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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 …

Glycolytic Requirement For Nk Cell Cytotoxicity And Cytomegalovirus Control, Annelise Y. Mah, Armin Rashidi, Molly P. Keppel, Nermina Saucier, Emily K. Moore, Joshua B. Alinger, Sandeep K. Tripathy, Sandeep K. Agarwal, Emily K. Jeng, Hing C. Wong, Jeffrey S. Miller, Todd A. Fehniger, Emily M. Mace, Anthony R. French, Megan A. Cooper

Open Access Publications

NK cell activation has been shown to be metabolically regulated in vitro; however, the role of metabolism during in vivo NK cell responses to infection is unknown. We examined the role of glycolysis in NK cell function during murine cytomegalovirus (MCMV) infection and the ability of IL-15 to prime NK cells during CMV infection. The glucose metabolism inhibitor 2-deoxy-ᴅ-glucose (2DG) impaired both mouse and human NK cell cytotoxicity following priming in vitro. Similarly, MCMV-infected mice treated with 2DG had impaired clearance of NK-specific targets in vivo, which was associated with higher viral burden and susceptibility to infection on the C57BL/6 …

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.

N-3 Pufas Induce Inflammatory Tolerance By Formation Of Keap1-Containing Sqstm1/P62-Bodies And Activation Of Nfe2l2, Jennifer Mildenberger, Ida Johansson, Ismail Sergin, Eli Kjøbli, Jan Kristian Damås, Babak Razani, Trude Helen Flo, Geir Bjørkøy

Open Access Publications

Inflammation is crucial in the defense against infections but must be tightly controlled to limit detrimental hyperactivation. Our diet influences inflammatory processes and omega-3 polyunsaturated fatty acids (n-3 PUFAs) have known anti-inflammatory effects. The balance of pro- and anti-inflammatory processes is coordinated by macrophages and macroautophagy/autophagy has recently emerged as a cellular process that dampens inflammation. Here we report that the n-3 PUFA docosahexaenoic acid (DHA) transiently induces cytosolic speckles of the autophagic receptor SQSTM1/p62 (sequestosome 1) (described as SQSTM1/p62-bodies) in macrophages. We suggest that the formation of SQSTM1/p62-bodies represents a fast mechanism of NFE2L2/Nrf2 (nuclear factor, erythroid 2 like …

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 …

A Novel Patient Engagement Platform Using Accessible Text Messages And Calls (Epharmix): Feasibility Study, Avik Som, Kunjan Patel, Eric Sink, Robert Mattson Peters, Kavon Javaherian, Jacob Groenendyk, Tonya An, Zhuchen Xu, Gregory M Polites, Melvin Blanchard, Will Ross

Open Access Publications

BACKGROUND: Patient noncompliance with therapy, treatments, and appointments represents a significant barrier to improving health care delivery and reducing the cost of care. One method to improve therapeutic adherence is to improve feedback loops in getting clinically acute events and issues to the relevant clinical providers as necessary (ranging from detecting hypoglycemic events for patients with diabetes to notifying the provider when patients are out of medications). Patients often don't know which information should prompt a call to their physician and proactive checks by the clinics themselves can be very resource intensive. We hypothesized that a two-way SMS system combined …

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 …

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 …

Alx Receptor Ligands Define A Biochemical Endotype For Severe Asthma, Isabell Ricklefs, Mario Castro, Andrea M. Coverstone, Et Al

Open Access Publications

BACKGROUND: In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA).

METHODS: ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] …

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 …

Chemoembolization Versus Radioembolization For The Treatment Of Unresectable Intrahepatic Cholangiocarcinoma In A Single Institution Image-Based Efficacy And Comparative Toxicity, Olaguoke Akinwande, Veer Shah, Abigail Mills, Christopher Noda, Eric Weiner, Gretchen Foltz, Nael Saad

Open Access Publications

Aim: Compare radioembolization (Y90) and chemoembolization (CE) for the treatment of unresectable intrahepatic cholangiocarcinoma (UICC).

Materials & methods: Institutional Review Board-approved, retrospective search was performed. Forty patients with UICC were treated with either Y90 (n = 25, 39 treatments) or CE (n = 15, 35 treatments). Comparative analysis was performed using Student's

Results: Median ages were 60 and 64 years for CE and Y90 groups, respectively (p = 0.798). Patient variables including age, Eastern Cooperative Oncology Group score, tumor burden, extra-hepatic disease, prior chemotherapy and prior surgery were similar between groups. Adverse events were similar in both groups (CE 20%, …

African American Prostate Cancer Survivorship: Exploring The Role Of Social Support In Quality Of Life After Radical Prostatectomy, Kellie R Imm, Faustine Williams, Ashley J Housten, Graham A Colditz, Bettina F Drake, Keon L Gilbert, Lin Yang

Open Access Publications

PURPOSE: The aim of this study was to explore the African American prostate cancer survivorship experience following radical prostatectomy and factors contributing to quality of life during survival.

