tbuckley/cabot-search huggingface dataset:
Author Correction: Linkage disequilibrium–dependent architecture of human complex traits shows action of negative selection
Authors: Steven Gazal, Hilary K. Finucane, Nicholas A. Furlotte, Po-Ru Loh, Pier Francesco Palamara, Xuanyao Liu, Armin Schoech, Brendan Bulik-Sullivan, Benjamin M. Neale, Alexander Gusev, Alkes L. Price
Journal: Nature Genetics (2019)
The G20 and development assistance for health: historical trends and crucial questions to inform a new era
Authors: Joseph L Dieleman, Krycia Cowling, Irene A Agyepong, Sarah Alkenbrack, Thomas J Bollyky, Jesse B Bump, Catherine S Chen, Karen A Grépin, Annie Haakenstad, Anton C Harle, Jennifer Kates, Rouselle F Lavado, Angela E Micah, Trygve Ottersen, Ajay Tandon, Golsum Tsakalos, Junjie Wu, Yingxi Zhao, Bianca S Zlavog, Christopher J L Murray
Journal: The Lancet (2019)
Abstract LB-104: Epigenetic and transcriptional alterations as potential vulnerabilities of diffuse intrinsic pontine glioma (DIPG)
Authors: Jia-Ray Yu, Gary LeRoy, James Stafford, Chul-Hwan Lee, Danny Reinberg
Journal: Cancer Research (2019)

Abstract A methionine substitution at lysine-27 on histone H3 variants (H3K27M) is present in more than 80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. We discovered that a number of parameters were involved in H3K27M-dependent inhibition of PRC2, including the ratio between H3K27M and PRC2 present in vivo, an enhanced affinity between H3K27M and the allosterically activated state of PRC2, and the displacement of PRC2 from chromatin containing H3K27M. Following these early events upon an introduction of H3K27M into wildtype cells, the steady-state chromatin manifested a global loss of H3K27 methylation but a gain of H3K36 methylaiton, an antagonistic histone modification associated with transcriptional elongation. These observations suggested that H3K36 methylation may function in displacing PRC2 from chromatin and the oncogenic transcription facilitated by H3K36 methylation could be a vulnerability of H3K27M DIPG. Indeed, ectopic expression of H3K36M in H3K27M DIPG cells depleted global H3K36 methylation and exerted an anti-proliferative effect, implicating a potential strategy in targeting the writer and reader proteins for H3K36 methylation against H3K27M DIPG. Citation Format: Jia-Ray Yu, Gary LeRoy, James Stafford, Chul-Hwan Lee, Danny Reinberg. Epigenetic and transcriptional alterations as potential vulnerabilities of diffuse intrinsic pontine glioma (DIPG) [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 LB-104.
Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Ameliorate Graft-Versus-Host Disease-Related Manifestations
Authors: Sumie Fujii, Yasuo Miura, Aya Fujishiro, Takero Shindo, Yutaka Shimazu, Hideyo Hirai, Akifumi Takaori-Kondo, Tatsuo Ichinohe, Taira Maekawa
Journal: Blood (2017)
Abstract 19074: NPPA Overexpression in Mice Increases Susceptibility to Atrial Fibrillation
Authors: Eleonora S Galimberti, Prince Kannankeril, Kaylen Kor, Raafia Muhammad, Marcia Blair, Dawood Darbar
Journal: Circulation (2012)

