tbuckley/cabot-search huggingface dataset:
NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model
Authors: Yan Liu, Yuyang Li, Shengwu Liu, Dennis O. Adeegbe, Camilla L. Christensen, Max M. Quinn, Ruben Dries, Shiwei Han, Kevin Buczkowski, Xiaoen Wang, Ting Chen, Peng Gao, Hua Zhang, Fei Li, Peter S. Hammerman, James E. Bradner, Steven N. Quayle, Kwok-Kin Wong
Journal: Cancer Research (2018)

Abstract Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line–derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC. Significance: These findings identify a novel therapeutic strategy for SCLC using a combination of HDAC6 and BET inhibitors. Cancer Res; 78(13); 3709–17. ©2018 AACR.
Coagulation Failure in Patients With Acute‐on‐Chronic Liver Failure and Decompensated Cirrhosis: Beyond the International Normalized Ratio
Authors: Annabel Blasi, Andrea Calvo, Verónica Prado, Enric Reverter, Juan Carlos Reverter, María Hernández‐Tejero, Fátima Aziz, Alex Amoros, Andres Cardenas, Javier Fernández
Journal: Hepatology (2018)

Balanced hemostasis with hypocoagulable and hypercoagulable features may occur in acute‐on‐chronic liver failure (ACLF). The characteristics and prognostic impact of the coagulation profile in ACLF are unknown. Consecutive patients with ACLF (n = 36) and acute decompensation (AD; n = 24) were included. Blood samples for thromboelastometry (TE) were obtained at admission and 72 hours thereafter. The coagulation profile was evaluated in patients with and without ACLF and in those with and without systemic inflammatory response syndrome. The impact of the coagulation profile on transfusion requirements, bleeding events, and short‐term survival was assessed. At admission, patients with ACLF showed more hypocoagulable characteristics compared to AD subjects, with prolonged time to initial fibrin formation and clot formation time and decreased maximum clot firmness and alpha‐angle values. TE parameters worsened at 72 hours in ACLF but improved in patients with AD. Prevalence of a hypocoagulable profile (three or more TE parameters outside range) was significantly higher in patients with ACLF either at admission (61% versus 29% in AD; P = 0.03) or during follow‐up. Hypocoagulability correlated with systemic inflammation and was associated with higher 28‐day (45% versus 16%; P = 0.02) and 90‐day (52% versus 19%; P = 0.01) mortality rates but not with transfusion requirements or bleeding. Prolonged time to initial fibrin formation (extrinsic TE assay &gt;80 seconds) and Model for End‐Stage Liver Disease score at baseline were independent predictors of 28‐day mortality. Conclusion: Patients with ACLF frequently show hypocoagulable features with prolonged time to initial fibrin formation and clot formation time and reduced clot firmness; these alterations worsen after admission, correlate with systemic inflammation, and translate into higher short‐term mortality; hypofibrinolysis could contribute to organ failure in ACLF.
Case 15-2018: An 83-Year-Old Woman with Nausea, Vomiting, and Confusion
Authors: Melissa L.P. Mattison, Victorine V. Muse, Leigh H. Simmons, Christopher Newton-Cheh, Rory K. Crotty
Journal: New England Journal of Medicine (2018)

An 83-year-old woman with a history of atrial fibrillation was admitted to the hospital because of weakness, nausea, vomiting, and diarrhea. Her family noted that she had been newly inattentive, confused, and lethargic. A diagnostic test was performed.
The Changing Treatment Landscape for Metastatic Urothelial Carcinoma
Authors: Thomas W. Flaig
Journal: Journal of the National Comprehensive Cancer Network (2018)

