tbuckley/cabot-search huggingface dataset:
Phase I Study of Chimeric Antigen Receptor–Modified T Cells in Patients with EGFR-Positive Advanced Biliary Tract Cancers
Authors: Yelei Guo, Kaichao Feng, Yang Liu, Zhiqiang Wu, Hanren Dai, Qingming Yang, Yao Wang, Hejin Jia, Weidong Han
Journal: Clinical Cancer Research (2017)

Abstract Purpose: This study is an expanded and parallel clinical trial of EGFR-specific chimeric antigen receptor–engineered autologous T (CART) cell immunotherapy (NCT01869166) to assess the safety and activity of CART-EGFR cell therapy in EGFR-positive advanced unresectable, relapsed/metastatic biliary tract cancers (BTC). Experimental Design: Patients with EGFR-positive (&amp;gt;50%) advanced unresectable, relapsed/metastatic BTCs were enrolled. Well-produced CART-EGFR cells were infused in a manner of dose escalation after the conditioning treatment with nab-paclitaxel (100–250 mg/m2) and cyclophosphamide (15–35 mg/kg). Results: A total of 19 patients (14 cholangiocarcinomas and 5 gallbladder carcinomas) received one to three cycles of CART-EGFR cell infusion (median CART cell dose, 2.65 × 106/kg; range, 0.8–4.1 × 106/kg) within 6 months. The CART-EGFR cell infusion was tolerated, but 3 patients suffered grade ≥3 acute fever/chill. Grade 1/2 target-mediated toxicities including mucosal/cutaneous toxicities and acute pulmonary edema and grade ≥3 lymphopenia and thrombocytopenia related to the conditioning treatment were observed. Of 17 evaluable patients, 1 achieved complete response and 10 achieved stable disease. The median progression-free survival was 4 months (range, 2.5–22 months) from the first cycle of treatment. Analysis of data indicated that the enrichment of central memory T cells (Tcm) in the infused CART-EGFR cells improved the clinical outcome. Conclusions: The CART-EGFR cell immunotherapy was a safe and active strategy for EGFR-positive advanced BTCs. The enrichment of Tcm in the infused CART-EGFR cells could predict clinical response. Clin Cancer Res; 24(6); 1277–86. ©2017 AACR. See related commentary by Kalos, p. 1246
Abstract 18909: Poly-ADP-Ribose Polymerase (PARP) Inhibition Enhances Ischemic/Diabetic Wound Healing by Promoting Angiogenesis Through FOSL1
Authors: Darshan K Patel, Xin Zhou, Adam Friedman, Anton Sidawy, Lopa Mishra, Sabyasachi Sen, Bao-Ngoc Nguyen
Journal: Circulation (2016)

Introduction: Amputations resulting from poor perfusion associated with ischemic/diabetic wounds is a major health problem globally. To improve upon limb-salvage therapeutics, a better understandin...
Intron retention enhances gene regulatory complexity in vertebrates
Authors: Ulf Schmitz, Natalia Pinello, Fangzhi Jia, Sultan Alasmari, William Ritchie, Maria-Cristina Keightley, Shaniko Shini, Graham J. Lieschke, Justin J-L Wong, John E. J. Rasko
Journal: Genome biology (2017)

