National Disease Research Interchange Research Articles

Abstract 19018: Unraveling the Regulatory Landscape of NKX2-5 in Human Left Atrial Tissue: Implications for Atrial Fibrillation

Cardiac transcription factors are emerging as crucial modulators of atrial fibrillation (AF), with rare and common variation implicated in AF. Mutations in NKX2-5 and more recently, NFATC1 were reported in families with autosomal dominant young-onset AF. Here, we explore the landscape of NKX2-5 and NFATC1 in human left atrium, using Chromatin Immunoprecipitation Sequencing (ChIP-seq), DAVID functional annotation and HOMER motif analyses. Post-mortem human left atrial tissue samples (n=5) were obtained from the National Disease Research Interchange (NDRI) within a recovery interval of < 4 hours. Preserved microstructural integrity and normal staining patters for TNNT2 and vimentin were verified using confocal microscopy. ChIP-seq analysis revealed an average of 2.62k NKX2-5 binding peaks, with 118 genes bound in all samples. Functional analysis identified significant enrichment in gene ontology categories and pathways (Table 1), including adrenergic and PPAR signaling pathways known to participate in AF susceptibility. Using HOMER, we mapped 55 NFATC1 consensus binding sites to the NKX2-5 ChIP peaks. Two NFATC1 consensus sites localized to an NKX2-5 binding peak located upstream from MEF2A (Figure 1). Published HI-C data from human right atrium indicates the NFATC1 binding sites are adjacent to the promoter of MEF2A in 3D space, suggesting that NKX2-5 and NFATC1 co-regulate MEF2A. In murine atria, mef2A regulates genes involved in fibrosis and adhesion, processes that are crucial in the pathogenesis of atrial fibrillation. Our data, together with published literature, provide a framework for understanding transcriptional networks that may predispose to human AF.

Morphometric and immunohistochemical analysis as a method to identify undifferentiated spermatogonial cells in adult subjects with Klinefelter syndrome: a cohort study

To study the prevalence of spermatogonia in adult subjects with Klinefelter syndrome (KS) using MAGE-A4 and UCHL1 (PGP9.5) immunohistochemistry as markers for undifferentiated spermatogonial cells. We aimed to compare this method to the gold standard of hematoxylin and eosin (H & E) staining with histologic analysis in the largest reported cohort of adult subjects with KS. A retrospective cohort study. Infertility Clinic and Institute for Regenerative Medicine. This study consisted of 79 adult subjects with KS and 12 adult control subjects. The subjects with KS (n = 79) underwent bilateral testicular biopsy in an initial effort to recover spermatozoa for invitro fertilization and intracytoplasmic sperm injection. The institutional review board approved the use of a portion of the archived diagnostic pathology paraffin blocks for the study. The samples were superimposed onto microscopic slides and labeled with the PGP9.5 and MAGE-A4 antibodies. Subjects (n = 12) who had previously consented to be organ donors via the National Disease Research Interchange were selected as controls. Dedicated genitourinary pathologists examined the H & E-, PGP9.5-, and MAGE-A4-stained tissue for presence of undifferentiated spermatogonia and spermatozoa with the use of a virtual microscopy software. The primary outcome was the presence of MAGE-A4-positive or UCHL1-positive tubules that indicate undifferentiated spermatogonia. Supportive outcomes include assessing the biopsy specimen for the following: total surface area; total seminiferous tubule surface area; total interstitium surface area; the total number of seminiferous tubules; and MAGE-A4- negative or UCHL1-negative tubules. Additionally, clinical information, such as age, karyotype, height, weight, mean testicle size, and hormonal panel (luteinizing hormone, follicle-stimulating hormone, and testosterone), was obtained and used in a single and multivariable analysis with linear regression to determine predictive factors for the number of UCHL1-positive tubules. The mean age of the subjects in the KS group was 32.9 ± 0.7 years (range, 16-48). UCHL1 (PGP9.5) and MAGE-A4 staining showed that 74.7% (n = 59) and 40.5% (n = 32) of the subjects with KS, respectively, were positive for undifferentiated spermatogonia compared with 100% (n = 12) of the control subjects who were positive for both the markers. Hematoxylin and eosin with microscopic analysis showed that only 10.1% (n = 8) of the subjects were positive for spermatogonia. The mean number of positive tubules per subject with KS was 11.8 ± 1.8 for UCHL1 and 3.7 ± 1.0 for MAGE-A4. Secondary analysis showed 7 (8.9%) adult subjects with KS as positive for spermatozoa on biopsy. The population having negative testicular sperm extraction results (n = 72) showed a spermatogonia-positive rate of 1.4%, (n = 1), 72.2% (n = 52), and 34.7% (n = 25) using H & E, UCHL1, and MAGE-A4, respectively. Further analysis showed that 54 (75.0%) subjects were either positive for UCHL1 or MAGE-A4. Twenty (27.8%) subjects were positive for both UCHL1 and MAGE-A4. Multivariate analysis with linear regression showed no significant correlation between clinical variables and the number of UCHL1-positive tubules found on biopsy specimens. We report a cohort of adult subjects with KS undergoing analysis for the presence of undifferentiated spermatogonia. UCHL1 and MAGE-A4 immunostaining appear to be an effective way of identifying undifferentiated spermatogonia in testicular biopsy specimens of subjects with KS. Despite observing deterioration in the testicular architecture, many patients remain positive for undifferentiated spermatogonia, which could be harvested and potentially used for infertility therapy in a patient with KS who is azoospermic and has negative testicular sperm extraction results.

