tbuckley/cabot-search huggingface dataset:
Daratumumab in Primary Effusion Lymphoma
Authors: Nirav N Shah, Arun K Singavi, Alexandra Harrington
Journal: New England Journal of Medicine (2018)

Daratumumab in Primary Effusion Lymphoma In primary effusion lymphoma, a herpesvirus 8 (HHV-8)–associated neoplasm that is most common in HIV-coinfected patients, cells often express CD38. In a pat...
Abstract 3467: Growth factor receptor trafficking in neuroblastoma differentiation
Authors: Jacqueline Lesperance, Divya Subramonian, Sarah Woodfield, Rongjun Guo, Andrew Bean, Dolores Lopez-Terrada, Michael Ittmann, Sara Hakim, Peter E. Zage
Journal: Cancer Research (2018)

Abstract Background/Objectives: UBE4B is an E3/E4 ubiquitin ligase involved in growth factor receptor (GFR) trafficking. The UBE4B gene is located in the chromosome 1p36 region commonly deleted in high-risk neuroblastoma tumors. We have previously identified associations of UBE4B expression with neuroblastoma patient outcomes. However, the functional roles of UBE4B in neuroblastoma tumor differentiation are not known. Design/Methods: We analyzed the association of UBE4B gene expression with expression of known markers of neuroblastoma tumor differentiation using publicly available databases and screened cell lines and neuroblastoma tumor samples for UBE4B protein expression using Western blot and quantitative immunohistochemistry. We measured UBE4B expression by Western blot in cell lines before and after induction of differentiation with 13-cis-retinoic acid treatment and determined the effects of UBE4B overexpression and depletion on retinoic acid-induced differentiation using continuous live-cell imaging of neurite morphology, immunohistochemistry, and Western blot for markers of differentiation. Effects on signaling through the Ras/MAPK pathway were measured using Western blots. Results: UBE4B expression was associated with neuroblastoma differentiation in patient tumors, and UBE4B gene and protein expression were associated with expression levels of known markers of neuroblastoma differentiation. Retinoic acid treatment resulted in increased UBE4B expression in retinoic acid-sensitive, but not -resistant, neuroblastoma cells, and UBE4B depletion was associated with increased ERK phosphorylation, increased proliferation, and inhibition of retinoic acid-induced neuroblastoma differentiation. Conclusion: We have demonstrated associations between UBE4B expression and tumor differentiation in gene expression databases and in neuroblastoma tumor samples, and our data suggests that UBE4B expression is required for retinoic acid-induced differentiation, potentially through effects on activation of the Ras/MAPK pathway. These associations between UBE4B and neuroblastoma differentiation combined with the established role of UBE4B in GFR trafficking suggest that UBE4B-mediated receptor trafficking may contribute to the responses of neuroblastoma tumors to therapy and to the outcomes of patients with neuroblastoma. Citation Format: Jacqueline Lesperance, Divya Subramonian, Sarah Woodfield, Rongjun Guo, Andrew Bean, Dolores Lopez-Terrada, Michael Ittmann, Sara Hakim, Peter E. Zage. Growth factor receptor trafficking in neuroblastoma differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3467.
Abstract 2365: A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion
Authors: Kelley E. McQueeney, Joseph M. Salamoun, Jennifer Ahn, Paula Pekic, Isabella K. Blanco, Heather Struckman, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo
Journal: Cancer Research (2018)

