Digital Commons Network^™

Randomized Study Of Continuous High-Dose Lenalidomide, Sequential Azacitidine And Lenalidomide, Or Azacitidine In Persons 65 Years And Over With Newly-Diagnosed Acute Myeloid Leukemia, Bruno C. Medeiros, Kelly Mccaul, Suman Kambhampati, Daniel A. Pollyea, Rajat Kumar, Lewis R. Silverman, Andrea Kew, Lalit Saini, C. L. Beach, Ravi Vij, Xiwei Wang, Jim Zhong, Robert Peter Gale

Open Access Publications

No abstract provided.

Application Of Neonatologist Performed Echocardiography In The Assessment And Management Of Neonatal Heart Failure Unrelated To Congenital Heart Disease, Philip T. Levy, Cecile Tissot, Beate Horsberg Eriksen, Eirik Nestaas, Sheryle Rogerson, Patrick J. Mcnamara, Afif El-Khuffash, Willem P. De Boode, European Special Interest Group 'Neonatologist Performed Echocardiography' (Npe)

Open Access Publications

No abstract provided.

Left Atrial Structure And Function In Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With And Without Left Ventricular Hypertrophy, Hoshang Farhad, Sara B Seidelmann, Davis Vigneault, Siddique A Abbasi, Eunice Yang, Sharlene M Day, Steven D Colan, Mark W Russell, Jeffrey Towbin, Mark V Sherrid, Charles E Canter, Ling Shi, Michael Jerosch-Herold, David A Bluemke, Carolyn Ho, Tomas G Neilan

Open Access Publications

BACKGROUND: Impaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH).

METHOD: Seventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15).

RESULTS: LA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was …

Increased Ca2+ Signaling Through Cav1.2 Promotes Bone Formation And Prevents Estrogen Deficiency-Induced Bone Loss, Chike Cao, Yinshi Ren, Adam S. Barnett, Anthony J. Mirando, Douglas Rouse, Se Hwan Mun, Kyung-Hyun Park-Min, Amy L. Mcnulty, Farshid Guilak, Courtney M. Karner, Matthew J. Hilton, Geoffrey S. Pitt

Open Access Publications

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage-gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 mutant in chondrogenic and/or osteogenic precursors in vivo …

B Cell-Derived Il-4 Acts On Podocytes To Induce Proteinuria And Foot Process Effacement, Alfred Hj Kim, Jun-Jae Chung, Shreeram Akilesh, Ania Koziell, Sanjay Jain, Jeffrey B. Hodgin, Mark J. Miller, Thaddeus S. Stappenbeck, Jeffrey H. Miner, Andrey S. Shaw

Open Access Publications

The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria. …

Cerebrospinal Fluid And Blood Biomarkers For Neurodegenerative Dementias: An Update Of The Consensus Of The Task Force On Biological Markers In Psychiatry Of The World Federation Of Societies Of Biological Psychiatry, Piotr Lewczuk, Anne M. Fagan, Brian A. Gordon, Et Al

Open Access Publications

No abstract provided.

Interleukin-17 Limits Hypoxia-Inducible Factor 1Α And Development Of Hypoxic Granulomas During Tuberculosis, Racquel Domingo-Gonzalez, Shibali Das, Kristin L. Griffiths, Mushtaq Ahmed, Monika Bambouskova, Suhas Gondi, Noor Al-Hammadi, Reid Townsend, Maxim N. Artyomov, Shabaana A. Khader, Et Al.

Open Access Publications

Mycobacterium tuberculosis (Mtb) is a global health threat, compounded by the emergence of drug-resistant strains. A hallmark of pulmonary tuberculosis (TB) is the formation of hypoxic necrotic granulomas, which upon disintegration, release infectious Mtb. Furthermore, hypoxic necrotic granulomas are associated with increased disease severity and provide a niche for drug-resistant Mtb. However, the host immune responses that promote the development of hypoxic TB granulomas are not well described. Using a necrotic Mtb mouse model, we show that loss of Mtb virulence factors, such as phenolic glycolipids, decreases the production of the proinflammatory cytokine IL-17 (also referred to as IL-17A). IL-17 …

Racial Differences In Prostate Inflammation: Results From The Reduce Study, Adriana C. Vidal, Zinan Chen, Lauren E. Howard, Daniel M. Moreira, Ramiro Castro-Santamaria, Gerald L. Andriole, Emanuela Taioli, Jay H. Fowke, Beatrice Knudsen, Charles G. Drake, J Curtis Nickel, Stephen J. Freedland