Urothelial carcinoma is the predominant histologic type of bladder cancer. After 30 years of minimal progress in the treatment of advanced-stage disease, recent advances in the genomic characterization of urothelial cancer and breakthroughs in bladder cancer therapeutics have rejuvenated the field. Nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab are among the exciting recent novel therapeutic advances gaining approvals by the FDA for treatment of advanced-stage urothelial carcinoma. Yet the challenge for clinicians is to determine the optimal choice of agents as first-line or second-line therapy and which offers the best chance for overall survival for the individual patient in this rapidly changing field.
Abstract 12: M6A Modification in RNA Regulates Cardiomyocyte and Cardiac Function in Heart Failure
Authors: Prabhu Mathiyalagan, Yaxuan Liang, Yassine Sassi, Erik Kohlbrenner, Jiqiu Chen, Djamel Lebeche, Maria Giovanna Trivieri, Kiyotake Ishikawa, Kenneth Fish, Roger J Hajjar, Susmita Sahoo
Journal: Circulation Research (2017)

Background: Adenosine in RNA is a substrate for addition or removal of methyl group. Reported five decades ago, methylated adenosine (m6A), the most abundant and functionally relevant chemical modification in RNA, whose transcriptome-wide mapping became possible only recently due to next generation sequencing (NGS). Coupled with NGS, m6A-methylated RNA capture (MeRIP-seq) identified widespread m6A distribution in ~8000 mRNA and ~1000 lncRNA transcripts in human and mouse transcriptome. Methods and Results: In a first of its kind approach, we examined m6A RNA methylation in both failing and non-failing hearts. We discovered that global m6A RNA methylation is significantly higher in left ventricles (LV) of failing human, swine and mouse hearts as compared to non-failing controls. Increase in m6A was associated with significantly lower expression of one of the key m6A demethylases, FTO, in the ischemic heart. siRNA-mediated silencing of FTO resulted in significant arrhythmias, loss of Ca 2+ dynamics such as Ca 2+ transient decay (Tau) and cardiomyocyte relaxation time in isolated adult rat cardiomyocytes. Conversely, FTO gene transfer reduced m6A and improved Ca 2+ transients and contractile function in primary cardiomyocytes under hypoxia. In a mouse model of MI, AAV-mediated gene transfer of FTO significantly improved cardiac function post-MI. We identified transcriptome-wide m6A distribution signatures and conserved methylated sites of several mRNAs and lncRNAs using MeRIP-seq in both human and mouse failing and non-failing LV. Detailed MeRIP map of individual transcripts identified differentially methylated 3’-UTR, 5’-UTR and exon sites within several cardiac mRNAs that are important for cardiac function. Conclusion: Our data provide first evidence that m6A modification in RNA is a regulator of cardiomyocyte Ca 2+ dynamics and cardiac function. Our findings on the dynamic nature of the cardiac m6A-epitranscriptome will add another portfolio to mRNA and lncRNA regulation of cardiac remodeling.
Characterization of genomic alterations and biomarker expression patterns of gastrointestinal cancers using a multiplatform molecular profiling tool.
Authors: Giselle Alexandra Suero-Abreu, Miguel Gonzalez Velez, Marshall McKenna, Narjust Duma, Shalini R Krishnasamy, Tracy Ann Proverbs-Singh, Martin Gutierrez
Journal: Journal of Clinical Oncology (2018)