Abstract Dysregulation of the tightly controlled protein phosphorylation networks that govern cellular behavior causes cancer. The membrane-associated, intracellular protein tyrosine phosphatase PTP4A3 is overexpressed in human colorectal cancer and contributes to cell migration and invasion. To interrogate further the role of PTP4A3 in colorectal cancer cell migration and invasion, we deleted the Ptp4a3 gene from murine colorectal tumor cells. The resulting PTP4A3-/- cells exhibited impaired colony formation, spheroid formation, migration, and adherence compared to the isogenic PTP4A3fl/fl cells. We replicated these phenotypic changes using the new small molecule allosteric PTP4A3 inhibitor, JMS-053. A related structure, JMS-038, which lacked phosphatase inhibition, displayed no cellular activity. Reduction in cell viability and colony formation by JMS-053 occurred in both mouse and human colorectal cell lines and required PTP4A3 expression. Ptp4a3 deletion increased the expression of extracellular matrix and adhesion genes, including the tumor suppressor Emilin 1. JMS-053 also increased Emilin 1 gene expression. Moreover, the human TCGA genomic database revealed colorectal tumors with high Ptp4a3 expression had low Emilin1 expression. These chemical and biological reagents reveal a previously unknown communication between the intracellular PTP4A3 phosphatase and the extracellular matrix and support efforts to pharmacologically target PTP4A3. Citation Format: Kelley E. McQueeney, Joseph M. Salamoun, Jennifer Ahn, Paula Pekic, Isabella K. Blanco, Heather Struckman, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2365.
Intravascular Ultrasound–Guided Balloon Angioplasty Compared With Stent
Authors: FrançoisSchiele, NicolasMeneveau, MartineGilard, JacquesBoschat, PhilippeCommeau, Liu PinMing, PradipSewoke, Marie-FranceSeronde, MarietteMercier, SanjivGupta, Jean-PierreBassand
Journal: Circulation (2003)

Background— Balloon angioplasty guided by intravascular ultrasound (IVUS) makes it possible to choose the balloon size according to the true vessel diameter and to detect suboptimal results requiring subsequent stent implantation. The Balloon Equivalent to STent (BEST) study aimed to assess whether this strategy would give the same results as systematic stenting. Methods and Results— A total of 132 of 254 patients were randomized to IVUS-guided percutaneous transluminal coronary angioplasty (aggressive PTCA), and 122 were randomized to stenting (stent group). We hypothesized that a difference of <8% in the 6-month angiographic restenosis rate (primary end point) could be considered noninferior. The aggressive PTCA procedure was longer and had a greater use of contrast medium than stenting. In the aggressive PTCA group, crossover to stent was needed in 58 patients (44%). At 6 months, 20 of 119 patients (16.8±6.7%) in the aggressive PTCA group and 21 of 116 patients (18.1±7.0%) in the stent group had resten...
Abstract 18790: Brown Adipose Tissue Enhances Exercise Performance
Authors: John J Guers, Marko Oydanich, Jie Zhang, Seonghun Yoon, Dorothy E Vatner, Stephen F Vatner
Journal: Circulation (2017)

Introduction: The beneficial effects of brown adipose tissue have become well characterized, however its effects on exercise performance are unknown. Hypothesis: Therefore, the goal of this investigation was to determine if brown adipose tissue could be a novel mechanism to improve exercise capacity. Methods: To examine the effects of brown adipose tissue on exercise performance, we transplanted brown adipose tissue from RGS14 KO to their WT littermates and examined exercise performance 3 days later. Results: Brown adipose tissue was obtained from Receptor G Protein Signaling 14 knock out (KO) (RGS14 KO) mice, where brown adipose tissue is increased by 47 % compared to wild type (WT) controls. Maximal treadmill exercise capacity, measured as distance, was greater in RGS14 KO mice than in their WT littermates. SIRT3, a mediator of both increased exercise performance and enhanced brown adipose tissue activity, was increased in skeletal muscle of RGS14 KO mice (p<0.05). We found that when RGS14 KO were cross...
Abstract 2343: Comprehensive evaluation of antibody-drug conjugate targets for drug development across tumor types: Analysis from TCGA
Authors: Roman Groisberg, Jason Rosznik, Funda Meric-Bernstam, Vivek Subbiah
Journal: Cancer Research (2018)