Diagnostic and predictive values of circulating tetrahydrobiopterin levels as a novel biomarker in patients with thoracic and abdominal aortic aneurysms

We have previously shown that circulating levels of tetrahydrobiopterin (H4B) function as a robust biomarker for aortic aneurysms in several independent animal models. In the present study, we examined diagnostic and predictive values of circulating H4B levels in human patients of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) for the first time, while clinically applicable biomarkers for aortic aneurysms have never been previously available. Ninety-five patients scheduled for TAA repair surgeries and 53 control subjects were recruited at University of California Los Angeles (UCLA) Ronald Regan Medical Center, while 44 control subjects and 29 AAA patients were recruited through National Institute of Health (NIH) National Disease Research Interchange (NDRI) program. We had intriguing observations that circulating H4B levels were substantially lower in TAA and AAA patients, linearly correlated with aortic H4B levels (blood: R = 0.8071, p < 0.0001, n = 75; plasma: R = 0.7983, p < 0.0001, n = 75), and associated with incidence of TAA (blood: adjusted OR 0.495; 95% CI 0.379–0.647; p < 0.001; plasma: adjusted OR 0.501; 95% CI 0.385–0.652; p < 0.001) or AAA (blood: adjusted OR 0.329; 95% CI 0.125–0.868; p = 0.025) after adjustment for other factors. Blood or plasma H4B levels below 0.2 pmol/μg serve as an important threshold for prediction of aortic aneurysms independent of age and gender (for TAA risk - blood: adjusted OR 419.67; 95% CI 59.191–2975.540; p < 0.001; plasma: adjusted OR 206.11; 95% CI 40.956–1037.279; p < 0.001). This threshold was also significantly associated with incidence of AAA (p < 0.001 by Chi-square analysis). In addition, we observed previously unrecognized inverse association of Statin use with TAA, and an association of AAA with arrhythmia. Taken together, our data strongly demonstrate for the first time that circulating H4B levels can serve as a first-in-class, sensitive, robust and independent biomarker for clinical diagnosis and prediction of TAA and AAA in human patients, which can be rapidly translated to bedside to fundamentally improve clinical management of the devastating human disease of aortic aneurysms.

Editorial introductions.

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Hal E. BroxmeyerHal E. BroxmeyerDr Hal E. Broxmeyer is Distinguished Professor, Professor of Microbiology and Immunology (Full-Time), Mary Margaret Walther Professor Emeritus, and was Co-Leader (1993–2019) Program on Hematopoiesis and Hematological Malignancies, NCI-Designated Comprehensive Indiana University Simon Cancer Center (IUSCC), and is currently, Senior Advisor to IUSCC Director, and former Chairman of Microbiology and Immunology and Scientific Director, Walther Oncology Center, at the Indiana University School of Medicine, Indianapolis, IN. He received a BS degree, Brooklyn College, City University of New York in 1966, an MS degree from Long Island University, Brooklyn Center in 1969 and a PhD from New York University in 1973. He did post-doctoral training in 1973–1975 at Kingston General Hospital, Queens University Kingston, Ontario, Canada. From 1975–1983 he worked at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City rising from the rank of Associate Researcher to that of Associate Member. He was also Assistant Professor of Biology, Sloan Kettering Division of Cornell University Graduate School of Medical Sciences, New York, before being recruited to the Indiana University School of Medicine in 1983 as an Associate Professor of Medicine. To date, he has published 823 scientific papers (561 refereed papers and 262 Reviews/Book Chapters). Broxmeyer's laboratory studies mechanisms regulating hematopoietic stem and progenitor cells, embryonic stem cells and induced pluripotent stem cells: proliferation, self-renewal, survival, differentiation and migration (homing/mobilization). He was involved in establishing the field of cord blood transplantation. His publications have been cited >69,815 times (Google Scholar; GS); H-Factor for publications is 125 (GS) with i10 index = 603 (GS). Dr Broxmeyer's Awards include: New York University Founders Day Award (1973); Mellor Award (2nd prize 1976; 1st prize 1977) and Boyer Award (1983) from MSKCC; Special Fellow (1976–1978) and Scholar Award (1978–1983) from the Leukemia Lymphoma Society; Merit Award, National Cancer Institute (1987–1995); Variety Club Award (1992 and 1993), Indiana; Gold Medal of City of Paris (1993); World of Difference Award, Indiana Health Industry Forum (1997); Who's Who in Health Care, Indianapolis Business Journal (IBJ) (2002); Health Care Heroes Award, IBJ (2002); Karl Landsteiner Award, American Association of Blood Banks (2002); Prestigious External Award Recognition, IUPUI (2003); Distinguished Alumni Award, Long Island University (2005); Joseph T. Taylor Excellence in Diversity Award, Indiana University (2006); Dirk van Bekkum Award, Autologous Blood and Bone Marrow Society (2006); E. Donnall Thomas Prize and Lecture, American Society of Hematology (2007); Glenn W. Irwin Jr. M.D., Distinguished Faculty Award, Indiana University School of Medicine Alumni Association (2008); State of Indiana General Assembly House Resolution No. 46 (2008); Mission Advancement Award, Leukemia Lymphoma Society (2008); Cord Blood Pioneering Award, Int. Cord Blood Symposium (2008); Till and McCullough Award, Canadian Bone Marrow Transplant Group (2010); Donald Metcalf Award, Int. Soc. Expt. Hematol. (2011); Elected Fellow of the American Association for the Advancement of Science (AAAS) (2013); Honorary Professorship, Peking Union Medical College, Beijing, China (2014); Thought Leader Award, 15th Annual Cord Blood Symposium (2017); NHLBI Outstanding Investigator Award (R35) (2018); IU President's Medal of Honor; highest honor given by IU (2019); Lifetime Achievement Award, Cord Blood Association (2019); Daughter's of the American Revolution Medal of Honor, their highest honor (2019); Bicentennial Award for IU, for those who have broadened the reach of IU around the state, nation, and world (2020); and Lifetime Achievement Award, Amer. Soc. Transplantation and Cell Therapy (ASTCT) (2021). Dr Broxmeyer is a former President of the American Society of Hematology (ASH; 2010), former President of the International Society for Experimental Hematology and Stem Cell Research (ISEH, 1990, 1991), former Chairman, and member, Board of Scientific Councilors, National Space Biomedical Research Institute (NSBRI/NASA, 1998–2006), and Chairman Emeritus, Board of Directors, National Disease Research Interchange, Philadelphia, PA. Maegan L. CapitanoMaegan L. CapitanoDr Maegan L. Capitano is an Assistant Professor in the Department of Microbiology and Immunology at Indiana University School of Medicine and Associate Member of the Hematopoiesis and Hematological Malignancies Program at Indiana University Simon Comprehensive Cancer Center. She earned her B.A. in Biology from St. Mary's College of Maryland in 2004. During her summers in college, she worked at Memorial Sloan Kettering Cancer Center in the laboratory of Dr Bo Dupont as a laboratory technician where she developed a passion for research. She next went on to earn a M.S. in Natural Science-Oncology in 2006 and her Ph.D. in Microbiology and Immunology in 2012 at the State University of New York at Buffalo- Roswell Park Cancer Center Division under the mentorship of Dr. Elizabeth Repasky where she was given the George Meyer's Award for Proficiency and Academic Excellence in Immunology. She received her post-doctoral training (2012–2016) in the laboratory of Dr. Hal E. Broxmeyer at Indiana University School of Medicine focusing on Experimental Hematology. In the fall of 2016, she joined the faculty of the Department of Microbiology and Immunology at Indiana University School of Medicine as an Assistant Research Professor. In 2021, Dr Capitano was promoted to Assistant Professor in the Department of Microbiology and Immunology. Dr Capitano has published 28 primary research articles and 9 reviews/editorials/book chapters with her current main research focusing on discovering potential new agents that regulate hematopoietic stem and progenitor cell migration, proliferation, differentiation and survival capacity under normal and stressed conditions.

