tbuckley/cabot-search huggingface dataset:
Variation in the Use of Vena Cava Filters for Venous Thromboembolism in Hospitals in Kentucky
Authors: Joshua D. Brown, Jeffery C. Talbert
Journal: JAMA Surgery (2016)

When examining performance by procedure, highperformance AMCs usually achieved top performances in only 2 of 5 quality indicators, with fewer achieving top performances in 3 or 4 metrics of quality outcomes (data not shown).Only 1 center achieved top performance in all 5 outcomes, which was for patients undergoing colectomy.However, most high-performance AMCs were not low performers in any outcome and were never a low performer in more than 1 outcome.Low-performance AMCs rarely achieved top performance in any outcome but frequently had low performance in 2 or 3 quality outcomes.However, lowperformance AMCs were rarely low performers in all 5 outcomes.These trends were consistent across all 4 procedures.Stepwise backward regression predicting mortality among AMCs showed that both morbidity and hospital volume were always independently associated with mortality.This was consistent across all 4 procedures.Discussion | Excellence in 1 procedure did not transfer to excellence in other procedures within the same health system.In fact, 15% of AMCs were high performers for 1 procedure but low performers for another.Individual surgeons and policies within specific surgical divisions may be more responsible for optimal outcomes than processes of care delivery throughout an entire health system.High-quality centers achieved that designation with top performance in only 2 or 3 of 5 quality metrics.Even high-quality AMCs have room to improve. 5,
Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma
Authors: Matthew F Buas, Qianchuan He, Lisa G Johnson, Lynn Onstad, David M Levine, Aaron P Thrift, Puya Gharahkhani, Claire Palles, Jesper Lagergren, Rebecca C Fitzgerald, Weimin Ye, Carlos Caldas, Nigel C Bird, Nicholas J Shaheen, Leslie Bernstein, Marilie D Gammon, Anna H Wu, Laura J Hardie, Paul D Pharoah, Geoffrey Liu, Prassad Iyer, Douglas A Corley, Harvey A Risch, Wong-Ho Chow, Hans Prenen, Laura Chegwidden, Sharon Love, Stephen Attwood, Paul Moayyedi, David MacDonald, Rebecca Harrison, Peter Watson, Hugh Barr, John deCaestecker, Ian Tomlinson, Janusz Jankowski, David C Whiteman, Stuart MacGregor, Thomas L Vaughan, Margaret M Madeleine
Journal: Gut (2016)

<h3>Objective</h3> Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett9s oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. <h3>Design</h3> We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. <h3>Results</h3> We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (<i>MGST1</i>); (p=0.0005, q=0.005). Assessment of 36 <i>MGST1</i> SNPs identified 14 variants associated with elevated BE risk (q&lt;0.05). Four of these were subsequently confirmed (p&lt;5.5×10<sup>−5</sup>) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for <i>MGST1</i>. Three such variants were associated with similar elevations in OA risk. <h3>Conclusions</h3> This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in <i>MGST1</i> influence disease susceptibility.
Abstract 3770: HEXIM1 as a pharmacodynamic marker for monitoring target engagement of ABBV-075
Authors: Xiaoli Huang, Xiaoyu Lin, Leiming Li, Rongqi Wang, Lisa Roberts, Paul Hessler, Tamar Uziel, Lloyd Lam, Terry Magoc, Daniel H. Albert, Steven W. Elmore, Guowei Fang, Saul H. Rosenberg, Keith McDaniel, Warren Kati, Yu Shen
Journal: Cancer Research (2016)