Introduction: Mutations in natriuretic peptide precursor A (NPPA) gene, which encodes atrial natriuretic peptide (ANP), have been linked with familial atrial fibrillation (AF). Although the precise mechanism by which NPPA mutations cause AF remains unclear, a shortening of the atrial action potential was demonstrated in an isolated rat heart model. Here, we overexpressed NPPA in a mouse model testing the hypothesis that these mice would be more susceptible to AF. Methods: A triple FLAG-tag (FLAG) was fused in-frame with the 3’ end of the either the wild-type (WT) human NPPA (WT-NPPA-FLAG) cDNA or the mutant NPPA peptide containing the COOH-terminal 12 amino acid extension (mut-NPPA-FLAG) isolated from individuals with familial AF. The FLAG-tag does not diminish NPPA biological activity. The expression of the mutated protein was confirmed by measuring mRNA by polymerase-chain reaction (PCR). We used transesophageal atrial pacing (15 second bursts from 50 to 15 ms) to assess inducibility and duration of AF. Results: Serial weekly transesophageal pacing starting at 16 weeks of age was performed in WT-NPPA-FLAG and mut-NPPA-FLAG mice. Mut-NPPA-FLAG mice had inducible AF at 16 weeks of age in 61±0.1% compared to WT-NPPA-FLAG (n=6 mice, P&lt;0.05). In addition, induced AF was longer lasting in the mut-NPPA-FLAG as compared to WT (AF burden: 19.2±2.9 [mut] sec vs. 12±4.1 s [WT], P&lt;0.05). Conclusions: We show that humanized NPPA overexpression mice are more susceptible to AF with longer AF episodes compared with WT using esophageal pacing.
Abstract 111: Tumor microenvironment derived NRG1 promotes antiandrogen resistance in prostate cancer
Authors: Zeda Zhang, Wouter Karthaus, Jose Mauricio Mota, Ping Mu, Chao Wu, Wassim Abida, Eliot Linton, Young Sun Lee, Eugine Lee, Ninghui Mao, Elizabeth Adams, Danielle Choi, Dana E. Rathkopf, Brett Carver, Anuradha Gopalan, Xuejun Jiang, Philip Watson, Charles Sawyers
Journal: Cancer Research (2019)

Abstract Despite the improved clinical outcomes for patients with advanced prostate cancer due to the use of second generation antiandrogens, acquired drug resistance inevitably occurs and remains the major challenge for prostate cancer therapy. While several cell-autonomous mechanisms of drug resistance have been elucidated previously, for a large number of patients the mechanism of resistance remains unclear. Recent studies point to the importance of the tumor microenvironment (TME), and cancer associated fibroblasts (CAF) in the TME, in mediating tumor progression and resistance to therapy, but whether CAFs specifically contribute to antiandrogen resistance in prostate cancer is not known. Using a preclinical model that faithfully mimics the typical progression of patients on antiandrogen therapy, we found that antiandrogen resistance develops significantly faster when cells are grown in the presence of their cognate CAFs. By carrying out biochemical purification and mass spectrometry analysis, we identified NRG1 as a CAF secreted factor, and found that it can promote antiandrogen resistance in tumor cells, via activation of HER3 in the tumor. Importantly, blocking either NRG1 or HER3 can re-sensitize tumors to antiandrogen treatment in this model. Moreover, NRG1 expression is up-regulated in CAFs after antiandrogen exposure or in androgen deprivation condition. Clinically, increased stroma-NRG1 expression was observed in patients post androgen deprivation therapy but not in hormonally intact men. Taken together, this work has revealed a novel, NRG1-mediated non-cell autonomous mechanism of antiandrogen resistance in prostate cancer, and suggests that therapeutically targeting NRG1 in the setting of metastatic, antiandrogen-resistant prostate cancer with elevated NRG1 could provide significant benefit to patients. Note: This abstract was not presented at the meeting. Citation Format: Zeda Zhang, Wouter Karthaus, Jose Mauricio Mota, Ping Mu, Chao Wu, Wassim Abida, Eliot Linton, Young Sun Lee, Eugine Lee, Ninghui Mao, Elizabeth Adams, Danielle Choi, Dana E. Rathkopf, Brett Carver, Anuradha Gopalan, Xuejun Jiang, Philip Watson, Charles Sawyers. Tumor microenvironment derived NRG1 promotes antiandrogen resistance in prostate cancer [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 111.
Pretransplant hemoglobin and serum creatinine levels correlate with progression free survival in myeloma patients undergoing autologous stem cell transplantation.
Authors: Taner Demirer, Guldane Cengiz Seval, Selami Kocak Toprak, Sinem Civriz Bozdag, Meltem Kurt Yuksel, Pervin Topcuoglu, Onder Arslan, Muhit Ozcan, Hamdi Akan, Osman Ilhan, Meral Beksac, Gunhan Gurman
Journal: Journal of Clinical Oncology (2019)

