tbuckley/cabot-search huggingface dataset:
Сравнительная распространенность и особенности течения неспецифического язвенного колита в странах одного географического меридиана: Украина — Тунис. Проверка гипотезы «Север — Юг»
Authors: A.E. Dorofeyev, V.I. Vdovichenko, Ya.V. Nahurna, Khaldi Hatem, A.A. Dorofeyeva
Journal: GASTROENTEROLOGY (2019)

Актуальность. Хронические воспалительные заболевания кишечника (неспецифический язвенный колит (НЯК) и болезнь Крона) относятся к тяжелым, неизлечимым страданиям, сопровождающимся в большинстве случаев потерей трудоспособности и ранней смертностью из-за их осложнений. Истинная распространенность этих заболеваний остается недостаточно изученной из-за статистической отчетности, построенной на обращаемости пациентов за медицинской помощью. Целью работы было проведение сравнительного анализа распространенности, особенностей течения и терапии НЯК в Украине и Тунисе, находящихся на одном географическом меридиане на расстоянии 1626 км. Результаты. При сравнении особенностей течения НЯК у жителей двух стран — Украины и Туниса, находящихся на одном гео­графическом меридиане и удаленных на расстояние более 1600 км, прослеживается градиентный фактор, установленный в пределах европейского континента. Это проявляется в том, что НЯК чаще страдает более молодое население Туниса (средний возраст (37,13 ± 1,24) года против (45,33 ± 1,65) года у жителей Украины); кроме того, среди больных НЯК жителей Туниса в 1,5 раза больше мужчин, чем женщин. Отмечается преобладание у пациентов Украины тотального поражения кишечника и тяжелого течения заболевания. Выводы. Таким образом, при анализе популяции пациентов с НЯК в Украине и Тунисе выявлено увеличение частоты встречаемости пациентов с НЯК в украинской популяции. Неспецифический язвенный колит у украинских пациентов имеет более распространенные формы и тяжелое течение, чем у больных из Туниса. Это связано с особенностями воздействия факторов внешней среды, генетической предрасположенностью, изменениями иммунитета и кишечного микробиома и подтверждает гипотезу «Север — Юг».
Abstract 5158: Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival
Authors: Mary C. Patton, Haseeb Zubair, Mohammad Aslam Khan, Seema Singh, Ajay P. Singh
Journal: Cancer Research (2019)

Abstract Pancreatic tumors are characterized by poor vasculature and fibrous stromal tissue networksthat create an extensive hypoxic tumor microenvironment. Extracellular vesicles (EVs) play important roles in pancreatic tumor pathobiology by supporting inter-cellular communications. They arebroadly classified into three subtypes: exosomes (Exo; 30-150 nm), microvesicles (MVs; 100 nm-1 µm) and apoptotic bodies (Abs; 1-5 µm), according to their cellular origin. Here, we studied the effect of hypoxic stress on the release kinetics and size distribution of EVs in pancreatic cancer cells. Further, we also investigated the role of different EV subtypes in adaptive survival of pancreatic cancer cells under hypoxia.Our data demonstrated that under hypoxic conditions, pancreatic cancer cells (MiaPaCa and AsPC1) shed greater amount of EVs with most noticeable changes recorded for the small size EVs. Moreover, all EVs (small, moderate, large) showed a shift towards reduced size depending upon the extent of hypoxia. When examined for subtype-specific markers, we observed mixed profiles. Thrombospondin (marker for Abs) and Arf6 (marker for MVs) were exclusively detected in large and moderate size fractions, respectively, under both normoxia and hypoxia. However, CD9 (marker for Exo) was detected in both small and moderate size EVs under hypoxia. Furthermore, in release kinetics studies we observed cyclic increases in accumulation of EV subtypes under hypoxic conditions. In addition, our data demonstrated that EVs from hypoxic cancer cells promoted survival of cancer cells under hypoxia,with small EVs being the most active. Altogether, our findings establish that hypoxia alters shedding of EVs in supporting adaptive survival of pancreatic cancer cells; associated differences could possibly be exploited for effective cancer management. Citation Format: Mary C. Patton, Haseeb Zubair, Mohammad Aslam Khan, Seema Singh, Ajay P. Singh. Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5158.
Abstract 3255: A novel small molecule inhibitor of AhR suppresses the polarization and activity of M2 macrophages
Authors: Candy Garcia, Hadia Lemar, Christina Galang, James Joseph, Marcos Gonzalez-Lopez, Jeffrey Hager, Michael P. Dillon, Fred J. Aswad
Journal: Cancer Research (2019)