Abstract Bromodomain and extra-terminal (BET) family are dual bromodomain-containing proteins that play an important role in transcription regulation. ABBV-075 is a small molecule BET bromodomain inhibitor currently in phase 1 clinical trials. Here we report the identification of Hexim1 and other BET-responsive genes as robust pharmacodynamic markers for monitoring ABBV-075 target engagement in tumors and in surrogate tissues such as whole blood and skin. Transcription profiling of cancer cell lines for their responses to BET inhibitors identified a set of 9 BET-regulated genes, including Hexim1, that responded to BET inhibition across cancer cell lines and in xenograft tumors. Further characterization of BET-responsive genes in surrogate tissues such as mouse skin, mouse/human PBMCs and whole blood revealed that the mRNA level of Hexim1 exhibited the best response to BETi treatment across different settings. A dose-dependent increase of Hexim1 expression was detected in the whole blood of ABBV-075 treated tumor bearing mice, and the Hexim1 response was closely correlated with the plasma drug concentration and largely reflected the anti-tumor efficacy at various dose levels of ABBV-075. Hexim1 is part of a protein/RNA complex that sequesters pTEFb and prevents its recruitment by BRD4. It also reportedly mediates the anti-proliferative activity of BRD4 in AML. Taken together, Hexim1 could serve as a functional relevant pharmacodynamic marker for monitoring ABBV-075 target engagement in animal models and in the clinical setting. Citation Format: Xiaoli Huang, Xiaoyu Lin, Leiming Li, Rongqi Wang, Lisa Roberts, Paul Hessler, Tamar Uziel, Lloyd Lam, Terry Magoc, Daniel H. Albert, Steven W. Elmore, Guowei Fang, Saul H. Rosenberg, Keith McDaniel, Warren Kati, Yu Shen. HEXIM1 as a pharmacodynamic marker for monitoring target engagement of ABBV-075. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3770.
Abstract 209: The effect of heme influx on initiation and tumorigenesis of NSCLC
Authors: Sagar Sohoni, Md Maksudul Alam, Chantal Vidal, Jagmohan Hooda, Li Zhang
Journal: Cancer Research (2016)

Abstract Heme is a central molecule for mitochondrial function and for all processes involved in oxygen utilization. Heme serves as a prosthetic group or as a cofactor for a number of oxidative phosphorylation enzymes and other oxygen-utilizing hemoproteins. Heme also directly regulates the synthesis, translocation and assembly of these enzyme complexes. Most, if not all, human cells can synthesize and uptake heme from the circulation. A number of epidemiological studies have shown that high heme intake is associated with increased risk of cancer, including lung cancer. Recent studies carried out in our lab showed intensified mitochondrial respiration and increased levels of heme and hemoproteins in non-small-cell lung cancer (NSCLC) cells. Together, these experimental and epidemiological studies strongly suggest that heme is an “oncometabolite.” To assess the status of heme metabolism in cancer cells, we performed a series of experiments in NSCLC cells and compared the results with an immortalized normal lung cell line, HBEC30KT. We used Zinc protoporphyrin, an analogue of heme to measure the level of heme uptake. We found that heme uptake as well as heme synthesis are significantly elevated in all NSCLC cells compared to HBEC. The rate of heme degradation was also measured in these cell lines. Previously, our lab demonstrated that lowering intracellular heme levels selectively decreases oxygen consumption in NSCLC cells and inhibits cell migration and colony formation. Experiments are underway to test ways to alter intracellular heme availability and characterize their effects on NSCLC tumor growth and metastasis. Citation Format: Sagar Sohoni, Md Maksudul Alam, Chantal Vidal, Jagmohan Hooda, Li Zhang. The effect of heme influx on initiation and tumorigenesis of NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 209.
Abstract 3356: Characterization and enrichment of head and neck cancer stem cells suggests differences between HPV+ and HPV- subtypes of HNSCC cells
Authors: Anirban Chatterjee, Kwangok Nickel, Randall J. Kimple
Journal: Cancer Research (2016)