594 Background: Given the heterogeneity of gastrointestinal cancers (GICs), molecular profiling is becoming part of the standard of care for many solid tumors. The aim of this study was to evaluate the molecular profile of patients (pts) with GICs using a multiplatform profiling tool and to assess how the pattern of detected molecular alterations could guide clinical decision-making in these tumors. Methods: We retrospectively analyzed samples of 85 pts with GICs via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) in order to evaluate clinically relevant genomic alterations (CRGAs) and clinically relevant biomarker expression (CRBs) in GICs. Results: A total of 85 pts with GICs were analyzed. 45 (53 %) were males and 40 (47%) were females. Tumors were colorectal 43 (51%), pancreatic 11 (13%) esophageal 11 (13%) gastric 8 (9%), hepatobiliary 8 (11%), anal canal 3 (4%), and small intestine 1 (1%). 80 cases (94%) had adequate sample for profiling. CRGAs were identified in 71 cases (89%) with a median of 3 CRGAs in the cohort. The most commonly detected CRGAs were TP53 45 (56%), APC 35 (44%), KRAS 32 (40%), ATM 14 (18%) and PTEN 5 (6%). The median number of CRBs was 9 and high expression levels were seen of mismatch repair biomarkers (MLH1, MSH2, MSH6, PMS2) in 45 (56%), TOPO1 in 44 (55%), PTEN in 27 (34%), TOP2A in 20 (25%), ERCC1 in 19 (24%), and both TS and TUBB3 in 17 (21%). Based on actionable CRGAs and CRBs, 94% of pts matched at least one FDA approved treatment with proven clinical benefit, with a median of 4 available therapies per pt. In addition, there was a median of 189 chemotherapy and 64 targeted therapy clinical trial opportunities available for these pts given the molecular blueprint of their GICs. Conclusions: Multiplatform molecular profiling identified a high frequency of actionable CRGAs and CRBs in GIC pts. This approach has the potential to aid in clinical decision-making by providing a stratification of beneficial therapeutic alternatives individualized to the molecular framework of tumor. Larger prospective studies are warranted to further investigate the impact of profiling guided treatment decisions on patient outcomes.
Large-scale genomic sequencing of colorectal cancer in the Japanese population.
Authors: Toshifumi Wakai, Masayuki Nagahashi, Yoshifumi Shimada, Hiroshi Ichikawa, Hitoshi Kameyama, Takashi Kobayashi, Jun Sakata, Nobuaki Sato, Hiroshi Izutsu, Keisuke Kodama, Mitsutaka Nakada, Meaghan Russell, Joerg Heyer, Winslow Powers, Ruobai Sun, Jennifer E. Ring, Shujiro Okuda, Kazuaki Takabe, Alexei Protopopov, Stephen Lyle
Journal: Journal of Clinical Oncology (2016)

e15121 Background: The advent of whole genomic sequencing has greatly facilitated the identification and characterization of cancer-relevant genes. Given the potential genetic and environmental differences between ethnic populations, it is unclear if the underlying oncogenic drivers detected by genomic profiling will be consistent across populations. CancerPlex is a large panel genomic test of 400-plus genes associated with cancer. Here we demonstrate alignment of CancerPlex with TCGA database and validate the utility of the platform. Further, we test the hypothesis that the large-scale genomic sequencing platform captures the actionable genomic driver mutations in the Japanese population. Methods: A retrospective analysis of genomic data obtained from 201 archived formalin-fixed, paraffin-embedded samples from Japanese patients with colorectal cancer (CRC) were analyzed by a large next generation sequencing panel of 415 genes including full-gene sequencing for single nucleotide polymorphisms, short insertions and deletions, and copy number variations. Mutations and frequency of variants present in key oncogenic drivers for each patient were quantified and compared to publicly available whole genome sequencing data of 489 colorectal cases in the TCGA database. Testing was performed in a CLIA-certified laboratory (KEW Group Inc., Cambridge, MA). Results: Actionable mutations were identified in > 99% of the Japanese colorectal patients. Sequencing data obtained from CancerPlex identified 60% of Japanese cases with alterations in the RTK/RAS pathways, similar to that determined in CRC cases by TCGA. Of these, 26 Japanese cases had BRAF mutations, in which only 13 harbored the V600E mutation. Additionally, 83% of Japanese cases presented with alterations in the DNA double strand break repair pathway, comparable to data obtained from TCGA demonstrating alterations in 70% cases. Conclusions: Large panel genomic profiling of CRC patients captures the actionable genomic driver mutations in the Japanese population, validating its utility in stratifying patients for therapy. In addition, significant differences in the BRAF mutation profile were detected, supporting the use of full-gene sequencing vs hot-spot testing.
Myelodysplastic syndromes current treatment algorithm 2018
Authors: David P. Steensma
Journal: Blood Cancer Journal (2018)