Abstract Tumor associated macrophages, mainly represented by the M2-like phenotype, are a highly immunosuppressive macrophage subset that exert a pro-tumorigenic role in a variety of cancer types. Understanding the factors that promote M2 macrophage differentiation and activity is of critical importance to unlocking the potential of anti-tumor immune therapy. Thus, we investigated the role of the AhR pathway in M2 macrophages. We found the Aryl Hydrocarbon Receptor (AhR) highly expressed in in vitro polarized human M2 macrophages derived from peripheral blood mononuclear cells. Stimulation of AhR with small molecule agonists TCDD or kynurenine resulted in a significant enhancement of the suppressive activity of M2 macrophages on anti-CD3/CD28 stimulated CD4 T cell proliferation and IFNγ production. Inhibition of AhR using a novel, highly potent and selective AhR inhibitor (IDE-AhRi-1) fully inhibited the suppressive activity of M2 macrophages on T cells. Surprisingly, stimulated CD4 T cells co-cultured with IDE-AhRi-1 exposed M2 macrophages had an enhanced ability to proliferate and produce IFNγ compared with stimulated T cells in the absence of M2 macrophages. This suggests that IDE-AhRi-1 not only inhibits the suppressive mechanisms of M2 macrophages, but also boosts their ability to generate pro-inflammatory responses that enhance T-cell activity. Further studies to elucidate the AhR-driven molecular mechanisms responsible for this activity are underway. To find out whether AhR driven M2 polarization and activity is evident in human cancer, we analyzed TCGA-derived RNA sequencing data from an array of solid tumor indications. In a subset of cancer indications, high AhR activity correlated with key M2 macrophage and immuno-regulatory signature genes. Surprisingly, expression of CYP1B1 also correlated with expression of TDO2 mRNA, but not IDO1 mRNA. These finding establish AhR as a key modulator of M2 macrophages and demonstrate a correlation between AhR activity and tumor associated macrophages in human tumor samples. Furthermore, we demonstrate that IDE-AhRi-1 can potently suppress M2 macrophages and propose IDE-AhRi-1 as a novel approach for potentiating anti-tumor immunity. Citation Format: Candy Garcia, Hadia Lemar, Christina Galang, James Joseph, Marcos Gonzalez-Lopez, Jeffrey Hager, Michael P. Dillon, Fred J. Aswad. A novel small molecule inhibitor of AhR suppresses the polarization and activity of M2 macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3255.
PRDM16s transforms megakaryocyte-erythroid progenitors into myeloid leukemia–initiating cells
Authors: Tianyuan Hu, Kiyomi Morita, Matthew C. Hill, Yajian Jiang, Ayumi Kitano, Yusuke Saito, Feng Wang, Xizeng Mao, Kevin A. Hoegenauer, Kazuhiro Morishita, James F. Martin, P. Andrew Futreal, Koichi Takahashi, Daisuke Nakada
Journal: Blood (2019)
Abstract 2033: Bidirectional paracrine IL-33-TGF-beta signaling underlies a tumor-promoting stem cell niche
Authors: Naoki Oshimori, Sachiko Oshimori, Ajit Elhance, Justin Leitenberger, Sushil Kumar
Journal: Cancer Research (2019)

Abstract Malignant tumor progression and aggressive tumor recurrence after treatment are driven by subsets of cancer stem cells (CSCs), but targeting CSCs remains a major challenge due to their plasticity. CSCs in squamous cell carcinoma reside at the tumor-stromal interface, a paramount tumor microenvironment (TME) for interactive crosstalk between cancer cells and various other cells via soluble mediators, and tumor-infiltrating immune cells are pivotal regulators of tumor progression. However, the molecular link between tumor-associated immune-inflammatory responses and the regulation of CSCs are largely unknown. To define a framework of the CSC niche, we have been focusing on crosstalk between TGF-beta-activated CSCs and their neighboring immune cells. By transcriptomic analysis, we identify interleukin-33 (IL-33) as the most upregulated cytokine in TGF-beta-activated CSCs. We find that IL-33 is secreted in response to the activation of antioxidant responses, and IL-33 mobilizes a subset of tumor-promoting macrophages that express the IL-33 receptor in the adjacent stroma. Tumor-specific IL33 knockdown in vivo dampens both invasive carcinogenesis and paracrine TGF-beta signaling in tumor cells, indicating that IL-33 has a crucial role in the formation of TGF-beta-rich tumor-promoting TME by affecting tumor-infiltrating bone marrow-derived monocytes. Together, these findings on a bidirectional paracrine signaling axis provide novel insights into mechanisms of the formation a CSC privilege niche, which may hold great potential to drastically improve the therapeutic efficacy of current and future cancer treatments. Note: This abstract was not presented at the meeting. Citation Format: Naoki Oshimori, Sachiko Oshimori, Ajit Elhance, Justin Leitenberger, Sushil Kumar. Bidirectional paracrine IL-33-TGF-beta signaling underlies a tumor-promoting stem cell niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2033.
Abstract 4462: Sensitivity and reproducibility of onco-panel sequencing across multiple laboratories and technologies
Authors: Joshua Xu, Binsheng Gong, Wendell Jones, Don Johann
Journal: Cancer Research (2019)