Modulation of Hedgehog Signaling by Kappa Opioids to Attenuate Osteoarthritis.

Inhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA. Primary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee OA in rats was used. A novel automated 3-dimensional indentation tester (Mach-1) was used to quantify the thickness and stiffness properties of the articular cartilage. Inhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes (P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants (P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle-treated controls). In JT09-treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% (P = 0.005 versus vehicle-treated controls). The results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.

Kappa opioids modulate hedgehog signaling to attenuate osteoarthritis

Purpose: Osteoarthritis (OA) affects 50 million Americans, at an annual cost of $100 billion. Pain management is currently a hallmark of OA treatment. One of the most frequently employed treatment strategies involves opioid analgesics. Opioids are highly addictive and have led to an opioid epidemic. One strategy to reduce opioid addiction is to implement kappa-opioid receptor (KOR) agonist medications which have been documented to provide pain-relief without the addictive potential of commonly used opioid medications (which target the mu-opioid receptor). Our previous work showed that KOR is expressed in chondrocytes and synovial cells. Previous studies have also shown that inhibition of the Hedgehog (Hh) signaling pathway prevents cartilage degeneration and promotes repair in animal models of OA. Current study was designed to explore if modulation of kappa opioid receptor (KOR) signaling may have a therapeutic potential for achieving disease-modifying activity in OA models through Hh modulation. Methods: Normal human primary tissues were obtained from the National Disease Research Interchange (NDRI). Human OA samples were collected from patients with severe osteoarthritis undergoing total joint replacements. Normal porcine articular cartilage tissue was used for explant studies. For in vivo studies a partial medial meniscectomy (PMM) rat model was used. A novel automated 3D indentation mapping mechanical tester (Mach-1) was used to quantify articular cartilage thickness and stiffness properties. Results: We have demonstrated that activation of KOR by a selective peptide agonist JT09 inhibits Hh signaling in normal and osteoarthritic human chondrocytes via cAMP/CREB pathway. JT09 has also markedly decreased matrix degeneration in porcine explants induced by a Hh agonist SAG. Moreover, in vivo application of JT09 via intra-articular injection significantly attenuated rat articular cartilage degeneration after PMM. In JT09 treated rats, cartilage content and structure were largely maintained, and osteophyte formation was greatly reduced. In addition, treatment with JT09 prevented functional compressive tissue degeneration following PMM. Conclusions: Current study defines a novel molecular mechanism for the role of the KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in processes and pathologies shown to involve opioid and Hh signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation in cartilage and/or synovial tissue can improve outcomes in patients with arthritis.

