancer; and among patients who develop the tumor, those taking the drug may have a reduced risk of death. But prior to the current study the mechanism of metformin’s action against pancreatic cancer was unclear, and no potential biomarkers of response to metformin had been reported.
We have uncovered a novel mechanism behind the ability of the diabetes drug metformin to inhibit the progression of pancreatic cancer. Metformin decreases the inflammation and fibrosis characteristic of the most common form of pancreatic cancer. We found that metformin alleviates desmoplasia – an accumulation of dense connective tissue and tumor-associated immune cells that is a hallmark of pancreatic cancer – by inhibiting the activation of the pancreatic stellate cells that produce the extracellular matrix and by reprogramming immune cells to reduce inflammation. Our findings in cellular and animal models and in patient tumor samples also indicate that this beneficial effect may be most prevalent in overweight and obese patients, who appear to have tumors with increased fibrosis.
Dr. Emily DeFranco[/caption]
MedicalResearch.com Interview with:
Emily A. DeFranco, D.O., M.S.
Associate Professor Maternal-Fetal Medicine
Center for Prevention of Preterm Birth, Perinatal Institute
Cincinnati Children's Hospital Medical Center
University of Cincinnati College of Medicine
Department of Obstetrics and Gynecology
Medical Sciences Building, Room 4553B
Cincinnati, OH
Medical Research: What is the background for this study?
Dr. DeFranco: The Infant Mortality Rate in the state of Ohio is higher than many other states. Additionally, there is a large disparity in the IMR with black infants impacted to a higher degree compared to white infants. For this reason, we are particularly interested in identifying factors that contribute to this disparity in order to identify potential areas where public health efforts can be focused.
We know that preterm birth is a major contributor to infant mortality, and that all babies born alive prior to 23 weeks of gestational age, i.e. "previable", die after birth and contribute to the infant mortality rate. In this study, we wanted to assess whether black women are more likely to have early preterm births at less than 23 weeks, and if so whether that may be part of the explanation of why black mothers are at higher risk of experiencing an infant mortality.
Medical Research: What are the main findings?
Dr. DeFranco: In this study, we found that black mothers were more likely to deliver than white mothers at very early preterm gestational ages, less than 23 weeks. We also found that the earlier the delivery, the larger the disparity with black mothers being at higher risk for the earliest deliveries compared to white mothers. From this data, we estimated that in Ohio, 44% of all infant mortality in black mothers is caused by previable preterm birth, whereas only 28% of infant mortality in white mothers is attributed to the same cause. We concluded that very early
Prof. Guy Boeckxstaens[/caption]
Dr. Yuxia Zhang[/caption]
MedicalResearch.com Interview with:
Yuxia Zhang PhD
Population Healthy and Immunity Division
Walter + Eliza Hall Institute
Parkville VIC 3052 Australia
Medical Research: What is the background for this study?
Dr. Zhang: There has been a dramatic increase in hospital presentations due to food allergy over recent decades, most among children under five years of age. In Melbourne Australia, up to one in every 10 babies develop food allergy during the first year of life. To understand the mechanisms underlying the increased incidences of allergy and other diseases in children, Associate Professor Peter Vuillermin and colleagues established the Barwon Infant Studies (BIS), following and collecting bio-speciments from pregnant mothers and their babies. Together with my colleagues Prof. Leonard Harrison and Mr. Gaetano Naselli from the Walter and Eliza Hall Institute of Medical Research, we examined the immune cell composition and function in cord blood in babies who developed food allergy compared to allergy-free babies at one year of age.
Medical Research: What are the main findings?
Dr. Zhang: Our initial observation was that in cord blood the proportions of CD14+ monocytes and CD4+T cells were inversely associated. In infants who developed food allergy, there was a higher ratio of CD14+monoctypes/CD4+T cells and a lower ratio of naive natural regulatory T cells (nTreg). The reduced nTreg frequency was also independently discovered by Dr. Fiona Collier in the BIS fresh blood cohort. CD14+ monocytes are the foot-solders of the immune system, which immediately release inflammatory cytokines upon infection. These inflammatory cytokines then guide the unexperienced CD4+T cells down to different paths to control infection. nTreg cells police the immune system to prevent unwanted damages during the elimination of the infections. Despite this widely accepted view of how our immune system are activated, we do not know if and how these interactions may cause an allergic reaction in babies. Through a series of in vitro experiments, we found that the inflammatory cytokines- most likely in the mucosal sites where food allergy was initiated-could lead the development of both CD4+T cells and nTregs towards a Th2-type immune phenotype. These Th2-type immune cells secrete large amount of IL-4, a cytokine through which may cause allergic reactions to some foods.