Abstract Onco-panel sequencing targets sequencing reads to few small regions of the genome and thus is better enabled to detect of rare but clinically relevant sub-clonal mutations. Accurate diagnosis and subsequent tailoring of therapy depends on thorough characterization of tumor mutational spectra. The lack of tumor reference samples, comprehensive approaches to assessing reproducibility and detection sensitivity, and standard practice guidelines is hindering the development of onco-panel sequencing and the realization of its benefits in cancer diagnosis and treatment. As a component of the FDA-led SEQC project phase 2 (SEQC2), the Onco-panel Working Group has designed and characterized a set of reference materials. These materials were created using cell line gDNA pooling and dilution to enable such comprehensive assessments of targeted mutation detection approaches. To this end, a cross-lab evaluation of eight Pan-Cancer panels and five ctDNA liquid biopsy assays is currently underway. Each panel was tested in three independent laboratories. To further evaluate methods to boost reproducibility, synthetic spike-in controls and synthetic plasma were also incorporated into the testing samples. Contrived samples for liquid biopsy testing were prepared through enzymatic fragmentation and size selection to mimic cell-free DNA. The onco-panels tested represent two target enrichment approaches (amplicon based and capture based) and sequencing technologies (multiple Illumina platforms and Ion Torrent). Of note, the liquid biopsy assays employ various molecular barcoding techniques to improve their detection sensitivity of rare mutations. Extensive lab QC data has been collected along with sequencing data. Performance measures have been devised to evaluate reproducibility and sensitivity of the variant/mutation calling results that are produced by the panel providers. Meta-analysis of performance measures will then be conducted for cross panel comparison. This comprehensive study will yield insights into factors underpinning sensitivity and reproducibility of onco-panel sequencing. Quantitative performance metrics and actionable data analysis recommendations will be presented to the targeted sequencing panel community. Citation Format: Joshua Xu, Binsheng Gong, Wendell Jones, Don Johann, Onco-panel Working Group of the Sequencing QualityControl Phase 2 (SEQC2) Consortium. Sensitivity and reproducibility of onco-panel sequencing across multiple laboratories and technologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4462.
Abstract 4678: Targeting MEK in EGFR amplified glioma stem like cells induces differentiation
Authors: Soon Young Park, Yuji Piao, Emmanuel Martinez-Ledesma, Jianwen Dong, Sabbir Khan, Sandeep Mittal, Ze-yan Zhang, Erik P. Sulman, Veerakumar Balasubramaniyan, John F. de Groot
Journal: Cancer Research (2019)