Abstract Head and neck squamous cell carcinomas (HNSCC) are the sixth most prevalent type of malignancy worldwide. Despite recent advances in multidisciplinary treatments, the overall survival and quality of life of patients with advanced HNSCC have not improved considerably over the past decade. Recent reports have demonstrated that tumors contain a small subpopulation of cells called cancer stem-like cells (CSCs), which are responsible for tumor maintenance and metastasis. CSCs have the ability to self-renew and are responsible for tumorigenesis, progression, metastasis, and relapse after treatment. Recent studies demonstrate that even established HNSCC cell lines contain a definite sub-population of CSC providing us with the opportunity to discerning their roles in progression, treatment, and relapse of the disease. In vitro Sphere Forming Assays (using ultra-low attachment plate and serum free media) were employed as the key method of CSC enrichment. qPCR analyses, aldehyde dehydrogenase (ALDH) activity, Side Population Phenotype assay (SPP) were used to confirm the results of the primary analyses. To confirm an in vivo CSC phenotype, xenograft tumor formation, through subcutaneous injection in immunocompromised mice was done. In vitro sphere forming assay followed by subsequent passaging of the sphere enriched cells (SECs) have successfully demonstrated the existence and enrichment of a CSC sub-population in HNSCC cell lines. Findings suggest a differential existence of CSCs related to the HPV status of the cell. ALDH assay and SPP assay confirmed the results of sphere formation. qPCR analyses of the SECs have confirmed enrichment in several stemness marker genes (Oct-4, Sox2, Nanog, Bmi-1, cMyc, KLF4, Beta catenin etc.), also following the identical differential pattern. Various EMT markers genes (Vimentin, Fibronectin, E-cadherin, N-cadherin, Snail, Slug, Twist, ZO-1 etc.) were also assessed, portraying a significant level of expression in CSC populations. SECs subcutaneously injected in immunocompromised mice formed tumors with as few as 50 cells. We have demonstrated that a definite subpopulation of CSCs exists in HNSCC cell lines. Significant differences were seen between the HPV+ and HPV- subtypes. Analyses of EMT marker genes and other molecular pathways in CSC confirm the differences between HPV+ and HPV- cells too following the similar pattern. In vivo tumor xenograft formation establishes the heightened tumorigenicity of CSCs/SECs. Citation Format: Anirban Chatterjee, Kwangok Nickel, Randall J. Kimple. Characterization and enrichment of head and neck cancer stem cells suggests differences between HPV+ and HPV- subtypes of HNSCC cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3356.
Abstract 2016: Paired box 2 promotes progression of endometrial cancer via cell cycle pathway
Authors: Jieyu Wang, Weiwei Feng, Yinhua Yu, Kwong-Kwok Wong, Nan Jia, Tianjiao Lyu
Journal: Cancer Research (2016)

Abstract Human paired box 2 (PAX2) plays a key role in cell fate, early patterning and organogenesis. To investigate the function of PAX2 on the biological behavior of endometrial cancer and the regulation mechanism, stable knocking-down and over-expression PAX2 endometrial cancer cell lines were established. CCK-8 and transwell assays were applied to determine proliferation, invasion and migration ability. Cell cycle distribution was analyzed by flow cytometry. Nude mice were used for in vivo experiments and Affymetrix GeneChip® human Exon 1.0 ST arrays was used to screen the downstream target genes of PAX2. The upstream regulation mechanism of PAX2 was explored by dual luciferase reporter gene assay and bioinformatics analysis.Results showed that,no matter in vivo or in vitro,PAX2 significantly enhanced tumorigenicity and invasiveness of endometrial cancer cells, and promoted liver metastasis in vivo. In addition, PAX2 influenced the expression of cyclin-dependent kinase 1(CDK1) and YWHAZ, which play pivotal roles in cell cycle pathway. Knocking down CDK1 in PAX2 over-expressing cells attenuated cell viability.A myeloid zinc finger gene-1(MZF-1)binding site was found in a negative regulation region of PAX2 upstream and down-regulation of MZF-1 reduced the transcriptional activity of PAX2, as well as its protein level.Together, PAX2, through influencing the activity of CDK1 and YWHAZ, promotes proliferation,invasion and progression of endometrial cancer and can be regulated by MZF-1. PAX2 may be a target therapeutic site for endometrial cancer. Citation Format: Jieyu Wang, Weiwei Feng, Yinhua Yu, Kwong-Kwok Wong, Nan Jia, Tianjiao Lyu. Paired box 2 promotes progression of endometrial cancer via cell cycle pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2016.
Abstract 4031: Different expression of programmed death 1 (PD1) and its ligand (PD-L1) in esophageal and gastric cancer
Authors: Silvio Däster, Serenella Eppenberger-Castori, Raoul A. Droeser, Hannah M. Schaefer, Giulio C. Spagnoli, Luigi Terracciano, Luigi Tornillo, Urs von Holzen
Journal: Cancer Research (2016)