While intron retention (IR) is now widely accepted as an important mechanism of mammalian gene expression control, it remains the least studied form of alternative splicing. To delineate conserved features of IR, we performed an exhaustive phylogenetic analysis in a highly purified and functionally defined cell type comprising neutrophilic granulocytes from five vertebrate species spanning 430 million years of evolution. Our RNA-sequencing-based analysis suggests that IR increases gene regulatory complexity, which is indicated by a strong anti-correlation between the number of genes affected by IR and the number of protein-coding genes in the genome of individual species. Our results confirm that IR affects many orthologous or functionally related genes in granulocytes. Further analysis uncovers new and unanticipated conserved characteristics of intron-retaining transcripts. We find that intron-retaining genes are transcriptionally co-regulated from bidirectional promoters. Intron-retaining genes have significantly longer 3′ UTR sequences, with a corresponding increase in microRNA binding sites, some of which include highly conserved sequence motifs. This suggests that intron-retaining genes are highly regulated post-transcriptionally. Our study provides unique insights concerning the role of IR as a robust and evolutionarily conserved mechanism of gene expression regulation. Our findings enhance our understanding of gene regulatory complexity by adding another contributor to evolutionary adaptation.
Evaluation of the impact of concomitant fibromyalgia on TNF alpha blockers’ effectiveness in axial spondyloarthritis: results of a prospective, multicentre study
Authors: Anna Moltó, Adrien Etcheto, Laure Gossec, Nadia Boudersa, Pascal Claudepierre, Nicolas Roux, Lucie Lemeunier, Antoine Martin, Lartitia Sparsa, Pascal Coquerelle, Martin Soubrier, Serge Perrot, Maxime Dougados
Journal: Annals of the Rheumatic Diseases (2017)

To describe the prevalence of fibromyalgia (FM) in an axial spondyloarthritis (axSpA) population and to confirm that concomitant FM had a negative impact on tumour necrosis factor blockers' (TNFb) response.Prospective observational study with two visits 3 months apart.Adult patients with AxSpa initiating a TNFb.FM was defined by the Fibromyalgia Rapid Screening Tool (FiRST) at baseline and also by a sustained positive FiRST (both visits) and by a fulfilment of the 1990 American College of Rheumatology criteria for FM.Prevalence of FM; evaluation of the impact of a concomitant FM on TNFb response (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50) as primary endpoint), adjusted by factors known to have an impact on TNFb response.Among the 508 patients included in the main analysis, 192 (37.8%) were screened at baseline as FM. Percentage of success after 12 weeks of treatment was lower in the FM group for most of the effectiveness endpoints (eg, BASDAI 50: 45.3% vs 54.1% in the FM/not FM groups according to the FiRST), except for the C reactive protein change endpoints which were not different across groups.This study confirms that FM coexists in patients with axSpA and that its presence seems to have a negative impact on TNFb response, which seems more related to the self-reported instruments used in its evaluation, rather than a different treatment effect of the molecule in this subgroup of patients.
Sentinel lymph node biopsy validation for large tumors
Authors: Gilles Houvenaeghel, Olivia Quilichini, Monique Cohen, Fabien Reyal, Jean-Marc Classe, Chafika Mazouni, Sylvie Giard, Nicolas Carrabin, Hélène Charitansky, Emile Darai, Delphine Hudry, Pierre Azuar, Richard Villet, Pierre Gimbergues, Christine Tunon-DE-Lara, Eric Lambaudie
Journal: International Journal of Surgery (2017)
Abstract 24075: Heart Failure Induced Upregulations of MicroRNAs in the Human Sinoatrial Node Associated with Pacemaker Dysfunction
Authors: Ning Li, Maria Petkova, Brian J Hansen, Prosper S Ssekayombya, Joseph Yanni, Brandon J Biesiadecki, Ahmet Kilic, Peter J Mohler, Paul M Janssen, Jonathan P Davis, Federica Accornero, Mark R Boyett, Halina Dobrzynski, Vadim V Fedorov
Journal: Circulation (2017)