Open Access Publications

Prostate cancer (PC) risk differs between races, and we previously showed prostate inflammation in benign prostate tissue was linked with a lower future PC risk. However, whether prostate tissue inflammation varies by race is unknown. We analyzed baseline acute and chronic prostate inflammation by race in REDUCE, a 4-year, multicenter, placebo-controlled study where all men had a negative prostate biopsy prior to enrollment. We included 7,982 men with standardized central pathology review to determine the presence or absence of chronic or acute inflammation in baseline prostate biopsy tissue. Logistic regression was used to compare prostate inflammation by race, adjusting for …

A Type Of Human Skin Dendritic Cell Marked By Cd5 Is Associated With The Development Of Inflammatory Skin Disease, Daniel Korenfeld, Laurent Gorvel, Adiel Munk, Joshua Man, Andras Schaffer, Thomas Tung, Caroline Mann, Eynav Klechevsky

Open Access Publications

Dendritic cells (DCs) are important in regulating immunity and tolerance and consist of functionally distinct subsets that differentially regulate T lymphocyte function. The underlying basis for this subset specificity is lacking, particularly in humans, where the classification of tissue DCs is currently incomplete. Examination of healthy human epidermal Langerhans cells and dermal skin cells revealed a tissue CD5-expressing DC subtype. The CD5+ DCs were potent inducers of cytotoxic T cells and Th22 cells. The products of these T cells, IL-22 and IFN-γ, play a key role in the pathogenesis of psoriasis. Remarkably, CD5+ DCs were significantly enriched in lesional psoriatic …

Redefining The Endophenotype Concept To Accommodate Transdiagnostic Vulnerabilities And Etiological Complexity, Theodore P. Beauchaine, John N. Constantino

Open Access Publications

In psychopathology research, endophenotypes are a subset of biomarkers that indicate genetic vulnerability independent of clinical state. To date, an explicit expectation is that endophenotypes be specific to single disorders. We evaluate this expectation considering recent advances in psychiatric genetics, recognition that transdiagnostic vulnerability traits are often more useful than clinical diagnoses in psychiatric genetics, and appreciation for etiological complexity across genetic, neural, hormonal and environmental levels of analysis. We suggest that the disorder-specificity requirement of endophenotypes be relaxed, that neural functions are preferable to behaviors as starting points in searches for endophenotypes, and that future research should focus on …

Injury-Induced Actin Cytoskeleton Reorganization In Podocytes Revealed By Super-Resolution Microscopy, Hani Y. Suleiman, Robyn Roth, Sanjay Jain, John E. Heuser, Andrey S. Shaw, Jeffrey H. Miner

Open Access Publications

The architectural integrity of tissues requires complex interactions, both between cells and between cells and the extracellular matrix. Fundamental to cell and tissue homeostasis are the specific mechanical forces conveyed by the actomyosin cytoskeleton. Here we used super-resolution imaging methods to visualize the actin cytoskeleton in the kidney glomerulus, an organized collection of capillaries that filters the blood to make the primary urine. Our analysis of both mouse and human glomeruli reveals a network of myosin IIA-containing contractile actin cables within podocyte cell bodies and major processes at the outer aspects of the glomerular tuft. These likely exert force on …

Whole Tumor Rna-Sequencing And Deconvolution Reveal A Clinically-Prognostic Pten/Pi3k-Regulated Glioma Transcriptional Signature, Yuan Pan, Erin C. Bush, Joseph A. Toonen, Yu Ma, Anne C. Solga, Peter A. Sims, David H. Gutmann

Open Access Publications

The concept that solid tumors are maintained by a productive interplay between neoplastic and non-neoplastic elements has gained traction with the demonstration that stromal fibroblasts and immune system cells dictate cancer development and progression. While less studied, brain tumor (glioma) biology is likewise influenced by non-neoplastic immune system cells (macrophages and microglia) which interact with neoplastic glioma cells to create a unique physiological state (glioma ecosystem) distinct from that found in the normal tissue. To explore this neoplastic ground state, we leveraged several preclinical mouse models of neurofibromatosis type 1 (NF1) optic glioma, a low-grade astrocytoma whose formation and maintenance …

Sexual Dimorphism In Glioma Glycolysis Underlies Sex Differences In Survival, Joseph E. Ippolito, Aldrin Kay-Yuen Yim, Jingqin Luo, Prakash Chinnaiyan, Joshua B. Rubin