DESIGN: African American men who were part of a larger prostate cancer cohort were invited to participate in a focus group. Eighteen open-ended questions were designed by the study team and an experienced moderator to elicit participants' survivorship experiences.

RESULTS: Twelve men consented to participate in the study. Emergent themes included views of prostate cancer in the African American community, perceptions of normalcy, emotional side effects following radical prostatectomy, and social support …

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 …

Investigator And Independent Review Committee Exploratory Assessment And Verification Of Tumor Response In A Non-Hodgkin Lymphoma Study, Robert R Ford, Robert W Ford, Michael O'Neal, Brad S Kahl, Ling Chen, Mihaela Munteanu, Bruce D Cheson

Open Access Publications

Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accurate and reliable measurement and identification of tumors. Regulatory agencies recommend blinded reviews of imaging data by independent review committees (IRCs). Differences in response outcomes that arise between IRCs and site investigators raise regulatory/sponsor concerns. Here, we evaluate discrepant tumor response assessments by the IRC and unblinded investigators (complete versus partial response, respectively) occurring in 52 (13% of 393 IRC-assessed responders) of 447 enrolled patients with treatment-naïve non-Hodgkin lymphoma from a randomized study. The IRC and investigators were 'likely correct' in 73% and 25% of cases, respectively …

Immunotherapy In Gastrointestinal Cancers, Patrick Grierson, Kian-Huat Lim, Manik Amin

Open Access Publications

Gastrointestinal (GI) cancers such as gastric, esophageal, pancreas, hepatobiliary, colorectal and anal cancers are a major cause of cancer related mortality worldwide. Traditional treatment options such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and anti-angiogenic agents have been the backbone of treatment of GI cancers in various stages. Current cancer research is moving forward to incorporate immunotherapies in the treatment of GI cancers either as single agent or in combination with current available treatment modalities. This review summarizes the existing and ongoing immunotherapies in the treatment of GI cancers.

The Improvedd Vte Risk Score: Incorporation Of D-Dimer Into The Improve Score To Improve Venous Thromboembolism Risk Stratification, C. Michael Gibson, Alex C. Spyropoulos, Alexander T. Cohen, Russell D. Hull, Samuel Z. Goldhaber, Roger D. Yusen, Adrian F. Hernandez, Serge Korjian, Yazan Daaboul, Alex Gold, Robert A. Harrington, Gerald Chi

Open Access Publications

No abstract provided.

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 …

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 …

Combination Epigenetic Therapy In Metastatic Colorectal Cancer (Mcrc) With Subcutaneous 5-Azacitidine And Entinostat: A Phase 2 Consortium/Stand Up 2 Cancer Study, Nilofer S. Azad, Douglas Adkins, Joel Picus, Richard Piekarz, Et Al

Open Access Publications

PURPOSE: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies.

EXPERIMENTAL DESIGN: We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2nd cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than …

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.

Cholinergic, But Not Dopaminergic Or Noradrenergic, Enhancement Sharpens Visual Spatial Perception In Humans, Caterina Gratton, Sahar Yousef, Esther Aarts, Deanna L. Wallace, Mark D'Esposito, Michael A. Silver

Open Access Publications

The neuromodulator acetylcholine modulates spatial integration in visual cortex by altering the balance of inputs that generate neuronal receptive fields. These cholinergic effects may provide a neurobiological mechanism underlying the modulation of visual representations by visual spatial attention. However, the consequences of cholinergic enhancement on visuospatial perception in humans are unknown. We conducted two experiments to test whether enhancing cholinergic signaling selectively alters perceptual measures of visuospatial interactions in human subjects. In Experiment 1, a double-blind placebo-controlled pharmacology study, we measured how flanking distractors influenced detection of a small contrast decrement of a peripheral target, as a function of target-flanker …

Are There Multiple Kinds Of Episodic Memory? An Fmri Investigation Comparing Autobiographical And Recognition Memory Tasks, Hung-Yu Chen, Adrian W. Gilmore, Steven M. Nelson, Kathleen B. Mcdermott

Open Access Publications

What brain regions underlie retrieval from episodic memory? The bulk of research addressing this question with fMRI has relied upon recognition memory for materials encoded within the laboratory. Another, less dominant tradition has used autobiographical methods, whereby people recall events from their lifetime, often after being cued with words or pictures. The current study addresses how the neural substrates of successful memory retrieval differed as a function of the targeted memory when the experimental parameters were held constant in the two conditions (except for instructions). Human participants studied a set of scenes and then took two types of memory test …

Nothing But Net: A Review Of Neuroendocrine Tumors And Carcinomas, Bryan Oronsky, Patrick C. Ma, Daniel Morgensztern, Corey A. Carter

Open Access Publications

No abstract provided.

Host And Bacterial Proteases Influence Biofilm Formation And Virulence In A Murine Model Of Enterococcal Catheter-Associated Urinary Tract Infection, Wei Xu, Ana L. Flores-Mireles, Zachary T. Cusumano, Enzo Takagi, Scott J. Hultgren, Michael G. Caparon

Open Access Publications

No abstract provided.