Background: Heart failure (HF), a leading cause of morbidity and mortality, involves significant dysfunction of the sinoatrial node (SAN). MicroRNAs (miRs) are abundant, non-coding RNAs that ultimately regulate protein expression at the post-transcriptional level and have been implicated in HF. However, nothing is known about the distribution and expression of miRs in the human SAN as well as their roles in regulating pacemaker channels and SAN dysfunction (SND) in HF. Methods: The human SAN was isolated and cryopreserved from failing hearts with implantable pacemakers (n=5) or non-diseased donor hearts (n=3) that were cardioplegically arrested in the surgery room. Utilizing immunohistochemistry, the intact 3D intramural SAN structure was precisely identified as the fibrotic region around the SAN artery containing Connexin43-negative pacemaker cardiomyocytes (Figure). Small biopsies from the central SAN compartment were used to characterize the expression pattern of 14 miRs and their associated pacemaker channels. Ingenuity software (Qiagen) was used to predict the relationship between miRs and their targeted mRNA of SAN ion channels Results: Out of 14 studied miRs, 3 miRs (mir-370-3p miR-133-3a and miR-1) were significantly upregulated in SAN, but not in atria, during HF. We found that mir-370-3p was predominantly expressed in the human SAN, but not atria. Whereas, both miR-133-3a and miR-1 were highly expressed in atria vs SAN. All three miRs were predicted to regulate pacemaker HCN1 and/or HCN4 channel expression. RT-PCR showed that HCN1 and HCN4 mRNA were downregulated in the HF SAN. Conclusions: This is the first study to explore the miRs profiles in healthy and diseased human SAN with SND. We demonstrate that miR-370, miR-133a and miR-1, thought to regulate SAN pacemaker HCN channel expression, are selectively upregulated in human HF SAN. We propose that understanding the function of miRs in human SAN might lead to novel SND treatments.
Metastatic Male Breast Cancer With Increased Uptake on 18F-Fluciclovine PET/CT Scan
Authors: Harkanwar S. Gill, Funmilayo Tade, David Theodore Greenwald, Paul M. Yonover, Bital Savir-Baruch
Journal: Clinical Nuclear Medicine (2017)

Abstract Prostate imaging with 18 F-labeled 1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC, 18 F-fluciclovine) PET/CT scan (Axumin) was recently approved by the US Food and Drug Administration for men with suspected prostate cancer recurrence based on elevated blood prostate-specific antigen levels following prior treatment. We present a rare case of a 77-year-old man with suspected recurrent prostate cancer with an incidental finding of advanced-stage breast cancer showing different degrees of 18 F-fluciclovine uptake.
A rules-based algorithm to identify patients who would benefit from re-addressing advance care planning.
Authors: Christine M. Bestvina, Robert Michael Daly, Kristen Wroblewski, Michael Huber, Monica Malec, Selina Lai-ming Chow, Andrew Hantel, Brittany Beach, Blase N. Polite
Journal: Journal of Clinical Oncology (2017)

4 Background: Advance care planning (ACP) should be initiated early and readdressed often for cancer patients. We hypothesize that a rules-based algorithm can predict decreased overall survival, and can be used to target patients who would benefit from readdressing ACP. Methods: We performed a retrospective analysis of 219 patients receiving palliative chemotherapy with leukemia, cholangiocarcinoma, esophageal, gastric, pancreatic, lung or urothelial cancer at the University of Chicago Medicine. Patients were included if they had an index outpatient oncology visit from April 1, 2015 through June 30, 2015. We examined a three-month window from the index visit for a “high-risk event,” defined as: 1. change in chemotherapy 2. emergency department visit 3. hospitalization. Patients were followed from index visit until date of death or last clinical encounter as of January 31, 2017. Each “high-risk event” was treated as a time-varying covariate in a Cox proportional hazards regression model to calculate a hazard ratio of death compared to those without an event. Results: Sixty-seven percent of patients (146/219) experienced at least one high-risk event. A change in chemotherapy regimen, an ED visit, and a hospitalization occurred in 54% (118/219), 10% (22/219) and 26% (57/219) of patients respectively. The hazard ratio of death for patients with at least one high-risk event when compared to those without was 1.72 (95% CI: 1.19-2.46, p=0.003), when adjusted for age, gender, race, marital status, disease type, ECOG, and Charlson score. Inpatient admission independently reached significant for hazard of death. (HR 2.74: 95% CI: 1.84-4.09, p&lt;0.001). Conclusions: The rules-based algorithm identified patients with a greater risk of death. Implementation of this algorithm in the electronic medical record can identify patients with increased urgency to readdress goals of care. [Table: see text]
Differentiating Merkel cell carcinoma of lymph nodes without a detectable primary skin tumor from other metastatic neuroendocrine carcinomas: The ELECTHIP criteria
Authors: Thibault Kervarrec, Julia Zaragoza, Pauline Gaboriaud, Amélie Le Gouge, Agnès Beby-Defaux, Yannick Le Corre, Ewa Hainaut-Wierzbicka, Francois Aubin, Guido Bens, Patrick Michenet, Hervé Maillard, Antoine Touzé, Mahtab Samimi, Serge Guyétant
Journal: Journal of the American Academy of Dermatology (2017)
Epidemiologia descritiva dos exantemas na região de Roterdão, Janeiro de 1997 a Junho de 1998
Authors: F Termorshuizen, M J W van de Laar
Journal: Eurosurveillance (1998)

