Author Interviews, Pediatrics, PNAS, Weight Research, Wistar / 15.10.2020

MedicalResearch.com Interview with: Kristina M. Rapuano PhD, Postdoctoral Research Fellow BJ Casey, PhD, Professor of Psychology at Yale University Richard Watts PhD Technical Consultant Department of Psychology Yale University, New Haven, CT MedicalResearch.com: What is the background for this study? Response: Around 35% of children and adolescents in the US are overweight or obese, dramatically increasing their likelihood of obesity as adults and the associated health risks. In our paper we use a novel MRI technique to investigate links between obesity and neurobiology in a large group of typically developing 9-10 year-olds. The data were acquired as part of the NIH-funded Adolescent Brain Cognitive DevelopmentSM (ABCD) study, which enrolled more than 11,000 children from across the US. We looked specifically at a reward-related region of the brain called the nucleus accumbens. Previous human studies have shown that healthy weight and obese children display different responses to food cues, for example adverts for unhealthy foods, in this region. Animal studies have also found that a high saturated fat (unhealthy) diet induces inflammation in the nucleus accumbens, and changes in behavior including sucrose-seeking. We wanted to investigate if we could use advanced MRI techniques to provide evidence of a similar effect in humans. (more…)
Author Interviews, Biomarkers, Breast Cancer, Genetic Research, Race/Ethnic Diversity, Wistar / 28.02.2017

MedicalResearch.com Interview with: Maureen E. Murphy, Ph.D. Professor and Program Leader, Molecular and Cellular Oncogenesis Program Associate Vice President for Faculty Affairs Associate Director for Education and Career Development The Wistar Institute Philadelphia, PA 19104 MedicalResearch.com: What is the background for this study? What are the main findings? Response: The Murphy group discovered a coding-region variant of the p53 tumor suppressor gene, called Pro47Ser, that exists in individuals of African descent. In previous studies this group reported that this amino acid change reduces the ability of p53 to function as a tumor suppressor. In this study, African American women from two different large cohorts were assessed for the incidence of the Pro47Ser variant in pre-menopausal breast cancer. A modest but statistically significant association was found between Pro47Ser and pre-menopausal breast cancer. (more…)
Author Interviews, Cancer Research, Nature, Wistar / 20.12.2016

MedicalResearch.com Interview with: Cecilia Caino, Ph.D. The Wistar Institute 3601 Spruce Street Philadelphia, PA 19104 MedicalResearch.com: What is the background for this study? What are the main findings? Response: Mitochondria have recently experienced a resurgence of interest in the field of cellular biology. Traditionally known for their role in energy production and in programmed cell death, mitochondria are more broadly recognized as signaling hubs and biosynthetic factories. Not surprisingly, mitochondria have been linked to several hallmarks of cancer, including evasion of apoptosis, tissue invasion and metastasis and abnormal metabolic pathways. It has become clear that mitochondria quality control and metabolism-regulated shape changes are dysregulated in cancer. Recent studies identified a novel therapy-resistance mechanism that involves mitochondrial subcellular re-localization and is responsible for enhanced metastatic potential of cancer cells. In this context, the molecular regulators of mitochondrial trafficking in cancer are largely unknown. Through analysis of shRNA screening results, we identified Syntaphilin (SNPH), which is considered to moderate mitochondrial trafficking in neurons, as a non-neuronal tissue specific factor to suppress cancer cell invasion. Using multi-disciplinary cell biological, real time imaging, in vivo studies and human clinical studies, SNPH was revealed to block cell motility and tumor metastasis by regulation of reprogramming of mitochondrial dynamics. We provided evidence from public databases and clinical samples that SNPH levels are decreased in different types of human tumors and low SNPH levels correlate with worse patient prognosis. Overall this study demonstrated a new mechanism by which tumor cell invasion is regulated by a SNPH-mediated pathway. (more…)
Aging, Author Interviews, Melanoma, Nature, Wistar / 08.04.2016

MedicalResearch.com Interview with: Ashani T. Weeraratna, Ph.D. Associate Professor Melanoma Research Center The Wistar Institute Philadelphia, PA 19104 MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Weeraratna: The background for this study is the fact that advancing age remains the greatest risk factor for the development of many cancers, and melanoma is no exception. We found that age-related changes in normal skin, specifically dermal fibroblasts, increase both the metastatic potential and therapeutic resistance of melanoma cells. The most fascinating thing is that even targeted therapy, which should depend solely on the interaction between the drug and the target within the tumor cell is affected by the age of the microenvironment. (more…)
Author Interviews, Flu - Influenza, Vaccine Studies, Wistar / 29.06.2015