Abstract Background: Prognosis of gastric and esophageal cancer remains poor. Improvements in gastric and esophageal cancer treatments are urgently needed. Programmed cell death 1 receptor (PD1) and its ligand 1 (PD-L1) are known to interact with T cells promoting epithelial cancer tolerance. Several therapeutic monoclonal antibodies blocking this interaction are reaching the clinical praxis. Therefore it is relevant to investigate the role of these biomarkers in different types of malignancy. Methods: Four different copies of tissue microarrays (TMA), each including healthy mucosa (n = 74) and a total of 241 clinically annotated malignancies of the esophagus (n = 80) and stomach (n = 161) were constructed and stained with PD1, PD-L1, and CD8 specific reagents. Results: Interestingly, only two cancer samples out of the 241 specimens investigated weakly expressed PD-L1. None of the normal mucosa epithelial cells expressed PD-L1. Stromal PD1 expression correlated with infiltration by CD8+ lymphocytes (rho = 0.4; P&amp;lt;0.0001). Elevated intraepithelial presence of CD8+ and/or PD1+ cells in gastric cancer was significantly correlated with longer patients’ survival. No correlation could be found in esophageal cancer. Conclusion: In contrast to other epithelial cancers, PD-L1 expression was virtually absent in the investigated malignancies of the esophagus and stomach. PD1 expression in the stroma surrounding such malignancies correlated with intraepithelial presence of T-cells CD8+ expression, and with better prognosis in gastric cancer patients. Citation Format: Silvio Däster, Serenella Eppenberger-Castori, Raoul A. Droeser, Hannah M. Schaefer, Giulio C. Spagnoli, Luigi Terracciano, Luigi Tornillo, Urs von Holzen. Different expression of programmed death 1 (PD1) and its ligand (PD-L1) in esophageal and gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4031.
Flamsa Sequential Chemotherapy Followed By Reduced Intensity Conditioning and Allogeneic Hematopoietic Transplantation for High Risk Acute Myeloid Leukemia Patients
Authors: Mauricette Michallet, Mohamad Sobh, Marie Y. Detrait, Helene Labussiere-Wallet, Sandrine Hayette, Isabelle Tigaud, Mohamed Elhamri, Lila Gilis, Laure L Lebras, Fiorenza Barraco, Sophie Ducastelle, Valentina Bozzoli, Franck E. Nicolini, Xavier Thomas
Journal: Blood (2014)
Abstract 2795: MARVELD1 regulates hypoxia-induced oxidative stress response and tumor growth
Authors: Ming Shi, Yuanfei Yao, Yu Li
Journal: Cancer Research (2016)