Dr. Sandra Jackson[/caption]
MedicalResearch.com Interview with:
Sandra L Jackson PhD
Epidemic Intelligence Service, CDC
Division for Heart Disease and Stroke Prevention
National Center for Chronic Disease Prevention and Health Promotion
Atlanta, Georgia
Medical Research: What is the background for this study? What are the main findings?
Dr. Jackson: Sodium reduction is an important public health strategy to reduce cardiovascular disease, and this study was the latest in CDC’s ongoing effort to monitor U.S. sodium intake. These findings reveal that nearly all Americans – regardless of age, race and gender – consume more sodium than is recommended for a healthy diet.
Specifically, over 90 percent of children (2 to 18) and 89 percent of adults (19 and up) eat more than the recommended limits in the 2015-2020 Dietary Guidelines for Americans, and that doesn’t even include salt added at the table. The newly released guidelines recommend limiting sodium to less than 2,300 mg per day for people over the age of 14, and less for those younger.
The analysis also examined specific populations. Among adults, a larger proportion of men (98 percent) than women (80 percent) consume too much
Dr. NaNa Keum[/caption]
Dr. Wilson Compton[/caption]
Dr. Jenny Löfgren[/caption]
MedicalResearch.com Interview with:
Dr. Jenny Löfgren
Surgery and Perioperative Sciences
Faculty of Medicine,
University Hospital of Umeå
Umeå Sweden
Medical Research: What is the background for this study? What are the main findings?
Response: There are an estimated 220 million groin hernia patients in the World. 20 million are operated on annually making it one of the worlds most commonly performed surgeries. The surgical repair rate in low income settings is very low. Also, the quality of the surgery is lower than in high income settings. The superior technique that uses a synthetic mesh to reinforce the abdominal wall at the site of the hernia is not affordable due to the high cost of that mesh. Mosquito mesh, which is very similar to the expensive mesh, is already used in several settings but its safety and effectiveness had not previously been investigated in a randomized trial of sufficient size with follow up for as long as one year.
Medical Research: What are the main findings?
Response: The most important finding of the study is that it was not able to detect any differences in terms of safety, effectiveness and patient satisfaction when outcomes in the group receiving the low-cost (mosquito) mesh with the group receiving a commonly used commercial mesh. The study also shows that high quality surgery, on par with standards in high income settings, can be provided for an underserved population in rural Uganda, at an affordable cost. Finally, the study shows that it is possible to conduct high quality surgical (clinical) research with high follow up rates also in settings such as rural Uganda. This should encourage us and others to conduct other trials in the future.
Dr. Islam Elgendy[/caption]
MedicalResearch.com Interview with:
Dr. Woodward[/caption]
MedicalResearch.com Interview with:
Maria A. Woodward, MD
Department of Ophthalmology and Visual Sciences
University of Michigan
Ann Arbor, MI 48105
Medical Research: What is the background for this study? What are the main findings?
Dr. Woodward: The research was sparked by questions whether changes to the eye with keratoconus affect other parts of the body. There is conflicting information from past research about connections between systemic diseases and keratoconus. This creates confusion for patients and for doctors treating these patients.
Dr.James DiNicolantonio[/caption]
MedicalResearch.com Interview with:
James J. DiNicolantonio, PharmD
Associate Editor BMJ Open Heart
Cardiovascular Research Scientist
Saint Luke's Mid America Heart Institute
Medical Research: What is the background for this study? What are the main findings?
Dr. DiNicolantonio: We comprehensively reviewed the literature looking at the cardiovascular effects of saturated fat and compared them with refined sugars (sucrose and high-fructose corn syrup). Our main finding is that saturated fat per se is not necessarily unhealthy. Importantly, people eat foods, not saturated fat, and depending on what foods are consumed determines if saturated fat associates with health risk. For example, the consumption of processed meat is associated with an increased risk of cardiovascular disease, whereas dairy is not. Importantly, the replacement of saturated fat with refined sugars seems to increase the risk of myocardial infarction. Hence, reducing added sugars should be the main focus rather than reducing saturated fat, as the latter could translate to reductions in healthy whole foods that just so happen to also be high in saturated fat (but also provide other healthy fats).
MedicalResearch.com Interview with:
Tanush Gupta, MD
Chief Resident & Instructor of Medicine and
Prakash Harikrishnan, MD
Fellow in Cardiology
New York Medical College at
Westchester Medical Center
Valhalla, NY
Medical Research: What is the background for this study?
Response: Complete heart block (CHB) is a relatively frequent complication in patients hospitalized with ST-elevation myocardial infarction (STEMI). Patients who develop complete heart block in the setting of STEMI have a 3- to 5-fold increase in in-hospital mortality compared to those without CHB. However, most of the existing reports on CHB complicating STEMI are from the pre-thrombolytic and thrombolytic era in the 1980s and 1990s, before the widespread use of percutaneous coronary intervention (PCI) and advent of modern adjunctive medical therapies.