Editorial introductions

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS Hal E. BroxmeyerHal E. BroxmeyerDr Hal E. Broxmeyer is Distinguished Professor, Professor of Microbiology and Immunology (Full-Time), Mary Margaret Walther Professor Emeritus, and Co-Leader Program on Hematopoiesis and Hematological Malignancies, and Immunology, NCI-Designated Indiana University Simon Cancer Center, and former Chairman of Microbiology and Immunology and Scientific Director, Walther Oncology Center, at the Indiana University School of Medicine, Indianapolis, IN. He received a BS degree, Brooklyn College, City University of New York in 1966, an MS degree from Long Island University, Brooklyn Center in 1969 and a PhD from New York University in 1973. He did post-doctoral training in 1973–1975 at Kingston General Hospital, Queens University Kingston, Ontario, Canada. From 1975–1983 he worked at the Memorial Sloan Kettering Cancer Center (MSKCC) in NewYork City rising from the rank of Associate Researcher to that of Associate Member. He was also Assistant Professor of Biology, Sloan Kettering Division of Cornell University Graduate School of Medical Sciences, New York, before being recruited to the Indiana University School of Medicine in 1983 as an Associate Professor of Medicine. To date, he has published 789 scientific papers (542 refereed papers and 247 Reviews/Book Chapters). Broxmeyer's laboratory studies mechanisms regulating hematopoietic stem and progenitor cell, embryonic stem cell and induced pluripotent stem cell: proliferation, self-renewal, survival, differentiation and migration (homing/mobilization). He was involved in establishing the field of cord blood transplantation. His publications have been cited 42,697 times (Web of Science; WOS)/61,149 times (Google Scholar; GS) and the H-Factor for publications is 103 (WOS)/ 117 (GS) with i10 index = 554 (GS). Dr Broxmeyer's Awards include: New York University Founders Day Award (1973); Mellor Award (2nd prize 1976; 1st prize 1977) and Boyer Award (1983) from MSKCC; Special Fellow (1976–1978) and Scholar Award (1978–1983) from the Leukemia Lymphoma Society; Merit Award, National Cancer Institute (1987–1995); Variety Club Award (1992 and 1993), Indiana; Gold Medal of City of Paris (1993); World of Difference Award, Indiana Health Industry Forum (1997); Who's Who in Health Care, Indianapolis Business Journal (IBJ) (2002); Health Care Heroes Award, IBJ (2002); Karl Landsteiner Award, American Association of Blood Banks (2002); Prestigious External Award Recognition, IUPUI (2003); Distinguished Alumni Award, Long Island University (2005); Joseph T. Taylor Excellence in Diversity Award, Indiana University (2006); Dirk van Bekkum Award, Autologous Blood and Bone Marrow Society (2006); E. Donnall Thomas Prize and Lecture, American Society of Hematology (2007); Glenn W. Irwin Jr. M.D., Distinguished Faculty Award, Indiana University School of Medicine Alumni Association (2008); State of Indiana General Assembly House Resolution No. 46 (2008); Mission Advancement Award, Leukemia Lymphoma Society (2008); Cord Blood Pioneering Award, Int. Cord Blood Symposium (2008); Till and McCullough Award, Canadian Bone Marrow Transplant Group (2010); Donald Metcalf Award, Int. Soc. Expt. Hematol. (2011); Elected Fellow of the American Association for the Advancement of Science (AAAS) (2013); Honorary Professorship, Peking Union Medical College, Beijing, China (2014); Thought Leader Award, 15th Annual Cord Blood Symposium (2017); and NHLBI Outstanding Investigator Award (R35) (2018). Dr Broxmeyer is a former President of the American Society of Hematology (ASH; 2010), former President of the International Society for Experimental Hematology (ISEH, 1990, 1991), former Chairman, and member, Board of Scientific Councilors, National Space Biomedical Research Institute (NSBRI/NASA, 1998–2006), and Chairman Emeritus, Board of Directors, National Disease Research Interchange, Philadelphia, PA. Maegan L. CapitanoMaegan L. CapitanoDr Maegan L. Capitano is an Assistant Research Professor in the Department of Microbiology and Immunology at Indiana University School of Medicine. She earned her B.A. in Biology from St. Mary's Honors College of Maryland in 2004. During her summers in college, she worked at Memorial Sloan Kettering Cancer Center in the laboratory of Dr Bo Dupont as a laboratory technician where she developed a passion for research. She next went on to earn a M.S. in Natural Science-Oncology in 2006 and her Ph.D. in Microbiology and Immunology in 2012 at the State University of New York- Roswell Park Cancer Center Division under the mentorship of Dr Elizabeth Repasky where she was given the George Meyer's Award for Proficiency and Academic Excellence in Immunology. She received her post-doctoral training (2012–2016) in the laboratory of Dr Hal E. Broxmeyer at Indiana University School of Medicine focusing on Experimental Hematology. In the fall of 2016, she joined the faculty of the Department of Microbiology and Immunology at Indiana University School of Medicine as an Assistant Research Professor. In addition to her laboratory research, Dr Capitano served on the Trainee Council for the American Society of Hematology, a committee made up of two Ph.D.s and ten M.D.s that are in the earlier stages of their careers in Hematology. Dr Capitano's research focuses on discovering potential new agents that regulate hematopoietic stem and progenitor cell migration, proliferation, differentiation and survival capacity under normal and stressed conditions. Ari M. MelnickAri M. MelnickAri M. Melnick, MD, is the Gebroe Family Professor of Hematology/Oncology and a Professor of Medicine and Pharmacology at Weill Cornell Medical College (WCMC) in New York City, USA. He is Chair of the Hematologic Malignancies Program of the Weill Cornell Cancer Center and is also Director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences and Director of the Epigenomics Core Facility, both of which are at WCMC. Dr Melnick was raised in Argentina and received his medical degree from the University of Buenos Aires, Argentina. He completed a residency in internal medicine and a fellowship in hematology/oncology, as well as a postdoctoral fellowship at the Mount Sinai School of Medicine in New York City, USA. Dr Melnick's research interests include the biology and molecular targeting of B-cell lymphomas, targeting transcriptional and epigenetic repressors for cancer therapy, and identifying the epigenetic basis of hematologic malignancies. He and his research associates have also developed novel therapies to correct aberrant transcriptional regulation and signaling in these tumors. Dr Melnick has authored or coauthored more than 250 published manuscripts in journals such as Nature, Science, Cell, Cancer Cell, Nature Medicine, Nature Immunology, and the New England Journal of Medicine. He is a past ASH Faculty Scholar, LLS Scholar and Kimmel Foundation Scholar and is a member of the American Society for Clinical Investigation and the American Association of Physicians. Dr Melnick has been Scientific Chair of the American Society of Hematology (ASH) annual meeting and has organized several meetings in the areas of epigenetics and hematologic malignancies.

The Microbiomes of Pancreatic and Duodenum Tissue Overlap and Are Highly Subject Specific but Differ between Pancreatic Cancer and Noncancer Subjects.

In mice, bacteria from the mouth can translocate to the pancreas and impact pancreatic cancer progression. In humans, oral bacteria associated with periodontal disease have been linked to pancreatic cancer risk. It is not known if DNA bacterial profiles in the pancreas and duodenum are similar within individuals. Tissue samples were obtained from 50 subjects with pancreatic cancer or other conditions requiring foregut surgery at the Rhode Island Hospital (RIH), and from 34 organs obtained from the National Disease Research Interchange. 16S rRNA gene sequencing was performed on 189 tissue samples (pancreatic duct, duodenum, pancreas), 57 swabs (bile duct, jejunum, stomach), and 12 stool samples. Pancreatic tissue samples from both sources (RIH and National Disease Research Interchange) had diverse bacterial DNA, including taxa typically identified in the oral cavity. Bacterial DNA across different sites in the pancreas and duodenum were highly subject specific in both cancer and noncancer subjects. Presence of genus Lactobacillus was significantly higher in noncancer subjects compared with cancer subjects and the relative abundance of Fusobacterium spp., previously associated with colorectal cancer, was higher in cancer subjects compared with noncancer subjects. Bacterial DNA profiles in the pancreas were similar to those in the duodenum tissue of the same subjects, regardless of disease state, suggesting that bacteria may be migrating from the gut into the pancreas. Whether bacteria play a causal role in human pancreatic cancer needs to be further examined. Identifying bacterial taxa that differ in cancer patients can provide new leads on etiologically relevant bacteria.

Mast Cell-Derived Tryptase in Geographic Atrophy.