Open Access Publications

The molecular bases for sex differences in cancer remain undefined and how to incorporate them into risk stratification remains undetermined. Given sex differences in metabolism and the inverse correlation between fluorodeoxyglucose (FDG) uptake and survival, we hypothesized that glycolytic phenotyping would improve glioma subtyping. Using retrospectively acquired lower-grade glioma (LGG) transcriptome data from The Cancer Genome Atlas (TCGA), we discovered male-specific decreased survival resulting from glycolytic gene overexpression. Patients within this high-glycolytic group showed significant differences in the presence of key genomic alterations (i.e., 1p/19q codeletion, CIC, EGFR, NF1, PTEN, FUBP1, and IDH mutations) compared with the low-glycolytic group. Although …

Pediatric And Adult Dilated Cardiomyopathy Represent Distinct Pathological Entities, Meghna D. Patel, Jayaram Mohan, Caralin Schneider, Geetika Bajpai, Enkhsaikhan Purevjav, Charles E. Canter, Jeffrey Towbin, Andrea Bredemeyer, Kory J. Lavine

Open Access Publications

Pediatric dilated cardiomyopathy (DCM) is the most common indication for heart transplantation in children. Despite similar genetic etiologies, medications routinely used in adult heart failure patients do not improve outcomes in the pediatric population. The mechanistic basis for these observations is unknown. We hypothesized that pediatric and adult DCM comprise distinct pathological entities, in that children do not undergo adverse remodeling, the target of adult heart failure therapies. To test this hypothesis, we examined LV specimens obtained from pediatric and adult donor controls and DCM patients. Consistent with the established pathophysiology of adult heart failure, adults with DCM displayed marked …

Ca2+-Permeable Ampars Mediate Glutamatergic Transmission And Excitotoxic Damage At The Hair Cell Ribbon Synapse, Joy Y. Sebe, Soyoun Cho, Lavinia Sheets, Mark A. Rutherford, Henrique Von Gersdorff, David W. Raible

Open Access Publications

We report functional and structural evidence for GluA2-lacking Ca

Genomic Landscape And Evolution Of Metastatic Chromophobe Renal Cell Carcinoma, Jozefina Casuscelli, James J. Hsieh, Et Al

Open Access Publications

Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%-10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) …

Early Detection Of Gastric Cancer Using Global, Genome-Wide And Irf4, Elmo1, Clip4 And Msc Dna Methylation In Endoscopic Biopsies, Francesca Pirini, Douglas E. Berg, Et Al

Open Access Publications

Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings.We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Perú, and validated it in 306 samples from the Cancer Genome Atlas project ("TCGA"). Global, epigenome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a …

Gastrointestinal Stromal Tumors (Gists): Point Mutations Matter In Management, A Review, Peter J. Oppelt, Angela C. Hirbe, Brian A. Van Tine

Open Access Publications

The therapeutic implications of the genomic alterations seen within the drivers of gastrointestinal stromal tumors (GIST) are among the best understood in all of solid tumors. Sequencing of cKIT and PDGFRα should be considered standard practice for the treatment of GIST patients. In this article, we will review the common mutations and how they are utilized in clinical management. In addition, we will review the rare D842V PDGFRα mutation and the diverse molecular group that lacks a mutation in either cKIT or PDGFRα (wild-type GIST) which are best treated on clinical trial. Finally, we will look forward at the future …

Promising Therapeutics Of Gastrointestinal Cancers In Clinical Trials, Lingling Du, Zheng Che, Andrea Wang-Gillam

Open Access Publications

Many novel therapeutics are being developed for patients with cancers along the gastrointestinal (GI) tract. These emerging agents are frequently classified by their biological targets such as tumor growth pathways, tumor metabolism, microenvironment, etc. Some agents targeting cancer growth pathways are based on existing clinically validated therapeutic targets, such as regorafenib for hepatocellular carcinoma (HCC), while other agents focus on newly identified targets, such as

Molecular Landscape And Sub-Classification Of Gastrointestinal Cancers: A Review Of Literature, Bita Fakhri, Kian-Huat Lim

Open Access Publications

The historical approach of diagnosing cancer types based entirely on anatomic origin and histologic features, and the "one-size-fit-all" therapeutic approach, are inadequate in modern cancer treatment. From decades of research we now know that cancer is a highly heterogeneous disease driven by complex genetic or epigenetic alterations. The advent of various high throughput molecular tools has now enabled us to view and sub-classify each cancer type based on their distinct molecular features, in addition to histologic classification, with the promise of individualized treatment strategies tailored towards each specific subtype to improve patient outcomes. In this review, we have made an …

Current Biologics For Treatment Of Biliary Tract Cancers, Diana Y. Zhao, Kian-Huat Lim

