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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 …

Elevated Urinary Creld2 Is Associated With Endoplasmic Reticulum Stress-Mediated Kidney Disease, Yeawon Kim, Sun-Ji Park, Scott R. Manson, Carlos A. F. Molina, Kendrah Kidd, Heather Thiessen-Philbrook, Rebecca J. Perry, Helen Liapis, Stanislav Kmoch, Chirag R. Parikh, Anthony J. Bleyer, Ying Maggie Chen

Open Access Publications

ER stress has emerged as a signaling platform underlying the pathogenesis of various kidney diseases. Thus, there is an urgent need to develop ER stress biomarkers in the incipient stages of ER stress-mediated kidney disease, when a kidney biopsy is not yet clinically indicated, for early therapeutic intervention. Cysteine-rich with EGF-like domains 2 (CRELD2) is a newly identified protein that is induced and secreted under ER stress. For the first time to our knowledge, we demonstrate that CRELD2 can serve as a sensitive urinary biomarker for detecting ER stress in podocytes or renal tubular cells in murine models of podocyte …

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 …

Pacritinib To Inhibit Jak/Stat Signaling In Refractory Metastatic Colon And Rectal Cancer, Thomas Regenbogen, Ling Chen, Kathryn Trinkaus, Andrea Wang-Gillam, Benjamin R. Tan, Manik Amin, Katrina S. Pedersen, Haeseong Park, Rama Suresh, Kian-Huat Lim, Emily Ratchford, Amberly Brown, A Craig Lockhart

Open Access Publications

Background: Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma.

Methods: A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard lines of treatment. Pacritinib 400 mg daily was administered orally continuously in 28 day cycles.

Results: The trial was discontinued prior to reaching the planned accrual due to an FDA hold on …

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.

The Impact Of Rare Variation On Gene Expression Across Tissues, Xin Li, Colby Chiang, Alexandra J Scott, Ira M Hall, Et Al

Open Access Publications

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here …

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 …

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 …

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 …

Monocyte Dysregulation And Systemic Inflammation During Pediatric Falciparum Malaria, Katherine R. Dobbs, Paula Embury, John Vulule, Peter S. Odada, Bruce A. Rosa, Makedonka Mitreva, James W. Kazura, Arlene E. Dent

Open Access Publications

BACKGROUND: Inflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood.

METHODS: We evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1- to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community.

RESULTS: Acute malaria was marked by elevated levels of …

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 …

Study Design Of Real World Evidence For Treatment Of Hyperkalemia In The Emergency Department (Reveal-Ed): A Multicenter, Prospective, Observational Study, Zubaid Rafique, Mikhail Kosiborod, Carol Clark, Adam Singer, Stewart Turner, Joseph Miller, Douglas Char, W. Frank Peacock

Open Access Publications

OBJECTIVE: Hyperkalemia affects up to 10% of hospitalized patients and, if left untreated, can lead to serious cardiac arrhythmias or death. Although hyperkalemia is frequently encountered in the emergency department (ED), and is potentially life-threatening, standard of care for the treatment is poorly defined, with little supporting evidence. The main objectives of this observational study are to define the overall burden of hyperkalemia in the ED setting, describe its causes, the variability in treatment patterns and characterize the effectiveness and safety of ED standard of care therapies used in the United States.

METHODS: This is an observational study evaluating the …

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 …

Digital Ischemia And Necrosis: A Rarely Described Complication Of Gemcitabine In Pancreatic Adenocarcinoma, Eiichiro So, Zachary D Crees, Danielle Crites, Andrea Wang-Gillam

Open Access Publications

No abstract provided.

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) …

Dna Methyltransferase 3b Regulates Articular Cartilage Homeostasis By Altering Metabolism, Jie Shen, Cuicui Wang, Daofeng Li, Taotao Xu, Jason Myers, John M. Ashton, Ting Wang, Michael J. Zuscik, Audrey Mcalinden, Regis J. O'Keefe

Open Access Publications

Osteoarthritis (OA) is the most common form of arthritis worldwide. It is a complex disease affecting the whole joint but is generally characterized by progressive degradation of articular cartilage. Recent genome-wide association screens have implicated distinct DNA methylation signatures in OA patients. We show that the de novo DNA methyltransferase (Dnmt) 3b, but not Dnmt3a, is present in healthy murine and human articular chondrocytes and its expression decreases in OA mouse models and in chondrocytes from human OA patients. Targeted deletion of Dnmt3b in murine articular chondrocytes results in an early-onset and progressive postnatal OA-like pathology. RNA-Seq and methylC-Seq analyses …

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 …

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