Abstract The median survival for patients with recurrent glioblastoma is nine to twelve months highlighting the need for better therapeutic strategies for this deadly disease. The revolution in cancer genomics has identified multiple amplification events as potential targets for therapeutic intervention in many cancers including glioblastoma. Multiple factors such as incorrect patient selection, inadequate drug delivery across the blood brain barrier, acquired resistance and drug-target heterogeneity may all lead to clinical failure of targeted therapies. Receptor tyrosine kinase (RTK) signaling mediated by EGFR and PDGFR account for the core RTK signaling alterations in glioblastoma. EGFR-amplification (in ~40%) and PDGFR amplification (in ~12%) are detected in receptor tyrosine kinase- dysregulated glioblastoma. The first generation or second-generation EGFR tyrosine kinase small molecule inhibitors failed to show long term therapeutic benefit in glioblastoma patients. Through an unbiased high-throughput screen utilizing our glioma stem-like cells (GSCs) we identified that glioblastoma cells harboring EGFR amplification are uniquely vulnerable to mitogen-activated protein kinase (MEK) inhibitors. MEK inhibition induces apoptosis in EGFR amplified cells at low concentration. Furthermore, RNA sequence analysis of MEK inhibition revealed upregulation of genes related to differentiation in MEK sensitive glioma stem cells. Based upon these in vitro studies we are currently investigating MEK inhibition in a GBM xenograft mouse model. Overall our data suggest that the MEK inhibition could be a potential therapeutic target in a selective group of glioblastoma patients. Note: This abstract was not presented at the meeting. Citation Format: Soon Young Park, Yuji Piao, Emmanuel Martinez-Ledesma, Jianwen Dong, Sabbir Khan, Sandeep Mittal, Ze-yan Zhang, Erik P. Sulman, Veerakumar Balasubramaniyan, John F. de Groot. Targeting MEK in EGFR amplified glioma stem like cells induces differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4678.
Over-expression of c-MET in Biliary Tract Cancer. Prevalence and Clinical-Molecular Correlation
Authors: R. Segovia, G. Arroyo, C. Ituarte, C. Inklemona, S. Rojo, A. Salvatierra, G. Berlinghieri, S. Saucedo, M. Monteros Alvi, R. lamas
Journal: Annals of Oncology (2019)
Efficacy and time to next treatment following lenalidomide/rituximab (R<sup>2</sup>) or rituximab/placebo in patients with R/R indolent NHL (AUGMENT).
Authors: John G. Gribben, Koji Izutsu, Nathan Hale Fowler, Xiaonan Hong, Huilai Zhang, Fritz Offner, Adriana A. S. Scheliga, Grzegorz S. Nowakowski, Antonio Pinto, Francesca Re, Laura Maria Fogliatto, Phillip Scheinberg, Ian Flinn, Cláudia Moreira, Stacey Anastasia Kalambakas, Pierre Fustier, Chengqing (Alan) Wu, John Paul Leonard
Journal: Journal of Clinical Oncology (2019)

7514 Background: Relapse is expected in treated indolent lymphoma patients, and an unmet need exists to prolong remission with effective therapies. Lenalidomide + rituximab (R 2 ) may improve the efficacy of next treatment by their unique mechanisms. Methods: The AUGMENT phase III study evaluated patients with R/R FL gr 1-3a (82%) and MZL (18%) after ≥ 1 prior systemic therapy (not rituximab refractory). Randomization was 1:1 to R 2 (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles [c] + rituximab [R] IV 375 mg/m 2 /wk, c1, d1, 8, 15, 22 and c2-5, d1) and R/placebo (same dosing schedule). The primary endpoint was PFS by 2007 IWG; secondary/exploratory analyses were time to next antilymphoma/chemotherapy treatment (TTNLT/TTNCT) and response to next treatment. Per regulatory guidance, PFS2 was defined as time from randomization to first PD or death from any cause after next antilymphoma treatment, or initiation of a third antilymphoma treatment. Results: Median PFS was superior for R 2 over R/placebo (39.4 vs 14.1 mo; HR = 0.46; P &lt; 0.0001). As of 22June2018, median TTNLT, TTNCT, and PFS2 were not reached for R 2 , and were significantly longer than R/placebo (HR = 0.54, 0.50, and 0.52, respectively). For 49/178 (28%) R 2 and 80/180 (44%) R/placebo patients receiving next antilymphoma therapy, response was generally higher with R 2 (57% ORR; 31% CR) than R/placebo (36% ORR; 16% CR; Table). Conclusions: These analyses suggest that R 2 (vs R/placebo) prolonged time to subsequent treatment and is associated with longer PFS2, enabling greater response to next therapy. Although patient numbers were modest, it is hypothesized that patients who received R 2 were generally more sensitive to subsequent therapy than those treated with R/placebo. Clinical trial information: NCT01938001. [Table: see text]
Economic decline, incarceration, and mortality from drug use disorders in the USA between 1983 and 2014: an observational analysis
Authors: Elias Nosrati, Jacob Kang-Brown, Michael Ash, Martin McKee, Michael Marmot, Lawrence P King
Journal: The Lancet Public Health (2019)