PurposeOur previous study demonstrated significantly more degranulating mast cells (MCs) in choroids from subjects with age-related macular degeneration compared to aged controls. This study examined the immunolocalization of tryptase, the most abundant MC secretory granule-derived serine protease, in aged control eyes and eyes with geographic atrophy (GA).MethodsPostmortem human eyes with and without GA were obtained from the National Disease Research Interchange. Tissue was fixed, cryopreserved, sectioned, and immunostained with a monoclonal antibody against tryptase. Sections were imaged on a Zeiss 710 Confocal Microscope.ResultsIn the posterior pole of all aged control eyes, tryptase was confined to choroidal MCs, which were located primarily in Sattler's layer. In eyes with GA, many MCs were located in the inner choroid near choriocapillaris and Bruch's membrane (BM). Tryptase was found not only in MCs but also diffusely around them in stroma, suggesting they had degranulated. In contrast with aged control eyes, eyes with GA also had strong tryptase staining in BM. Tryptase was observed within BM in regions of RPE atrophy, at the border of atrophy, and extending well into the nonatrophic region.ConclusionsOur results demonstrate that tryptase, released during choroidal MC degranulation, binds to BM in GA in advance of RPE atrophy. Tryptase activates MMPs that can degrade extracellular matrix (ECM) and basement membrane components found in BM. ECM modifications are likely to have a profound effect on the function and health of RPE and choroidal thinning in GA.

Editorial introductions

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Hal E. BroxmeyerHal E. BroxmeyerDr Hal E. Broxmeyer is a distinguished Professor, Professor of Microbiology and Immunology, Mary Margaret Walther Professor Emeritus, and Co-Leader Program on Hematopoiesis, Malignant Hematology, and Immunology, Indiana University Simon Cancer Center, and former Chairman of Microbiology and Immunology and Scientific Director, Walther Oncology Center, at the Indiana University School of Medicine, Indianapolis, IN, USA. From 1975 to 1983, he worked at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City rising from the rank of Associate Researcher to that of Associate Member. He was also Assistant Professor of Biology, Sloan Kettering Division of Cornell University Graduate School of Medical Sciences, New York, USA, before being recruited to the Indiana University School of Medicine in 1983 as an Associate Professor of Medicine. To date, he has published 764 scientific papers (527 refereed papers and 237 Reviews/Book Chapters). Dr Broxmeyer's laboratory studies mechanisms regulating hematopoietic stem and progenitor cell, embryonic stem cell and induced pluripotent stem cell: proliferation, self-renewal, survival, differentiation and migration (homing/mobilization) and he was involved in establishing the field of cord blood transplantation. Dr Broxmeyer has been the recipient of numerous awards since the 1970's. The more recently include Indiana University School of Medicine Alumni Association (2008); State of Indiana General Assembly House Resolution No. 46 (2008); Mission Advancement Award, Leukemia Lymphoma Society (2008); Cord Blood Pioneering Award, Int. Cord Blood Symposium (2008); Till and McCullough Award, Canadian Bone Marrow Transplant Group (2010); Donald Metcalf Award, Int. Soc. Expt. Hematol. (2011); Elected Fellow of the American Association for the Advancement of Science (AAAS) (2013); and Honorary Professorship, Peking Union Medical College, Beijing, China (2014). Dr Broxmeyer is a Past President of the American Society of Hematology (ASH; 2010), past President of the International Society for Experimental Hematology (ISEH, 1990, 1991), past Chairman, and member, Board of Scientific Councilors, National Space Biomedical Research Institute (NSBRI/NASA, 1998–2006), and Chairman Emeritus, Board of Directors, National Disease Research Interchange, Philadelphia, PA, USA. Ari MelnickAri MelnickAri Melnick, MD, is the Gebroe Family Professor of Hematology/Oncology and a Professor of Medicine and Pharmacology at Weill Cornell Medical College (WCMC) in New York City, USA. He is Chair of the Hematologic Malignancies Program of the Weill Cornell Cancer Center and is also Director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences and Director of the Epigenomics Core Facility, both of which are at WCMC. Dr Melnick was raised in Argentina and received his medical degree from the University of Buenos Aires, Argentina. He completed a residency in internal medicine and a fellowship in hematology/oncology, as well as a postdoctoral fellowship at the Mount Sinai School of Medicine in New York City, USA. Dr Melnick's research interests include the biology and molecular targeting of B-cell lymphomas, targeting transcriptional and epigenetic repressors for cancer therapy, and identifying the epigenetic basis of hematologic malignancies. He and his research associates have also developed novel therapies to correct aberrant transcriptional regulation and signaling in these tumors. Dr Melnick has been Scientific Chair of the American Society of Hematology (ASH) annual meeting and has organized several meetings in the areas of epigenetics and hematologic malignancies. Dr Melnick is a past ASH Faculty Scholar and Kimmel Foundation Scholar, and he has been recognized for this work by the Leukemia & Lymphoma Society. He is also co-leader of the New York Leukemia Working Group. Dr Melnick has authored or coauthored more than 150 published manuscripts in journals such as Nature, Science, Cell, Cancer Cell, Nature Medicine, Nature Immunology, and the New England Journal of Medicine.

The National Disease Research Interchange and Collaborators on: What Are the Major Hurdles to the Recovery of Human Tissue to Advance Research?

The National Disease Research Interchange and Collaborators on: What Are the Major Hurdles to the Recovery of Human Tissue to Advance Research?

Evaluation of the efficacy of postmortem human bladder tissue as a normal comparator for case-controlled gene expression studies in urology.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood disease with no absolute diagnostic marker. A molecular-based tool (biomarker) for IC/BPS diagnosis would have immediate clinical utility. We have generated a bank of bladder biopsy tissue from IC/BPS patients and require a control group for comparative gene expression studies. The objective of this pilot study was to investigate the feasibility of cadaveric bladder specimens as a viable source of control tissue. Cryopreserved cadaveric bladder specimens were obtained through the National Disease Research Interchange (NDRI) tissue repository. Decedent demographics, postmortem interval to autopsy, necropsy location and size were recorded. At least two punch biopsies were taken from each bladder sample and total RNA was extracted. Nucleic acid concentration and quality were measured as was the RNA integrity number (RIN). We purchased 15 necropsy bladder specimens that had been harvested from women postmortem and flash-frozen. For each bladder specimen, RNA was isolated from multiple sites for comparison both within and between individuals. Bioanalyzer results revealed severe degradation in the majority of samples as indicated by RINs ranging from "n/a" to 6.6, with most samples yielding RINs ≤2.5. Shorter postmortem interval did not correlate with an increase in RNA quantity or quality. Cadaver-derived bladder tissue from the NDRI does not routinely yield high-quality RNA needed for downstream gene expression applications, such as microarray and next-generation sequencing and, therefore, cannot be used as a reliable source for control samples.