Abstract Nuclear factor MARVELD1 (MARVEL domain-containing 1) is a potential tumor suppressor, which negatively regulates tumor cell proliferation. It is widely expressed in human normal tissues, but down-regulated in multiple primary carcinomas. In this study, we show that MARVELD1 acts as tumor suppressor via its ability to inhibit reative oxygen species (ROS) in response to hypoxic condition. Data showed that overexpression of MARVELD1 in uterine cancer cells significantly suppressed tumor growth, while MARVELD1 silencing promoted colony formation of tumor cells in hypoxic environment. Furthermore, we found that ROS production in hypoxia-treated cancer cells was elevated by MARVELD1 silencing. Mitochondria function assay showed that compared to RL952/vector cells, a decrease in oxygen consumption and derived mitochondrial ATP production was observed in hypoxia-treated RL952/MARVELD1 cells. Moreover, considering that ROS that induced by hypoxia promoted tumor cell proliferation, our data further indicated ROS generation that inhibited by MARVELD1 alleviated the growth of uterine tumor cells. Taken together, MARVELD1 regulated hypoxia-induced oxidative stress response and cell growth through inhibiting ROS generation in uterine cancer, suggesting that targeting MARVELD1 might be a novel strategy to cancer therapy. Keywords: MARVELD1, Hypoxia, Oxidative stress, ROS Citation Format: Ming Shi, Yuanfei Yao, Yu Li. MARVELD1 regulates hypoxia-induced oxidative stress response and tumor growth. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2795.
Effect of a novel recombinant alphaviral vector on tolerance to self-antigen in the setting of elevated regulatory T cells.
Authors: M. Morse, A. Hobeika, T. Osada, P. Berglund, S. Negri, D. Niedzwiecki, B. Hubby, B. K. Burnett, T. M. Clay, H. K. Lyerly
Journal: Journal of Clinical Oncology (2010)

2544 Background: Improving efficacy of cancer vaccines may depend on increasing the efficiency of antigen delivery to dendritic cells and overcoming suppressive cell populations such as regulatory T cells (Treg). Alphavirus vectors can efficiently infect dendritic cells, possess a natural adjuvant effect, and express high levels of protein from heterologous genes. We tested the safety, immunogenicity, and clinical efficacy of immunizations with a novel alphavirus vector encoding the tumor-associated antigen CEA (VRP-CEA(6D), AV×701) in metastatic cancer patients with high levels of Treg. Methods: Cohorts of 3-6 patients with advanced CEA- expressing malignancies who had progressed on prior therapies were enrolled at successive dosage levels (4×107, 1×108, 4×108 IU) of VRP-CEA(6D) given as 4 IM injections every 3 weeks. Dose escalation occurred if DLT occurred in <33% of patients in a given dosage level. Following establishment of safety, an additional cohort of 14 patients received VRP-CEA(6D) at the maximum tolerated dose (MTD). Treg levels and CEA-specific T cell and antibody responses were measured before and after immunization. Results: Patients had colorectal cancer (n=23), appendiceal (1), pancreas (n=1), lung (n=2), and breast (n=1) cancer, a performance status of 80-100%, and had failed a median of 4 prior chemotherapeutic regimens. DLT was not reached and the highest dose tested (4×108 IU) was determined to be the maximal feasible dose. Immunizations were well tolerated with 6 grade 3 events, all related to tumor progression, and no grade 4 events. Patients generally possessed higher blood CD4posCD25highFoxP3pos Treg cells compared to normal donors. CEA-specific T cell and antibody responses following VRP-CEA(6D) vaccination were observed regardless of patients' Treg level. There were two patients with stable disease and one with a CR of a small liver lesion. With a median follow-up of 13 months among surviving patients, 2 of 4 patients without immune response and 9 of 11 patients with immune response are alive. Conclusions: Activation of CEA-specific T cells and functional antibodies is possible using VRP-CEA(6D) despite high Treg levels in this heavily pre-treated patient population. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Alphavax Alphavax Alphavax Alphavax
From the Medical Board of the National Psoriasis Foundation: Perioperative management of systemic immunomodulatory agents in patients with psoriasis and psoriatic arthritis
Authors: Young M. Choi, Maya Debbaneh, Jeffrey M. Weinberg, Paul S. Yamauchi, Abby S. Van Voorhees, April W. Armstrong, Michael Siegel, Jashin J. Wu
Journal: Journal of the American Academy of Dermatology (2016)