e19532 Background: High dose melphalan and autologous stem cell transplantation (ASCT) significantly prolong survival for patients with multiple myeloma (MM). The purpose of this study is to assess the effects of hemoglobin (Hgb) and serum creatinine (Crea) values at the time of transplantation on the overall outcome of patients with multiple myeloma treated at our transplant center. Material &amp; Methods: This analysis included 247 consecutive patients who underwent ASCT for MM between 2010-2016. Hemoglobin was grouped as low or high relative to their sample median. Patients were also stratified according to serum Crea value at the time of transplantation ( &lt; 2 or ³2 mg/dl). Results: The median age was 57 (29-75) years and most patients were male (n = 151, 61.1%), IgG subtype (n = 124, 50.2%), and ISS stage 3 (n = 122, 49.4%). The interval from the time of diagnosis to ASCT was median 7 months and median follow-up from ASCT was 49 months (range, 3-198 months). The most commonly induction regimens included VAD (vincristine, doxorubicin and dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone), respectively. Since maintenance was not an approved treatment in myeloma most patients did not receive any. For the entire cohort, the median Hgb and Crea were 11.5 g/dL and 0.9 mg/dL respectively. No difference in progression free survival (PFS) was observed between a lower and higher Hgb (82 vs. 81 months, p = 0.96). However, the median PFS was significantly longer in patients with a lower Crea compared to those with a higher Crea (83 vs. 48 months, p = 0.01). Patients with both a lower hemoglobin and higher Crea experienced shorter PFS compared to those with a higher hemoglobin and lower Crea (45 vs. 82 months, p &lt; 0.001). We failed to demonstrate the impact of creatinin levels on time to neutrophil and platelet engraftment. There were no differences in OS according to lower vs. higher Hgb (58 vs. 52 months; p = 0.29, respectively) but in higher crea cohort worse OS was observed (41 months vs. 57 months; p = 0.02, respectively). Conclusions: We demonstrate that hemoglobin and creatinine represent important determinants of clinical outcomes after ASCT. A lower hemoglobin and higher creatinine, individually and when combined, were associated with shorter PFS. Therefore, further studies of larger randomized cohorts are required to clarify the impact of pre-transplant Hgb and Crea levels on ASCT outcomes.
Abstract 16086: Spectrum of Imaging Findings on Cardiac MR in Subjects with an Arrythmogenic Right Ventricular Cardiomyopathy-Associated Gene Mutation
Authors: Neda Rastegar, jeremy R Burt, Celia P Coronal Villalobos, Anneline S Te Riele, Cynthia James, Brittney Murray, Hugh Calkins, Harikrishna Tandri, Aditya Bhonsale, David Bluemke, Stefan L Zimmerman, Ihab R Kamel
Journal: Circulation (2012)

Introduction: Arrythmogenic right ventricular cardiomyopathy (ARVC) is thought to predominantly affect the right ventricle. Our objective was to evaluate the incidence and extent of both right and ...
Abstract 3661: GLI1 contributes to proliferation, survival and drug-resistance of Ewing sarcoma (EWS) cells
Authors: Joon Won Yoon, Marilyn Lamm, Philip Iannaccone, David Walterhouse
Journal: Cancer Research (2019)

Abstract Ewing sarcoma (EWS) is characterized by TET-ETS fusions, most commonly the EWSR1-FLI1 fusion. GLI1, a transcription factor in the Hedgehog (HH) signal transduction pathway and target of canonical HH signaling, is a direct transcriptional target of EWSR1-FLI1. A role for the HH signaling pathway and GLI1 in acquisition of a multidrug resistance phenotype has been previously observed in several human cancers. The role of the HH signal transduction pathway and GLI1 in the biology of EWS remains incompletely understood. We hypothesize that the majority of EWS cell lines express GLI1 based on non-canonical up-regulation by EWSR1-FLI1 and that further up-regulation of GLI1 may be associated with the development of drug resistance. Here, we show that EWS cell lines (CHLA-9, CHLA-10, CHLA-258, TC-32 and TC-71) express canonical HH pathway components (PTCH1, SMO, GLI1 and GLI3) and that cells lines established at the time of recurrence have higher GLI1 expression (CHLA-258 and TC-71) than those established at the time of diagnosis (CHLA-9, CHLA-10 and TC-32). Exposure to Sonic HH ligand in order to activate canonical HH signaling did not affect cell viability (MTT assay), proliferation (BrdU assay), or apoptosis (caspase 3/7 assay). However, inhibition of GLI1 activity with GANT61 reduced GLI1 expression (qRT PCR), cell viability (MTT assay) and cell proliferation (BrdU assay) but increased apoptosis (caspase 3/7 assay) and sensitivity of the cells to vincristine (VCR) (MTT assay), suggesting GLI1 plays roles in each of these processes. We then established VCR-resistant EWS cell lines (TC-71 [45-fold increase in the IC-50] and TC-32 [27-fold increase in the IC-50]) by exposing cells to serially increasing concentrations of VCR. We used an 86-gene cancer drug resistance PCR array (Qiagen) to characterize gene expression differences between untreated vs. recurrent EWS cell lines and between parental vs. VCR-resistant EWS cell lines. Among the changes in gene expression, we showed higher GLI1 expression in the recurrent EWS cell lines (CHLA-258 cells [4.8-fold] and TC-71 [3.4-fold]) vs. untreated CHLA-9 cells, and in VCR-resistant TC-71 cells (2.2-fold) vs. parental TC-71 cells. Down-regulation of GLI1 by GANT61 or GLI1 siRNA enhanced sensitivity of the cells to VCR. Our results suggest that GLI1 expression contributes to proliferation, survival and drug-resistance of EWS cell lines. Strategies to inhibit GLI1 may have therapeutic benefit in EWS. Citation Format: Joon Won Yoon, Marilyn Lamm, Philip Iannaccone, David Walterhouse. GLI1 contributes to proliferation, survival and drug-resistance of Ewing sarcoma (EWS) cells [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 3661.
Olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer: phase III POLO trial
Authors: T. Golan, P. Hammel, M. Reni, E. Van Cutsem, T. Macarulla, M. Hall, J. Park, D. Hochhauser, D. Arnold, D. Oh, A. Reinacher-Schick, G. Tortora, H. Algül, E. O’Reilly, D. McGuinness, K. Cui, K. Schlienger, G. Locker, H. Kindler
Journal: Annals of Oncology (2019)
Using Real-World Data to Predict Findings of an Ongoing Phase IV Cardiovascular Outcome Trial: Cardiovascular Safety of Linagliptin Versus Glimepiride
Authors: Elisabetta Patorno, Sebastian Schneeweiss, Chandrasekar Gopalakrishnan, David Martin, Jessica M. Franklin
Journal: Diabetes Care (2019)