Scott E. Hensley, Ph.D. Assistant Professor Wistar Institute Philadelphia, PA 1910MedicalResearch.com Interview with: Scott E. Hensley, Ph.D. Assistant Professor Wistar Institute Philadelphia, PA 1910   Medical Research: What is the background for this study? What are the main findings? Response: Previous studies documented that the the 2014-2015 H3N2 flu vaccine strain was antigenically distinct compared to most recent H3N2 flu strains.  Recent H3N2 strains possess several mutation and it was previously unknown which of these mutations contributed to the 2014-2015 vaccine mismatch.  We used a reverse-genetic engineering approach to identify specific viral mutations that contributed to the 2014-2015 vaccine mismatch. (more…)
Author Interviews, Biomarkers, Lung Cancer, Wistar / 11.06.2015

MedicalResearch.com Interview with: Qihong Huang, M.D., Ph.D. Associate professor in the Tumor Microenvironment and Metastasis Program The Wistar InstituteQihong Huang, M.D., Ph.D. Associate professor in the Tumor Microenvironment and Metastasis Program The Wistar Institute Medical Research: What is the background for this study? What are the main findings? Dr. Huang: Lung cancer is the leading cause of cancer deaths in both men and women in the United States and results in more deaths globally than breast, prostate and colon cancers combined. While the five year survival rate for early stage non-small cell lung cancer (NSCLC) is above 50%, it is less than 5% in patients with metastatic disease.  Clearly, early detection can save lives, but accurate screening tests for high-risk individuals are still lacking. Although low dose computed tomography (LDCT) has been successfully used for screening in high-risk populations, multiple negative factors are associated with recurrent LDCT screening, including false-positives and false-negatives, unnecessary invasive procedures, radiation exposure, global availability of the technology and cost. Although several non-invasive tests for lung cancer using body fluids such as blood, urine or sputum are under investigation, none are currently available. When low dose computed tomography is used for screening, patients who are 50 years old or older are frequently diagnosed with pulmonary nodules.  However, only a small fraction of the nodules detected are subsequently diagnosed as lung cancer.  In cases where it is difficult to differentiate malignant from benign nodules, it is recommended that patients with these indeterminate nodules be followed with serial LDCT, which increases radiation exposure and financial cost. A simple, inexpensive blood test that differentiates malignant from benign nodules would fill an important clinical need. In this study, we validated AKAP4 as a highly accurate biomarker in a cohort of 264 blood samples from patients with known non-small cell lung cance and 135 controls samples from two different sites including a subset of controls with high risk lung nodules.   When all 264 lung cancers were compared with all 135 controls, the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers were compared with all controls, the AUC is 0.9795, and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules – a comparison of significant clinical importance – the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage but independently of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer, lung cancer recurrence, and distinguishing malignant from benign lung nodules. (more…)
Author Interviews, Cancer Research, Wistar / 14.05.2015

Katherine Aird, Ph.D. Gene Expression and Regulation Program The Wistar Institute, Philadelphia, PAMedicalResearch.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. (more…)
AACR, Author Interviews, Genetic Research, Melanoma, NYU, Personalized Medicine, Wistar / 21.04.2015

Melissa Wilson, MD, PhD Assisstant Professor Perlmutter Cancer Center NYU Langone Medical Center New York, NYMedicalResearch.com Interview with: Melissa Wilson, MD, PhD Assisstant Professor Perlmutter Cancer Center NYU Langone Medical Center New York, NY Medical Research: What is the background for this study? What are the main findings? Dr. Wilson: Metastatic cutaneous melanoma is an extremely aggressive form of skin cancer.  Traditionally, it has been characterized by clinicopathologic characteristics.  More recently, melanoma tumors have also been stratified by common somatic mutations for which targeted therapies have been developed or are under investigation, including BRAF, NRAS and KIT.  In addition to somatic mutations, aberrant intracellular signaling pathways and cell cycle disruption contribute to melanoma pathogenesis.  Indeed, recent next generation sequencing studies have identified a number of new genes involved in melanomagenesis.  A comprehensive evaluation and understanding of concurrent and mutually exclusive mutations in tumors has been lacking.  Therefore, we developed a comprehensive custom targeted capture of 108 genes previously implicated in melanoma pathogenesis.  We used the targeted panel to perform massively parallel sequencing on 94 well-established human melanoma cell lines, 67 patient-derived xenografts (PDX), and 5 cell lines made from PDX, all untreated. Samples were clustered based on deleterious mutations.  Eighty-three percent of samples had deleterious mutations in the MAPK signaling pathway (including BRAF, RAS) and NF1.  Ten percent of samples had PI3K pathway mutations which were predominantly associated with BRAF mutations.  TP53 was found to be mutated in 24% of the samples and were also associated with mutations in the MAPK pathway.  Mutations in chromatin remodeling genes were mutually exclusive with each other, but were associated with BRAF and NRAS mutations.  Of particular interest, five of the 10 NF1mutated samples harbored likely deleterious mutations in MAP3K5 or MAP3K9, suggesting the potential involvement of JNK signal transduction pathway in a cohort of samples. (more…)
AACR, Author Interviews, Melanoma, Wistar / 20.04.2015