Myelodysplastic syndromes (MDS) include a group of clonal myeloid neoplasms characterized by cytopenias due to ineffective hematopoiesis, abnormal blood and marrow cell morphology, and a risk of clonal evolution and progression to acute myeloid leukemia (AML). Because outcomes for patients with MDS are heterogeneous, individual risk stratification using tools such as the revised International Prognostic Scoring System (IPSS-R) is important in managing patients-including selecting candidates for allogeneic hematopoietic stem cell transplantation (ASCT), the only potentially curative therapy for MDS. The IPSS-R can be supplemented by molecular genetic testing, since certain gene mutations such as TP53 influence risk independent of established clinicopathological variables. For lower risk patients with symptomatic anemia, treatment with erythropoiesis-stimulating agents (ESAs) or lenalidomide (especially for those with deletion of chromosome 5q) can ameliorate symptoms. Some lower risk patients may be candidates for immunosuppressive therapy, thrombopoiesis-stimulating agents, or a DNA hypomethylating agent (HMA; azacitidine or decitabine). Among higher risk patients, transplant candidates should undergo ASCT as soon as possible, with HMAs useful as a bridge to transplant. Non-transplant candidates should initiate HMA therapy and continue if tolerated until disease progression. Supportive care with transfusions and antimicrobial drugs as needed remains important in all groups.
杜匹鲁单抗结合伴随性局部皮质类固醇治疗对环孢素A应答不充分或不耐受或者在医学上不建议采用环孢素A治疗的过敏性皮肤炎成人患者:安慰剂对照随机阶段III临床试验(LIBERTY AD CAFÉ)
Authors: M. de Bruin-Weller, D. Thaçi, C.H. Smith, K. Reich, M. Cork, A. Radin, Q. Zhang, B. Akinlade, A. Gadkari, L. Eckert, T. Hultsch, Z. Chen, G. Pirozzi, N.M.H. Graham, B. Shumel
Journal: British Journal of Dermatology (2018)

过敏性皮肤炎(又称为AD或湿疹)是一种导致身体大部分皮肤出现瘙痒皮疹的慢性皮肤病,10名成人中就有一名患者。环孢素是常用于AD的口腔治疗药物(口服),药效不稳定,并且有严重的副作用。有时也会使用其他广泛有效的口腔药物,但这些药物未经批准用于AD。杜匹鲁单抗是一种新药物,在很多国家或地区被批准用于控制不足的中度到重度AD成人患者。杜匹鲁单抗专门作用于促进AD的身体通道。欧洲的研究人员评估了杜匹鲁单抗注射对于改善需要环孢素治疗AD,但环孢素无效果、环孢素会导致无法忍受的副作用或者医疗状况不允许使用该药物的患者的皮疹、瘙痒和日常生活的效果。在325名参与者中,110名参与者每周使用一次300 mg杜匹鲁单抗,107名参与者每两周使用一次,其余108名参与者每周使用一次安慰剂(无效药物)。在16周研究期内,所有参与者均使用了局部(用于皮肤)皮质类固醇。杜匹鲁单抗改善了AD皮疹:在第0周,参与者的湿疹面积和严重指数(EASI)分数约为31(范围:0~72),但到了第16周,使用杜匹鲁单抗的参与者中有59%到62%的人的EASI改善了至少75%,而安慰剂组参与者仅改善了29.6%。杜匹鲁单抗还改善了瘙痒、其他症状、情绪和生活质量。结膜炎和注射点反应在使用杜匹鲁单抗的患者中更频繁;皮肤感染(不包括疱疹)和AD恶化则在安慰剂组中更频繁。作者得出结论,杜匹鲁单抗结合局部皮质类固醇可显著改善AD病情,甚至是对于之前治疗失败或者无法使用环孢素的患者。
New Therapies for Ovarian Cancer
Authors: Deborah K. Armstrong
Journal: Journal of the National Comprehensive Cancer Network (2018)