Abstract Introduction: Cancer cells over-express proteins on their cell surface that can be exploited as drug targets and has led to development of two successful Anti-body Drug Conjugates (ADCs), Brentuximab and Trastuzumab Emtansine. Because a strong correlation exists between mRNA levels and protein expression we analyzed RNAseq data from TCGA to look at known ADC targets as a proof-of-concept to discovering new therapeutic targets. Methods: We used mRNA expressions (transcripts per million, TPM) from publicly available RNA sequencing data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project to analyze the expression of ADC targets in tumor and normal tissues. We chose thirty-seven targets with known ADCs in clinical development. Graphs were generated to show distribution of each gene's expression across all tumor and normal tissue types in TCGA and GTEx. Potential targets were determined based on tumor expression of at least two times the highest expression in any normal tissue. Proteins known to be secreted in the blood stream at high levels were excluded as they are unlikely to make a good ADC target (eg. AFP, FOLH1). Results: Using ERBB2 as the prototype gene, we were able to detect over-expression in all tumors that have HER-2 ove-rexpression in the literature including breast, bladder, NSCLC, Gastroesophageal, endometrial, HNSCC, ovarian, and colon cancer. Other genes with overexpression in select tumors including BSG (RCC, Melanoma, ACC), CD70 (RCC, DLBCL, mesothelioma, cervical), ENPP3 (RCC, endometrial, breast, lung adeno), FGFR2 (breast, gastric), FOLR1 (ovarian, lung adeno), GPNMB (lung, melanoma, HNSCC, renal), MSLN (lung adeno, mesothelioma, ovarian), SLC39A6 (breast), TDGF1 (thymoma, testicular, adrenocortical) were discovered as well. Tumors exhibited a significantly higher expression compared to normal tissue for ERBB2: breast cancer vs normal breast: p &amp;lt; 0.001; bladder cancer vs normal bladder: p &amp;lt; 0.001; lung adenocarcinoma vs normal lung: p &amp;lt; 0.001; ovarian cancer vs normal ovary: p &amp;lt; 0.001. Conclusion: Overall, this large-scale analysis from TCGA reveals that RNA-seq can be used as an initial screen to identify novel targets for ADCs. Further analysis will identify previously unappreciated targets that can be exploited for drug development across diverse cancers. Further confirmation with protein expression is warranted. Citation Format: Roman Groisberg, Jason Rosznik, Funda Meric-Bernstam, Vivek Subbiah. Comprehensive evaluation of antibody-drug conjugate targets for drug development across tumor types: Analysis from TCGA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2343.
Cardiac Release of Cytokines and Inflammatory Responses in Acute Myocardial Infarction
Authors: Franz-JosefNeumann, IlkaOtt, MeinradGawaz, GertRichardt, HeidiHolzapfel, MarianneJochum, AlbertSchömig
Journal: Circulation (1995)

Background In animal models of myocardial infarction (MI), inflammatory responses compromise microcirculation during reperfusion and restrict functional recovery. To investigate cardiac inflammatory responses in patients with acute MI, we examined the cardiac release of cytokines, the expression on neutrophils of the β2-integrin Mac-1 (CD11b/CD18) and L-selectin (CD62L), and the cardiac release of thrombomodulin as a marker of endothelial injury. Methods and Results In 12 patients with acute anterior MI, blood samples were obtained from the coronary sinus and from the aorta immediately before and after recanalization of the coronary occlusion by balloon angioplasty. Twelve patients undergoing elective balloon angioplasty served as control subjects. Plasma concentrations of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and thrombomodulin were determined by immunoassay, and surface expression of CD11b and CD62L was assessed by flow cytometry. Differences in coronary sinus and arterial blood were...
Abstract 302: Vitamin D Deficiency Is Associated with Poor Neurological Outcome After Sudden Cardiac Arrest
Authors: JinWi, JaeSunUhm, BoyoungJoung, Hui-NamPak, Moon-HyoungLee
Journal: Circulation (2014)

Background: Vitamin D deficiency has been reported to be related to various cardiovascular diseases, including sudden cardiac arrest (SCA). This study investigated the association of vitamin D deficiency with neurologic outcome after SCA. Methods: We prospectively analyzed clinical data from all unconscious patients resuscitated from a SCA of presumed cardiac cause. Neurologic outcome was assessed by Cerebral Performance Category (CPC) score at 6 months after discharge. Good neurologic outcome was defined as CPC score of 1 or 2, whereas poor one as CPC scores of 3 through 5. Vitamin D deficiency was defined as 25(OH)D <10 ng/mL. Results: A total of 65 patients [51 men (79%), mean age 59 ± 14 years] were included from May 2012 to October 2013 in this study. First monitored rhythm was shockable rhythm, including ventricular fibrillation or tachycardia, in 44 (68%) and non-shockable rhythm, including pulseless electrical activity or asystole, in 21 (32%). Bystander cardiopulmonary resuscitation (CPR) was per...
Abstract 3059: SOX2 is a novel biomarker for poor long-term outcomes in oral cancer
Authors: Xuefeng Zhang, Hao Xu, Chongkui Sun, Xinhua Liang, Peng Deng, Xin Zeng, Qianming Chen
Journal: Cancer Research (2018)