Adina Vultur, Ph.D. Staff Scientist Meenhard Herlyn Laboratory Melanoma Research Center The Wistar Institute, PhiladelphiaMedicalResearch.com Interview with: Adina Vultur, Ph.D. Staff Scientist Meenhard Herlyn Laboratory Melanoma Research Center The Wistar Institute, Philadelphia Medical Research: What is the background for this study? What are the main findings? Dr. Vulture: Our goal was to identify new drugs with anti-melanoma activity but with minor effects on normal cells. We screened structurally distinct kinase inhibitors first, against multiple cell lines and normal cells, and identified the organometallic compound SM200 as being the most effective and selective molecule, capable of halting melanoma cell growth and invasion. Further characterization of SM200 indicated that PIM kinases are highly inhibited by this compound compared to other targets. We then confirmed the contribution of PIM kinases to melanoma pathobiology by knockdown studies and by using a clinically available PIM-inhibitor. Encouraging results with PIM kinase inhibition in multiple melanoma models including xenografts suggests that this could be a useful strategy against melanoma. (more…)
Author Interviews, Melanoma, Wistar / 19.03.2015

Russel E. Kaufman, MD President Emeritus Professor, Molecular and Cellular Oncogenesis Program Molecular and Cellular Oncogenesis Program The Wistar InstituteMedicalResearch.com Interview with: Russel E. Kaufman, MD President Emeritus Professor, Molecular and Cellular Oncogenesis Program Molecular and Cellular Oncogenesis Program The Wistar Institute Medical Research: What is the background for this study? What are the main findings? Response: Targeted therapies in cancer were hailed as a “magic bullet” because of their ability to act upon the mutations responsible for cancer while leaving nearby healthy cells alone. Using an approach like this, it would make sense that therapies designed to target mutations of BRAFV600E/K could be effective for melanoma, since that gene is mutated in about half of all cases of the disease. However, we’ve learned over time that these targeted therapies simply aren’t as effective as we had hoped they would be. In the case of these BRAF inhibitors, while patients do live slightly longer, they eventually relapse within months of treatment. We wanted to know why this was happening. We decided to look at macrophages, which are the most abundant inflammatory cells in melanoma. The more macrophages present in a patient with melanoma, the worse his or her outcome will be. They’ve been linked to cancer progression, but before this study, no one had really looked at the role they may play in the resistance to treatment with BRAF inhibitors. We found that BRAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway in macrophages. When this pathway is activated, it leads to the production of vascular endothelial growth factor (VEGF), a signaling protein closely associated with angiogenesis. The VEGF produced in the macrophages is able to activate the MAPK pathway in melanoma cells, thereby stimulating the growth of cancer cells. Taking these findings one step further, we discovered that when we blocked the MAPK pathway or VEGF signaling, we appeared to reverse macrophage-mediated resistance. When we targeted macrophages, we were able to increase the antitumor activity of BRAF inhibitors in mouse and human models. (more…)
Author Interviews, Flu - Influenza, Vaccine Studies, Wistar / 22.10.2014

Scott E. Hensley, Ph.D. Assistant Professor, The Wistar Institute Philadelphia, PA 19104MedicalResearch.com Interview with Scott E. Hensley, Ph.D. Assistant Professor, The Wistar Institute Philadelphia, PA 19104   Medical Research: What are the main findings of the study? Dr. Hensley: We found that H1N1 viruses recently acquired a mutation that abrogates binding of influenza antibodies that are present in a large number of middle-aged adults.  We propose that this mutation lead to increased disease among middle-aged adults during the 2013-2014 influenza season. (more…)