In the latest NCCN Guidelines for Ovarian Cancer, the histologic subtypes of ovarian cancer are described in more depth as they vary by frequency, typical age and disease stage at presentation, treatment recommendations, and survival probabilities. The less common subtypes are also discussed. The update with the greatest impact on the treatment of ovarian cancer, however, is probably the use of maintenance therapy with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, and 3 PARP inhibitors are now included in the guidelines. These drugs have made a large difference in outcome, both for patients with BRCA mutations and in unselected patients.
Effects of Antitumor Compounds and Radiation on the Glycolysis and Respiration of Ascites-Tumor Cells
Authors: Toshiaki Ebina, Moriji Kurosu
Journal: JNCI Journal of the National Cancer Institute (1958)

Journal Article Effects of Antitumor Compounds and Radiation on the Glycolysis and Respiration of Ascites-Tumor Cells Get access Toshiaki Ebina, Toshiaki Ebina Search for other works by this author on: Oxford Academic PubMed Google Scholar Moriji Kurosu Moriji Kurosu Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 20, Issue 6, June 1958, Pages 1023–1036, https://doi.org/10.1093/jnci/20.6.1023 Published: 01 June 1958 Article history Received: 10 September 1957 Published: 01 June 1958
PTU-016 Using the multi-assistant rating scale (mars) tool to assess endoscopic non-technical skills (ents) performance in independently practising endoscopists
Authors: N Hawkes, F Kokwara, B Davies, J Cornish
Journal: Gut (2017)

Introduction  Endoscopists regularly appraise the technical aspects of their performance as part of the delivery of a high-quality endoscopy service. Patient outcomes are however linked to team performance and the measurement of Endoscopic Non-Technical Skills (ENTS) may highlight areas where endoscopists can further improve their skills. We used the novel Multi-Assessor Rating Scale (MARS) to provide a 360 degree assessment of ENTS skills and performance enhancing feedback for endoscopists.  Method  The MARS tool was used to rate nine colonoscopists who had consented to the assessment. This validated questionnaire comprises 10 items in each of 4 ENTS domains – Communication (COMM), Situational Awareness (SITA), Leadership (LEAD) and Judgement and Decision-making (J and DM). Each question is assessed on a seven point rating scale – these responses were then given a binary coding of good [GD] (very strong to quite strong rating) and need improvement [NI] (neutral to very poor ratings) which increases intra-rater reliability. A threshold of 90% good (GD) ratings in each ENTS domain was set as a performance standard. A report format was developed to provide the endoscopist with the percentage GD ratings in each ENTS domain as a graphic display, providing a comparison of their ratings against peers. Analysis of differences in proportion of GD/NI ratings was analysed using Kruskal-Wallis test.  Results  9 endoscopists were assessed using the MARS tool. Each was rated by 10 nurse (90 assessments, based on 40 item scores). 5 colonoscopists met the performance standard of 90% in all 4 ENTS domains, 1 colonoscopist met the standard in the COMM, SITA and J and DM domains but did not meet the standard in the LEAD domain. The remaining 3 colonoscopists failed to meet the performance standards in all 4 ENTS domain. Compared to the other colonoscopists their scores were significantly lower in the COMM and LEAD domains (both Kruskal-Wallis H=7.107, p 90%, AMBER=80–90, RED   Conclusion  The MARS tool is a practical 360-degree assessment to measure of ENTS performance. Using 10 raters we demonstrated significant differences in performance in these domains and to provide performance enhancing feedback to endoscopists. A follow-up study is underway to provide further validation data and assess the effects of ENTS training interventions on MARS scores.  Disclosure of Interest  None Declared
Abstract 17150: Prognostic Significance of QT Interval Dispersion in the Response to Intravenous Immunoglobulin Therapy in Kawasaki Disease
Authors: Noriko Motoki, Yohei Akazawa, Shoko Yamazaki, Akira Hachiya, Hirohiko Motoki, Satoshi Matsuzaki, Kenichi Koike
Journal: Circulation (2016)