OBJECTIVE Using real-world data (RWD) from three U.S. claims data sets, we aim to predict the findings of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) comparing linagliptin versus glimepiride in patients with type 2 diabetes (T2D) at increased cardiovascular risk by using a novel framework that requires passing prespecified validity checks before analyzing the primary outcome. RESEARCH DESIGN AND METHODS Within Medicare and two commercial claims data sets (May 2011–September 2015), we identified a 1:1 propensity score–matched (PSM) cohort of T2D patients 40–85 years old at increased cardiovascular risk who initiated linagliptin or glimepiride by adapting eligibility criteria from CAROLINA. PSM was used to balance &amp;gt;120 confounders. Validity checks included the evaluation of expected power, covariate balance, and two control outcomes for which we expected a positive association and a null finding. We registered the protocol (NCT03648424, ClinicalTrials.gov) before evaluating the composite cardiovascular outcome based on CAROLINA’s primary end point. Hazard ratios (HR) and 95% CIs were estimated in each data source and pooled with a fixed-effects meta-analysis. RESULTS We identified 24,131 PSM pairs of linagliptin and glimepiride initiators with sufficient power for noninferiority (&amp;gt;98%). Exposure groups achieved excellent covariate balance, including key laboratory results, and expected associations between glimepiride and hypoglycemia (HR 2.38 [95% CI 1.79–3.13]) and between linagliptin and end-stage renal disease (HR 1.08 [0.66–1.79]) were replicated. Linagliptin was associated with a 9% decreased risk in the composite cardiovascular outcome with a CI including the null (HR 0.91 [0.79–1.05]), in line with noninferiority. CONCLUSIONS In a nonrandomized RWD study, we found that linagliptin has noninferior risk of a composite cardiovascular outcome compared with glimepiride.
Indication and results of surgery following imatinib treatment of locally advanced or metastatic GI stromal tumors (GIST)
Authors: P. Hohenberger, C. Langer, S. Pistorius, I. Iesalnieks, E. Wardelmann, P. Reichardt
Journal: Journal of Clinical Oncology (2006)