BackgroundDrug use disorders are an increasing cause of disability and early death in the USA, with substantial geographical variation. We aimed to investigate the associations between economic decline, incarceration rates, and age-standardised mortality from drug use disorders at the county level in the USA.MethodsIn this observational analysis, we examined age-standardised mortality data from the US National Vital Statistics System and the Institute for Health Metrics and Evaluation, household income data from the US Census Bureau, and county-level jail and prison incarceration data from the Vera Institute of Justice for 2640 US counties between 1983 and 2014. We also extracted data on county-level control variables from the US Census Bureau, the National Center for Health Statistics, and the US Centers for Disease Control and Prevention. We used a two-way fixed-effects panel regression to examine the association between reduced household income, incarceration, and mortality from drug use disorders within counties over time. To assess between-county variation, we used coarsened exact matching and a simulation-based modelling approach.FindingsAfter adjusting for key confounders, each 1 SD decrease in median household income was associated with an increase of 12·8% (95% CI 11·0–14·6; p<0·0001) in drug-related deaths within counties. Each 1 SD increase in jail and prison incarceration rates was associated with an increase of 1·5% (95% CI 1·0–2·0; p<0·0001) and 2·6% (2·1–3·1; p<0·0001) in drug-related mortality, respectively. The association between drug-related mortality and income and incarceration persisted after controlling for local opioid prescription rates. Our model accounts for a large proportion of within-county variation in mortality from drug use disorders (R2=0·975). Between counties, high rates of incarceration were associated with a more than 50% increase in drug-related deaths.InterpretationReduced household income and high incarceration rates are associated with poor health. The rapid expansion of the prison and jail population in the USA over the past four decades might have contributed to the increasing number of deaths from drug use disorders.FundingNone.
Abstract 2692: Preclinical development of a novel, highly selective PI3Kδ inhibitor, IOA-244, for the treatment of solid malignancies
Authors: Katherine Ewings, Amy MacQueen, Pritom Shah, Anna Tsapara, Evangelia Papakonstanti, Lars van der Veen, Michael Lahn, Zoe Johnson
Journal: Cancer Research (2019)

Abstract The Class I Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family is an attractive target class for the treatment of hematological and solid malignancies. In addition to the direct effects of PI3Kδ inhibition on B cell malignancies, inhibiting PI3Kδ preferentially targets regulatory T cells and myeloid derived suppressor cells, thus breaking tumor-induced immune tolerance and restoring anti-tumor immunity. To date, the development of selective inhibitors of the Class I PI3K family has been hampered by the lack of isoform specificity as well as safety issues. IOA-244 is a novel, highly selective, orally bioavailable PI3Kδ inhibitor, with the unique property of being ATP non-competitive; these characteristics make IOA-244 the ideal drug to explore the hypothesis that PI3Kδ inhibition can modulate anti-tumor immunity as a monotherapy and in combination in clinical trials. In mouse models, IOA-244 inhibited tumor growth when combined with either anti-PD-1 or anti-PD-L1. In the CT26 model the composition of the tumour infiltrating lymphocytes showed a marked decrease in the suppressor cell populations, i.e. Tregs and MDSCs, as well as tumor associated macrophages (TAMs). Conversely a concomitant increase in natural killer cells as well as the ratio of cytotoxic CD8+ T cells: Treg cells was observed. Furthermore, in vitro studies using primary human T cells demonstrated a selective and concentration-dependent suppression of Treg cells by IOA-244 whilst leaving CD8+ T cell proliferation intact. In addition to effects on the immune system, we are exploring the potential of IOA-244 to mediate direct anti-cancer effects on solid tumors with a high expression of PIK3CD. IOA-244 induced a concentration-dependent inhibition of p-AKT in MDA-MB-231 cells. Furthermore, we demonstrate strong anti-proliferative activity by IOA-244 on hepatocellular tumor lines in vitro. Activity in these and other cell and patient derived lines is being studied, both in xenograft in vivo studies and in vitro models. Based on GLP toxicology studies, IOA-244 has the potential to be a best-in-class PI3Kδ inhibitor with a safety and pharmacokinetic profile that is amenable for use alone and in combination with immunotherapies for the treatment of solid malignancies. IOA-244 is poised to enter phase I clinical testing in selected cancer indications in the first half of 2019. Citation Format: Katherine Ewings, Amy MacQueen, Pritom Shah, Anna Tsapara, Evangelia Papakonstanti, Lars van der Veen, Michael Lahn, Zoe Johnson. Preclinical development of a novel, highly selective PI3Kδ inhibitor, IOA-244, for the treatment of solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2692.