Introduction:  Increased QT interval dispersion (QTD) has been shown to reflect cardiac instability in several cardiovascular diseases. QTD has been associated with cardiac involvement and disease activity in patients with cardiovasculitis, such as SLE.   Hypothesis:  We hypothesize that QTD could assess disease severity in Kawasaki disease (KD).   Methods:  QTD was recorded in 86 patients with KD before intravenous immunoglobulin (IVIG) therapy, who were separated into IVIG responders (R group; n=62; median age: 2.0 ± 1.8 years) and non-responders (N group; n=24; median age: 3.2 ± 1.9 years). The association between baseline QTD and response to IVIG was investigated, and the predictive response value was compared with established risk scores from Gunma and Kurume universities.   Results:  Baseline QTD and corrected QTD with Bazzet’s (QTbcD) and Fridericia’s formulae (QTfcD) were significantly increased in the N group (R group vs. N group: 20.0 ± 23.1 ms vs. 41.3 ± 13.0 ms, 31.6 ± 35.2 ms vs. 64.3 ± 18.9 ms and 27.4 ± 30.8 ms vs. 55.5 ± 16.6 ms, respectively, both P   Conclusion:  QTD was significantly associated with a response to IVIG in KD and may represent a useful identifier of IVIG non-responders with severe vasculitis and high risk of coronary aneurysm.
Patterns of care study of adult medulloblastoma.
Authors: Rasha Cosman, Chris Brown, Kevin DeBraganca, Mustafa Khasraw
Journal: Journal of Clinical Oncology (2013)

2086 Background: Medulloblastoma (MB) accounts for less than 1% of adult intracranial tumours. While pediatric MB has been investigated in several randomized studies, the evidence in adults is limited to case reports and retrospective series, with no accepted standard of care. The Australian Cooperative Trials Group for Neuro-Oncology (COGNO) sought to determine the range and consistency of clinicians’ approaches to management as a basis for future trials. Methods: We aimed to identify current treatment strategies for adult MB through an international electronic survey launched at the 2012 meeting of the Society of Neuro-Oncology and by email invitation. Clinicians who had treated at least 1 adult patient with MB, central primitive neuroectodermal tumor (cPNET), or pinealoblastoma in the preceding year were asked about their most recent patient and asked to discuss their approach to management of a typical clinical scenario. Results: Between Nov 2012 and Jan 2013, 45 clinicians (11 medical oncologists, 7 radiation oncologists, 5 pediatric oncologists, and 22 others) from Australia (n = 24), USA (n = 3), Europe (n = 4) and other countries (n = 14) completed the survey. Responding clinicians had treated 54 cases in the past 12 months. The commonest histological type was MB (64%), followed by cPNET (20%). Most patients were male (68%), and most had high-risk disease (65%). 56% had complete surgical resection and 32% had molecular testing. Radiotherapy was predominantly craniospinal (92%) and mostly post-resection (80%). Combination chemotherapy was more common than single agent. Vincristine, cisplatin, cyclophosphamide was the most common protocol (43%). Others included carboplatin, etoposide, ifosfamide (29%), vincristine, lomustine, cisplatin (19%), vincristine, lomustine, prednisone (5%). Further details will be presented at the 2013 ASCO Annual Meeting. Conclusions: Our study has shown substantial international variation in the treatment of adult MB, most pronounced in the choice of chemotherapeutic agents, highlighting the need for further collaborative research to guide evidence-based treatment strategies.
Abstract 17042: Unique Hemodynamic Parameters Predict GI Bleeding in Patients With Continuous Flow Ventricular Assist Devices
Authors: Joanna M Joly, Ashraf EL-Dabh, Robert N Brown, James K Kirklin, Ramey Marshell, Arka Chatterjee, Michelle G Smith, Margaret A Tresler, Jose A Tallaj, Deepak Acharya, Salpy V Pamboukian
Journal: Circulation (2016)

Introduction: Gastrointestinal (GI) bleeding remains a major morbid event during continuous flow left ventricular assist device (LVAD) support. Hypothesis: This study investigated whether a common ...