MP70-05 DEVELOPMENT OF A NOVEL 3 DIMENSIONAL (3D) TESTICULAR ORGANOID MODEL FOR THE STUDY OF HUMAN SPERMATOGENESIS AND GENOTOXICITY IN VITRO

You have accessJournal of UrologyInfertility: Basic Research & Pathophysiology1 Apr 2016MP70-05 DEVELOPMENT OF A NOVEL 3 DIMENSIONAL (3D) TESTICULAR ORGANOID MODEL FOR THE STUDY OF HUMAN SPERMATOGENESIS AND GENOTOXICITY IN VITRO Samuel Pendergraft, Hooman Sadri-Ardekani, Tanya Reid, Anthony Atala, and Colin Bishop Samuel PendergraftSamuel Pendergraft More articles by this author , Hooman Sadri-ArdekaniHooman Sadri-Ardekani More articles by this author , Tanya ReidTanya Reid More articles by this author , Anthony AtalaAnthony Atala More articles by this author , and Colin BishopColin Bishop More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1430AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Mammalian spermatogenesis is regulated through paracrine-endocrine activity, cell signaling, and local control mechanisms. These highly specific signaling interactions are effectively absent upon placing testicular cells into two-dimensional (2D) primary culture. Current protocols to produce mature germ cells in vitro are inefficient and are limited in supporting post-meiotic cells. In order to address these limitations we have developed a 3D testis organoid in vitro by combining stem cell and tissue engineering approaches. This model can be utilized as a means to evaluate gonadotoxic agents, and to address critical deficiencies in our understanding of basic human spermatogenesis Human testes tissues for this study were obtained through the National Disease Research Interchange (NDRI). METHODS Development of this model system consisted of (1) Identification and analysis of specific cellular components necessary for use in a 3D culture method, (2) establishment of basic design parameters, culture conditions, and characterization of human testicular organoids using live cell imaging, immunofluorescence, immunohistochemistry, gene expression, and viability assays, and (3) assess the potential to demonstrate testicular organoid function and as a tool for screening for testicular drug toxicity. RESULTS Human Spermatogonial stem cells (SSCs), Sertoli, and Leydig cells were isolated from human adult testes tissues, characterized, and expanded. These cell types were integrated successfully into 3D organoids and maintained viability as determined by ATP and Live/Dead assays for over 3 weeks in culture. These organoids were responsive to hCG and able to produce testosterone in vitro. Changes in gene expression within these multicellular human testis organoids was measured over time for cell and stage-specific markers including UCHL1, ITGA6, DAZL, SYCP3, PRM1, ACROSIN, FSHr, CYP19a1, HSD3B1, and CYP11a1. Dose response curves were generated using a luminescent viability assay in response to exposure to 3 commonly used genotoxic chemotherapeutic drugs and dose-response was compared to corresponding cells cultured in 2D. Calculated IC50 values were determined to be significantly higher for 3D organoid cultures. CONCLUSIONS Functional human 3D testicular organoids were successfully generated. Future directions include optimizing the spermatogenic capacity of the organoids and continuing to evaluate their use as a novel testicular toxicity model © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e907 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Samuel Pendergraft More articles by this author Hooman Sadri-Ardekani More articles by this author Tanya Reid More articles by this author Anthony Atala More articles by this author Colin Bishop More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

Times Are Changing: 35 Years of Human Biospecimen Procurements for the National Disease Research Interchange.

The fields of basic biological and biomedical research have greatly benefitted from studies using human biospecimens. The National Disease Research Interchange (NDRI) joined the pursuit of scientific advancement over thirty-five years ago with the exclusive mission of supporting the acceleration of diabetes research. In the first few years of its existence, NDRI’s primary activity was providing diabetes researchers with non-transplantable human pancreas biospecimens. In doing so, NDRI played a pivotal role in supporting the development of the experimental methods for isolating human pancreatic islet cells for scientific analysis. This pioneering work is still highly relevant today; diabetes researchers currently use isolated pancreatic islet cells for a wide range of studies such as the development of transplantation therapies and regeneration studies.

On the Dielectric Properties of Human Skin

Electrochemical impedance spectroscopy has become a powerful tool to assess the response of human skin to external stimuli. Two approaches have been taken to analyze the skin impedance data. The skin properties have been assumed to be independent of spatial position but dependent on frequency,[1] and, alternatively, skin properties have been assumed to be independent of frequency but dependent on spatial position.[2] Recent data published by White et al.[3] provides a unique opportunity to assess the validity of the two distinct approaches. The data used in the present study were part of a larger study intended to correlate changes in the flux of p-chloronitrobenzene and 4-cyanophenol in response to physical and chemical damage. Split-thickness human cadaver skin (300-400 microns thick) from the back was purchased from the National Disease Research Interchange (NDRI, Philadelphia, PA). The skin was collected within 24 h post mortem, frozen immediately, and stored at temperatures less than -60 C until used. The protocol described by White et al.[4] was used to ensure that skin samples had sufficient integrity for meaningful measurements of in-vitro chemical permeability.The impedance was measured in the four-electrode configuration, in which two Ag/AgCl (In Vivo Metric, Healdsburg, CA) reference electrodes were used to sense the potential drop across the skin, and two Ag/AgCl working electrodes were used to drive the current. The skin was exposed on both sides for roughly eight hours to a phosphate buffered saline solution (PBS) (0.01 M, pH 7.4, Sigma P-3813) prepared in de-ionized water. The impedance measurements were collected with a 10 mV potential perturbation after two eight-hour long, permeation experiments in which 4-cyanophenol-saturated PBS was placed in the donor chamber and PBS was placed in the receptor chamber. After the first 4-cyanophenol permeation experiment, the frame holding the skin was removed from the diffusion cell, the skin was pierced by a 26 gauge needle (with a 464 micron outside diameter), the cell was reassembled, and the donor and receptor chambers refilled with fresh 4-cyanophenol-saturated PBS and PBS, respectively, for the second permeation experiment. Before perforation with a needle, the impedance diagrams showed a capacitive loop with a depressed semi-circle, consistent with a CPE model. The impedance measured after perforation with the needle could be fit by a CPE model, but the capacitive loop was substantially smaller. Perforation by a needle also caused a substantial shift in the characteristic frequency. These data were used to evaluate models for the impedance response of skin under the hypothesis that perforation by a needle introduces an additional parallel pathway for current to flow, but should not change the dielectric properties of the skin. Under the assumption that skin properties are a function of frequency, this hypothesis means that the frequency-dependent dielectric response should not be altered by perforation of the skin. The observed frequency shift provides a means of assessing different proposed distributions of skin properties. The analysis presented in this paper supports the hypothesis that skin may be described as a system with frequency-independent properties that are functions of position within the skin. The frequency-dependent relative permittivity and resistivity were changed substantially by perforation of the skin. References S. Grimnes and O­. G. Martinsen, Bioimpedance and Bioelectricity Basics, 3rd edition (Amsterdam: Academic Press, 2015). M. E. Orazem, B. Tribollet, V. Vivier, S. Marcelin, N. Pebere, A. L. Bunge, E. A. White, D. P. Riemer, I. Frateur, and M. Musiani, J. Electrochem. Soc., 160 (2013) C215-C225. E. A. White, M. E. Orazem, and A. L. Bunge, Pharm. Res., 30 (2013), 2036-2049. E. A. White, M. E. Orazem,  and A. L. Bunge, J. Electrochem. Soc., 159 (2012) G161-G165.