9500 Background: Imatinib mesylate efficiently induces tumor remission in advanced GIST however the curve of progression-free survival (PFS) in the large randomised trials does not reach a plateau. Surgery after achieving a PR is often recommended to remove tumor remnants or seems to be the treatment of choice to control tumor progression not or no longer controlled by drugs. The true impact of surgery is unclear and we analysed the indication and outcome of resective procedures including patients treated outside randomised trials. Patients: In a multi-institutional setting, we collected data from 113 patients after surgery for histologically confirmed GIST after imatinib treatment since April 2002. Primary tumor location: esophagus 3, stomach 23, small bowel 46, rectum 21, extraintestinal 20 pts. Indication for resection: to remove remnants of tumor sites responding well to imatinib 44 pts, resection of progressive lesions 55 pts, resection of a primary tumor after intended neadjuvant treatment 14 pts. Median duration of imatinib treatment prior to surgery was 11 (7–30) months for responding tumors, 14 months (4–28) for progressive lesions and 7 months (3–14) in the neoadjuvant group. Results: Median follow-up postoperatively is 16 months. Operative procedures: hepatic resection 13 pts., abdomino-perineal excision/anterior resection 27 pts, multivisceral resection 73 pts, peritoneal debulking 31 pts. An R0 resection could be achieved in 72% in the PR group, 86% in the neoadjuvant group, but only 26% in the progression group, postop. mortality was 1.7%. Median PFS in the R0 group is 16 (7-39) months and 7 months (2-25±) in the progressive group. In 14 pts imatinib treatment was not continued after R0 resection, 8 pts developed a recurrence. Conclusion: Progression-free survival after R0 resection of responding GIST is encouraging and the data could be used for planning a randomized trial of delayed vs. immediate resection in responding lesions after criteria ‘best response’ are agreed upon. Outside a trial, GIST patients developing a good PR with imatinib should be evaluated for resection as early as possible. However, even patients with a limited number of progressive lesions may benefit from surgery for a longer duration of time. [Table: see text]
Abstract 2556: Enhanced expression of human cyclin G1 (CCNG1) gene in metastatic cancer, a novel biomarker in development for CCNG1 inhibitor therapy
Authors: Erlinda M. Gordon, Christopher Szeto, Joshua R. Ravicz, Sandeep Reddy, Michael Morse, Sant Chawla, Frederick Hall
Journal: Cancer Research (2019)

Abstract Background: Metastatic cancer is associated with, hitherto, an invariably fatal outcome. DeltaRex-G, a CCNG1 inhibitor, has induced long term (9-12 year-) survivorship in patients with metastatic melanoma, sarcoma, lymphoma and cancer of pancreas and breast. Purpose: To evaluate CCNG1 expression in tumors as a novel biomarker for identification of patients who are likely to benefit from CCNG1 inhibitor therapy. Methods: RNA sequence analysis was used to compare CCNG1 expression in tumor (TCGA, N=9161) versus normal tissues (TGCA, N=678 and GTEx, N=7187) from 20 organ sites, and in primary vs metastatic melanoma (N=106 &amp; 367 respectively). Using IHC staining, the significance of differences between the number of CCNG1+ and Ki-67+ cells in normal tissues vs tumors were evaluated using paired Student’s t test. Pearson’s coefficient of correlation was used to evaluate the relationship between the number of Ki-67+ vs CCNG1+ cells. Results: CCNG1 gene expression, by RNA sequence analysis, was significantly enhanced in melanoma, sarcoma, leukemia, and cancers of the lung, thyroid, brain, liver, prostate, testicle, head and neck, bladder, kidney, adrenal, cervix, and pancreas, compared to normal tissues (p = 0.006- 1.8E-58), and even greater, in metastatic vs primary melanoma. In a subset of melanoma tumors, there was overall positive correlation with progression/metastasis in both Ki67 and CCNG1 expression levels. Consistent with these findings, IHC showed significant differences when comparing CCNG1 nuclear staining percentages between analogous healthy and cancerous tissues (p = 0.002, df = 11). The nuclear staining percentages of CCNG1 and Ki-67 share a statistically significant, positive correlation (r = .936977, p &amp;lt; 0.00001). Further, in some patients, the level of CCNG1 expression by IHC fluctuated over time. Conclusion: Taken together, these data indicate that (1) CCNG1 expression, is frequently enhanced in cancerous tumors compared to their normal analogous counterparts, and (2) the level of CCNG1 expression may change over time, necessitating real time analysis in order to determine the optimal timing for CCNG1 inhibitor therapy. A Phase 2 basket study of DeltaRex-G cell cycle checkpoint inhibitor therapy is planned to correlate treatment outcome parameters with CCNG1 expression in patients’ tumors and circulating tumor cells. Citation Format: Erlinda M. Gordon, Christopher Szeto, Joshua R. Ravicz, Sandeep Reddy, Michael Morse, Sant Chawla, Frederick Hall. Enhanced expression of human cyclin G1 (CCNG1) gene in metastatic cancer, a novel biomarker in development for CCNG1 inhibitor therapy [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 2556.