Hence, the purpose of this investigation was to examine the association of complete heart block with in-hospital outcomes in patients hospitalized with STEMI and to examine the temporal trends in the incidence and outcomes of CHB complicating STEMI using the National Inpatient Sample (NIS) databases from 2003 to 2012.
Dr. Cuilin Zhang[/caption]
MedicalResearch.com Interview with:
Cuilin Zhang MD, PhD
Senior Investigator, Epidemiology Branch
Division of Intramural Population Health Research
NICHD/National Institutes of Health
Rockville, MD 20852
Medical Research: What is the background for this study? What are the main findings?
Dr. Zhang: Potatoes are the third most commonly consumed food crop in the world. In the United States, about 35% of women of reproductive age consume potatoes daily, accounting for 8% of daily total energy intake. Gestational diabetes mellitus (GDM) is a common complication of pregnancy characterized by glucose intolerance with onset or first recognition during pregnancy.
Prof. Dimitrios Karussis[/caption]
MedicalResearch.com Interview with:
Prof. Dimitrios Karussis M.D., Ph.D.
Professor of Neurology
Head, Multiple Sclerosis Center
Hadassah BrainLabs
Medical Research: What is the background for this study? What are the main findings?
Prof. Karussis: BrainStorm Cell Therapeutics is developing innovative, autologous stem cell therapies for highly debilitating neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson’s Disease (PD). Our technology, NurOwn™ is a first-of-its-kind approach that induces autologous bone marrow-derived Mesenchymal Stem Cells (MSCs) to secrete Neurotrophic Growth Factors (NTFs). These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases.
Data from the clinical trials described in the recent issue of the Journal of American Medicine – Neurology (JAMA Neurology), suggest that NurOwn can help patients with
Dr. Fox[/caption]
MedicalResearch.com Interview with:
Dr. Caroline Fox, MD MPH
National Heart, Lung, and Blood Institute
Assistant Clinical Professor of Medicine
Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Dr. Fox: There is evidence linking sugar sweetened beverages with obesity and type 2 diabetes. There is also evidence suggesting that specific adipose tissue depots may play a role in the pathogenesis of these diseases. We found that higher levels of
Dr. Aaron Dawes[/caption]
MedicalResearch.com Interview with:
Aaron J. Dawes, MD
Fellow, VA/RWJF Clinical Scholars Program
Division of Health Services Research
University of California Los Angeles
Los Angeles, CA 90024
Medical Research: What is the background for this study? What are the main findings?
Dr. Dawes: We reviewed the published literature to answer three basic questions about bariatric surgery and mental health conditions.
First, how common are mental health conditions among patients being referred for or undergoing bariatric surgery?
Dr. Diana Schendel[/caption]
MedicalResearch.com Interview with:
Diana Schendel, Professor MSO
Department of Public Health
Institute of Epidemiology and Social Medicine and
Department of Economics and Business National Centre for Register-based Research
Aarhus University
Denmark
Medical Research: What is the background for this study? What are the main findings?
Dr. Schende: Elevated mortality has been reported in persons with autism spectrum disorder (ASD), especially with comorbid epilepsy and intellectual disability. The effect of comorbidity on the risk for mortality in ASD, however, has not been rigorously examined in large, population-based studies. Our study aim was to investigate ASD mortality patterns overall and to assess the specific effects of comorbid mental, behavioral, and neurologic disorders on ASD mortality into young adulthood. Our study comprised a nation-wide Danish cohort of 1.9 million children of whom 20,492 were diagnosed with ASD. We observed 68 deaths in persons with ASD; 83% of the persons with ASD who died had comorbid mental/behavioral or neurologic disorders. The risk for mortality was two-fold higher in persons with
Dr. R. Jeffrey Karnes[/caption]
MedicalResearch.com Interview with:
R. Jeffrey Karnes MD
Department of Urology, Mayo Clinic,
Rochester, MN 55905
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Karnes: Cancer recurrence following radical prostatectomy is a concern for men undergoing definitive surgical treatment for prostate cancer. Approximately 20-35% of patients develop a rising prostate specific antigen following radical prostatectomy for clinically localized prostate cancer. PSA monitoring is an important tool for cancer surveillance; however, a standard PSA cutpoint to indicate biochemical recurrence has yet to be established. Over 60 different definitions have been described in literature. This variation creates confusion for the patients and clinicians. By studying a large group of patients who underwent radical prostatectomy at Mayo Clinic, we found that a PSA cutpoint of 0.4 ng/mL is the optimal definition for biochemical recurrence.