Abstract Purpose: Sex determining region Y-BOX2 (SOX2), a key regulator of the self-renewal ability of stem cells, plays a role in the initiation and development of head and neck squamous cell carcinoma (HNSCC). However, the association between SOX2 expression and the outcomes of patients with oral squamous cell carcinoma (OSCC) has not been investigated. Thus, in this study, we investigated the possibility of predicting the survival outcomes of patients with OSCC by evaluating SOX2 expression. Experiment design: First, we analyzed SOX2 expression in patients with OSCC in The Cancer Genome Atlas (TCGA) dataset by a bioinformatics approach. In addition, samples of 219 patients with OSCC from two independent Chinese centers were collected. The median follow-up time and 95% confidence interval (CI) for the cohorts were 36 (25.06, 46.93) months and SOX2 expression in these samples was determined by immunostaining using tissue microarray. The Kaplan-Meier analysis, log-rank test, and Cox proportional hazards regression model were used to determine univariate and multivariate analyses, and hazard ratios for overall survival (OS), respectively. Results: In TCGA database, amplification of SOX2 was negatively correlated with the OS rate for patients who survived more than 300 days after the first diagnosis. Moreover, 39.7% of the samples from the cohorts showed high SOX2 expression. We found a significant difference in the survival rate between patients with high and low SOX2 expression ranging from 13 to 126 months. Conclusion: High SOX2 expression can predict poor long-term, but not short-term, survival outcomes in patients with OSCC. Our findings not only indicated that SOX2 may be a novel biomarker for the long-term prognosis of OSCC but also strongly supported the cancer stem cell theory that dysregulation of the self-renewal ability of stem cells may contribute to the development of OSCC. Citation Format: Xuefeng Zhang, Hao Xu, Chongkui Sun, Xinhua Liang, Peng Deng, Xin Zeng, Qianming Chen. SOX2 is a novel biomarker for poor long-term outcomes in oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3059.
Abstract SY17-01: Metabolic impact on immune cell subsets in the tumor microenvironment and its therapeutic relevance
Authors: Weiping Zou
Journal: Cancer Research (2018)

Abstract We have studied the crosstalk among immune cell subsets (Tregs, Th17, Th22, CD8+ T cells, and APCs) and tumor (stem) cells in the tumor microenvironment, and its impact on tumor immunity and therapy. Over the past few years, our team has achieved important insights into cancer immunopathogenesis. Our research efforts demonstrate that the tumor microenvironment comprises immune cells that have been reprogrammed by active tumor-mediated processes to defeat tumor immunity and promote tumor progression in a highly effective manner. These studies have helped define the nature of immune responses in the cancer microenvironment, form the concept of immunosuppressive networks in the cancer microenvironment, and provide significant insights into designing current immune therapies including inhibitory B7 checkpoint blockade (PD-L1, B7-H1) to treat cancer patients. In this talk, we focus on how glycolysis and oxidative stress affect naïve T cells, effector T cells, and Tregs in the tumor microenvironment. We have demonstrated that tumor-associated glycolysis affects naïve T-cell phenotype via the FIP200-associated autophagy pathway and controls effector T-cell poly-functionality via EZH2-H3K27me3 mediated-epigenetic regulatory mechanism. Furthermore, we have found that tumor Tregs sustain and amplify their suppressor capacity by inadvertent death via oxidative stress. This process is highly regulated through energy metabolism. The work highlights the metabolic pathways controlling T-cell subset functional behavior and affecting cancer immune checkpoint therapy. Citation Format: Weiping Zou. Metabolic impact on immune cell subsets in the tumor microenvironment and its therapeutic relevance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY17-01.
Abstract B09: IGF axis plays a pivotal role in the ovulation-induced malignant transformation of fallopian tube fimbrial epithelial cells
Authors: Tang-Yuan Chu, Hsuan-Shun Huang, Che-Fang Hsu, Pao-Chu Chen
Journal: Clinical Cancer Research (2018)