Quantification and Potential Functions of Endogenous Agonists of Transient Receptor Potential Channels in Patients With Irritable Bowel Syndrome

In mice, activation of the transient receptor potential cation channels (TRP) TRPV1, TRPV4, and TRPA1 causes visceral hypersensitivity. These receptors and their agonists might be involved in development of irritable bowel syndrome (IBS). We investigated whether polyunsaturated fatty acid (PUFA) metabolites, which activate TRPs, are present in colon tissues from patients with IBS and act as endogenous agonists to induce hypersensitivity. We analyzed colon biopsy samples from 40 patients with IBS (IBS biopsies) and 11 healthy individuals undergoing colorectal cancer screening (controls), collected during colonoscopy at the University of Bologna, Italy. Levels of the PUFA metabolites that activate TRPV1 (12-hydroperoxyeicosatetraenoic acid, 15-hydroxyeicosatetraenoic acid, 5-hydroxyeicosatetraenoic acid, and leukotriene B4), TRPV4 (5,6-epoxyeicosatrienoic acid [EET] and 8,9-EET), and TRPA1 (PGA1, 8-iso-prostaglandin A2, and 15-deoxy-Δ-prostaglandin J2) were measured in biopsies and their supernatants using liquid chromatography and tandem mass spectrometry; we also measured levels of the PUFA metabolites prostaglandin E2 (PGE2) and resolvins. C57Bl6 mice were given intrathecal injections of small interfering RNAs to reduce levels of TRPV4, or control small interfering RNAs, along with colonic injections of biopsy supernatants; visceral hypersensitivity was measured based on response to colorectal distension. Mouse sensory neurons were cultured and incubated with biopsy supernatants and lipids extracted from biopsies or colons of mice. Immunohistochemistry was used to detect TRPV4 in human dorsal root ganglia samples (from the National Disease Research Interchange). Levels of the TRPV4 agonist 5,6-EET, but not levels of TRPV1 or TRPA1 agonists, were increased in IBS biopsies compared with controls; increases correlated with pain and bloating scores. Supernatants from IBS biopsies, but not from controls, induced visceral hypersensitivity in mice. Small interfering RNA knockdown of TRPV4 in mouse primary afferent neurons inhibited the hypersensitivity caused by supernatants from IBS biopsies. Levels of 5,6-EET and 15-HETE were increased in colons of mice with, but not without, visceral hypersensitivity. PUFA metabolites extracted from IBS biopsies or colons of mice with visceral hypersensitivity activated mouse sensory neurons in vitro, by activating TRPV4. Mouse sensory neurons exposed to supernatants from IBS biopsies produced 5,6-EET via a mechanism that involved the proteinase-activated receptor-2 and cytochrome epoxygenase. In human dorsal root ganglia, TPV4 was expressed by 35% of neurons. Colon tissues from patients with IBS have increased levels of specific PUFA metabolites. These stimulate sensory neurons from mice and generate visceral hypersensitivity via activation of TRPV4.

Macular pigment carotenoids in the retina and occipital cortex are related in humans

Objectives: Lutein and zeaxanthin are dietary carotenoids that preferentially accumulate in the macular region of the retina. Together with meso-zeaxanthin, a conversion product of lutein in the macula, they form the macular pigment. Lutein is also the predominant carotenoid in human brain tissue and lutein status is associated with cognitive function in adults. The study objective was to evaluate the relationship between retinal and brain lutein and zeaxanthin in humans.Methods: Donated brain tissue (occipital cortex and hippocampus) and matched retina were obtained from the National Disease Research Interchange, a national human tissue resource center which adheres to strict consent and confidentiality procedures. Decedents were men and women aged >50 years who either had normal cognitive function or Alzheimer's disease. Tissues were analyzed using standard lipid extractions followed by analysis on reverse-phase high performance liquid chromatography (HPLC) and normal-phase HPLC (for meso-zeaxanthin).Results: Macular pigment carotenoids (lutein, meso-zeaxanthin, and zeaxanthin combined) in the retina were significantly related to the combined concentrations of lutein and zeaxanthin in the occipital cortex. When analyzed separately, only retinal lutein (plus meso-zeaxanthin), not zeaxanthin, was significantly related to lutein in the occipital cortex. No correlations were observed with lutein and zeaxanthin in the hippocampus.Discussion: Total macular pigment density measured via non-invasive, psychophysical techniques can be used as a biomarker to ascertain brain lutein and zeaxanthin status in clinical studies.