Open Access Publications

Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option. Due to the paucity of effective treatments, BTCs have a dismal prognosis. There is a tremendous need to better understand the disease biology, discover new therapies, and improve …

Biologic Therapy In Esophageal And Gastric Malignancies: Current Therapies And Future Directions, Pamela Samson, A. Craig Lockhart

Open Access Publications

Biologic agents, including targeted antibodies as well as immunomodulators, are demonstrating unparalleled development and study across the entire spectrum of human malignancy. This review summarizes the current state of biologic therapies for esophageal, esophagogastric, and gastric malignancies, including those that target human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-Met, mechanistic target of rapamycin (mTOR) and immunomodulators. We focus primarily on agents that have been included in phase II and III clinical trials in locally advanced, progressive, or metastatic esophageal and gastric malignancies. At this time, only two biologic therapies are …

Gdf15 Is Elevated In Mice Following Retinal Ganglion Cell Death And In Glaucoma Patients, Norimitsu Ban, Carla J. Siegfried, Jonathan B. Lin, Ying-Bo Shui, Julia Sein, Wolfgang Pita-Thomas, Abdoulaye Sene, Andrea Santeford, Mae Gordon, Rachel Lamb, Zhenyu Dong, Shannon C. Kelly, Valeria Cavalli, Jun Yoshino, Rajendra S. Apte

Open Access Publications

Glaucoma is the second leading cause of blindness worldwide. Physicians often use surrogate endpoints to monitor the progression of glaucomatous neurodegeneration. These approaches are limited in their ability to quantify disease severity and progression due to inherent subjectivity, unreliability, and limitations of normative databases. Therefore, there is a critical need to identify specific molecular markers that predict or measure glaucomatous neurodegeneration. Here, we demonstrate that growth differentiation factor 15 (GDF15) is associated with retinal ganglion cell death. Gdf15 expression in the retina is specifically increased after acute injury to retinal ganglion cell axons and in a murine chronic glaucoma model. …

Incidental Angiosarcoma Of The Pancreas: A Case Report Of A Rare, Asymptomatic Tumor, Patrick J Worth, Michael Turner, Chet W Hammill

Open Access Publications

No abstract provided.

Lrrk2 But Not Atg16l1 Is Associated With Paneth Cell Defect In Japanese Crohn's Disease Patients, Ta-Chiang Liu, Takeo Naito, Zhenqiu Liu, Kelli L Vandussen, Talin Haritunians, Dalin Li, Katsuya Endo, Yosuke Kawai, Masao Nagasaki, Yoshitaka Kinouchi, Dermot P. B. Mcgovern, Tooru Shimosegawa, Yoichi Kakuta, Thaddeus S Stappenbeck

Open Access Publications

No abstract provided.

Mapk Signaling Promotes Axonal Degeneration By Speeding The Turnover Of The Axonal Maintenance Factor Nmnat2, Lauren J. Walker, Daniel W. Summers, Yo Sasaki, Ej Brace, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

Injury-induced (Wallerian) axonal degeneration is regulated via the opposing actions of pro-degenerative factors such as SARM1 and a MAPK signal and pro-survival factors, the most important of which is the NAD

Aberrantly Activated Cox-2 And Wnt Signaling Interact To Maintain Cancer Stem Cells In Glioblastoma, Megan Wu, Jennifer Guan, Chris Li, Simon Gunter, Labeeba Nusrat, Sheena Ng, Karan Dhand, Cindi Morshead, Albert Kim, Sunit Das

Open Access Publications

No abstract provided.

Cell-Free Measurements Of Brightness Of Fluorescently Labeled Antibodies, Haiying Zhou, George Tourkakis, Dennis Shi, David M. Kim, Hairong Zhang, Tommy Du, William C. Eades, Mikhail Y. Berezin

Open Access Publications

No abstract provided.

Targeting Dendritic Cells To Accelerate T-Cell Activation Overcomes A Bottleneck In Tuberculosis Vaccine Efficacy, Kristin L. Griffiths, Mushtaq Ahmed, Shibali Das, Radha Gopal, William Horne, Terry D. Connell, Kelly D. Moynihan, Jay K. Kolls, Darrell J. Irvine, Maxim N. Artyomov, Javier Rangel-Moreno, Shabaana A. Khader

Open Access Publications

No abstract provided.

Cis-Regulatory Circuits Regulating Nek6 Kinase Overexpression In Transformed B Cells Are Super-Enhancer Independent, Yue Huang, Olivia I. Koues, Jiang-Yang Zhao, Regina Liu, Sarah C. Pyfrom, Jacqueline E. Payton, Eugene M. Oltz

Open Access Publications

No abstract provided.