Abstract Owing to uncertain tissue-of-origin and elusive etiology, high-grade serous ovarian carcinoma (HGSC) is typically diagnosed at late stages with poor prognosis. Recent studies have unveiled the fallopian tube fimbria as the major tissue of origin and incessant ovulation as the main etiology, but the mechanism of cancer initiation remains elusive. In a series of studies we have found a majority of preovulatory follicular fluids (FF) contain high level of ROS that induce DNA double-strand breaks as well as apoptosis to the fimbrial epithelial cells in vitro and in vivo. We also found that hemoglobin (Hb) in pelvis, most likely contributed by retrograde menstruation of previous cycles, reduces the ovulatory ROS level extracellularly and results in a shifting from the apoptotic to the survival fate of ROS-stressed fimbrial epithelial cells. These initiating factors in FF, although they may contribute to the TP53 mutation and other early genetic hits in the genesis of HGSC, cannot fully transform the immortalized fimbrial epithelial cell lines with loss of p53 and Rb. Here we show that IGF axis proteins, including IGFBP2- and IGFBP6-bound IGFs as well as the IGFBP-lytic enzyme PAPP-A, are abundant in ovulatory FF. Upon engaging with glycosaminoglycans (GAG) on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases bioactive IGF in close proximity to its receptor IGF-1R. Through the PI3K/Akt/mTOR signaling pathway, the FF-derived IGF exerts transformation effects on immortalized fimbrial epithelial cells, inducing anchorage independent growth and xenograft tumorigenesis. By contrast, much less transformation was noted when IGFBP2/6 or PAPP-A was depleted from the FF, when the GAG-docking was blocked, or when IGF-1R ormTOR was inhibited. Taken together, the serial studies have unveiled multiple cancer initiating factors in ovulation and retrograde menstruation where ROS acts as the mutagen, hemoglobin serves as the surviving rescuer, and the IGF axis acts as the main transforming signal. Citation Format: Tang-Yuan Chu, Hsuan-Shun Huang, Che-Fang Hsu, Pao-Chu Chen. IGF axis plays a pivotal role in the ovulation-induced malignant transformation of fallopian tube fimbrial epithelial cells. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B09.
What Should Be the Target Blood Pressure for This Older Patient With Hypertension?
Authors: Gerald W. Smetana, Jennifer Beach, Lewis Lipsitz, Howard Libman
Journal: Annals of Internal Medicine (2018)

Hypertension is prevalent and the most important risk factor for cardiovascular disease. Controversy exists regarding the optimum threshold above which to begin antihypertensive therapy and the optimum target blood pressure once medication is begun. This controversy is particularly true for older patients, who may be more likely to benefit from treatment because of their higher risk for cardiovascular events, but may also be more at risk for adverse effects of treatment. Two guidelines published in 2017 address this issue. The American College of Physicians/American Academy of Family Physicians guideline recommends initiating antihypertensive therapy for older patients (aged 60 years or older) if systolic blood pressure is 150 mm Hg or higher and to treat to the same target. They recommend a lower threshold for starting treatment and a lower target systolic blood pressure (140 mm Hg) for patients with cerebrovascular disease and potentially those at high risk for cardiovascular events. The American College of Cardiology/American Heart Association guideline, which is based primarily on SPRINT (Systolic Blood Pressure Intervention Trial), advises a target systolic blood pressure of 130 mm Hg for community-dwelling ambulatory patients aged 65 years or older. This article presents the case of a 79-year-old man who is contemplating antihypertensive therapy. Two experts discuss the optimal approach for the patient and suggest how to apply the 2 guidelines to his care.
The (Pro)renin Receptor/ATP6AP2 is Essential for Vacuolar H+-ATPase Assembly in Murine Cardiomyocytes
Authors: KenichiroKinouchi, AtsuhiroIchihara, MotoakiSano, Ge-HongSun-Wada, YohWada, AsakoKurauchi-Mito, KanakoBokuda, TatsuyaNarita, YoichiOshima, MariyoSakoda, YoshitakaTamai, HiromuSato, KeiichiFukuda, HiroshiItoh
Journal: Circulation Research (2010)

Rationale: The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H+-ATPase (V-ATPase), implicating a non–RAS-related function of ATP6AP2. Objective: We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. Methods and Results: Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the VO subunits of V-ATPase, resulting in deacidification of the intracellular vesicl...