Abstract 77: Distinct Profiles of Transient Receptor Potential Canonical (TRPC) Channel Expression in Biventricular Failure

Heart failure is a major cause of morbidity and mortality. The transient receptor potential canonical (TRPC) family of channels mediate pathologic cardiac remodeling. In particular, TRPC6 participates in a self-propagating circuit that amplifies cardiac hypertrophy and fibrosis. The objective of this study was to explore biventricular expression of TRPCs in advanced heart failure. Methods: Viable left (LV) and right (RV) ventricular free wall tissue was obtained from human subjects with end-stage heart failure (n=12) referred for transplantation or biventricular assist devices. Control LV and RV tissue was obtained from the National Disease Research Interchange (n=3/group). To explore TRPC expression in a murine model, adult male C57BL/6 mice underwent thoracic aortic constriction (TAC) for 10 weeks (n=6/group). Biventricular tissue was analyzed by real-time polymerase chain reaction. Results: Compared to normal LV and RV, levels of TRPC 1, 3, 4 and 6 were increased in failing LV and RV samples, respectively. Levels of TRPC1 and TRPC6 were greater in failing RV than failing LV samples. TRPC 5 and 7 expression were not consistently detected in normal or failing tissue samples. Compared to sham LV, levels of TPRC 1, 4 and 6 increased in the LV after TAC. Compared to sham RV, levels of TRPC 3, 4, and 6 increased in the RV after TAC. Levels of TRPC3 were greater in the RV than LV after TAC. Conclusions: Our results identify distinct profiles of TRPC expression in the RV versus LV in both human tissue and in a murine model of advanced biventricular failure. Levels of select TRPCs are higher in the failing RV compared to LV, suggesting a potentially important role for TRPCs in RV remodeling.

Editorial introductions

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Section Editors for this issue. SECTION EDITORS Hal E. BroxmeyerHal E. BroxmeyerDr Hal E. Broxmeyer is Distinguished Professor, Professor of Microbiology and Immunology, Mary Margaret Walther Professor Emeritus, and Co-Leader Program on Hematopoiesis, Leukemia, and Immunology, Indiana University Simon Cancer Center, USA, and former Chairman of Microbiology and Immunology and Scientific Director, Walther Oncology Center, at the Indiana University School of Medicine, Indianapolis, IN, USA. He received a BS degree, Brooklyn College, City University of New York, USA, in 1966, an MS degree from Long Island University, Brooklyn Center, USA in 1969 and a PhD from New York University, USA, in 1973. He did post-doctoral training in 1973–1975 at Kingston General Hospital, Queens University Kingston, Ontario, Canada. From 1975–1983 he worked at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, USA, rising from the ranks of Associate Researcher to that of Associate Member. He was also Assistant Professor of Biology, Sloan Kettering Division of Cornell University Graduate School of Medical Sciences, New York, USA, before being recruited to the Indiana University School of Medicine in 1983 as an Associate Professor of Medicine. To date, he has published 729 scientific papers (505 refereed papers and 224 Reviews/Book Chapters). Broxmeyer's laboratory studies mechanisms regulating hematopoietic stem and progenitor cell, embryonic stem cell and induced pluripotent stem cell: proliferation, self-renewal, survival, differentiation and migration (homing/mobilization). He was involved in establishing the field of cord blood transplantation. His publications have been cited 35,844 times and the H-Factor for publications is 98. Dr Broxmeyer's Awards include: New York University Founders Day Award (1973); Mellor Award (2nd prize 1976; 1st prize 1977) and Boyer Award (1983) from MSKCC; Special Fellow (1976–1978) and Scholar Award (1978–1983) from the Leukemia Lymphoma Society; Merit Award, National Cancer Institute (1987–1995); Variety Club Award (1992 and 1993), Indiana; Gold Medal of City of Paris (1993); World of Difference Award, Indiana Health Industry Forum (1997); Who's Who in Health Care, Indianapolis Business Journal (IBJ) (2002); Health Care Heroes Award, IBJ (2002); Karl Landsteiner Award, American Association of Blood Banks (2002); Prestigious External Award Recognition, IUPUI (2003); Distinguished Alumni Award, Long Island University (2005); Joseph T. Taylor Excellence in Diversity Award, Indiana University (2006); Dirk van Bekkum Award, Autologous Blood and Bone Marrow Society (2006); E. Donnall Thomas Prize and Lecture, American Society of Hematology (2007); Glenn W. Irwin Jr. M.D., Distinguished Faculty Award, Indiana University School of Medicine Alumni Association (2008); State of Indiana General Assembly House Resolution No. 46 (2008); Mission Advancement Award, Leukemia Lymphoma Society (2008); Cord Blood Pioneering Award, Int. Cord Blood Symposium (2008); Till and McCullough Award, Canadian Bone Marrow Transplant Group (2010); Donald Metcalf Award, Int. Soc. Expt. Hematol. (2011); and Elected Fellow of the American Association for the Advancement of Science (AAAS) (2013). Dr Broxmeyer is a Past President of the American Society of Hematology (ASH; 2010), past President of the International Society for Experimental Hematology (ISEH, 1990, 1991), past Chairman, and member, Board of Scientific Councilors, National Space Biomedical Research Institute (NSBRI/NASA, 1998–2006), and Chairman Emeritus, Board of Directors, National Disease Research Interchange, Philadelphia, PA. Ari M. MelnickAri M. MelnickDr Melnick is the Gebroe Family Professor of Hematology/Oncology at Weill Cornell Medical College (WCMC), New York, USA (holding this role since 2013), Director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences, New York, USA, Director of the Internal Medicine Research Residency and Director of the WCMC Epigenomics Core Facility. He completed his medical degree at the University of Buenos Aries, Argentina, in 1990 and continued his clinical training with residencies in internal medicine and subsequently, hematology and oncology at Mount Sinai Medical Center, New York, USA. Following this, he completed post-doctoral fellowships in transcriptional regulation in leukemias with Dr Jonathan Licht at Mount Sinai Medical Center and transcriptional regulation of chromatin with Dr Leonard Freedman at Memorial Sloan-Kettering Cancer Center, USA. Dr Melnick started his own lab in 2002 and has published over 125 papers. His research interests are focused on transcriptional and epigenetic regulation in hematology malignancies, which has led to the development of novel therapies to correct aberrant transcriptional regulation by his group. He has received a number of awards for his work including the Leukemia and Lymphoma Society Scholar Award and the Burroughs Wellcome Clinical Scientist Award in Translational Research. In addition to this, Dr Melnick was the director of the Mount Sinai School of Medicine fellowship program and the Weill Cornell Research Track Residency Program, where he was able to pursue his interest in mentoring trainees and helping to widen career development and training programs for junior scientists.