O Grupo de Aconselhamento Europeu sobre a Imunizacao recomendou que o sarampo deve ser eliminado da Europa no ano 2007 (1), um objectivo aceite pelos Responsaveis do Programa de Imunizacao Nacional da Organizacao Mundial de Saude (OMS) para os paises da Regiao Europeia. Na corrida para a eliminacao do sarampo e importante estudar a epidemiologia dos exantemas (rashes associados a doenca febril). No passado, o sarampo era a doenca exantematica mais comum na Europa, mas cada vez tem sido menos observada, a medida que a cobertura da vacina aumenta. Na Holanda, a cobertura da vacina tem permanecido estavel num nivel de 93% ha varios anos, com as duas doses de vacina anti-sarampo, papeira e rubeola incluidas no programa nacional de vacinacao (aos 14 meses e 9 anos), sendo a incidencia nacional dos casos de sarampo notificados em 1997 de apenas 0,14/100 000 (2).
Validity and reliability of Korean version of simplified nutritional appetite questionnaire in patients with advanced cancer: A multicenter, longitudinal study.
Authors: Su-Jin Koh, So Yeon Oh, Ji Yeon Baek, Kyung A. Kwon, Hei-Cheul Jeung, Kyung Hee Lee, Young-Woong Won, Hyun Jung Lee
Journal: Journal of Clinical Oncology (2017)

211 Background: Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. Nutrition risk screening aims to increase awareness and allow early recognition and treatment of cancer cachexia. Therefore, screenings should be brief, inexpensive, highly sensitive, and have good specificity. SNAQ is a simple screening tool including 4 questions, and validated to predict weight loss within 6 months in community-dwelling adults and nursing home residents. Our study aimed to translate the SNAQ into Korean, and to assess the validity and reliability of the translated screening tool in advanced cancer patients. Methods: The SNAQ was translated into Korean according to linguistic validation. The internal consistency of the SNAQ was evaluated by Cronbach’s alpha coefficient. Test–retest reliability was evaluated using the intraclass correlation coefficient. Concurrent validity was evaluated by measuring the Pearson’s correlation coefficient between the SNAQ and Mini-Nutritional Assessment (MNA) and Patient-Generated Subjective Global Assessment (PG-SGA). Results: In the 194 patients included in full analysis set, cancer stage was predominantly (98.5%) metastatic, the mean age was 60 years, and the mean BMI was 24 kg/m 2 . According to MNA score ≤11, 57 patients (29.3%) were malnourished. The mean score of the Korean version of the SNAQ was 13.8 (SD = 2.5) with a range of 6–19. Cronbach’s alpha coefficient was 0.74, and intraclass correlation coefficient was 0.87. The SNAQ was moderately correlated with MNA(r = 0.4043, p &lt; 0.0001) and PG-SGA(r = -0.5297, p &lt; 0.0001). A significant weight loss of 5% of the original body weight within 6 months occurred in 46 (24.7%) of the 186 patients. SNAQ score ≤14 predicted 5% weight loss with a sensitivity of 56.5% and a specificity of 44.3%. Conclusions: The Korean version of the SNAQ had high validity and reliability. SNAQ is useful for the screening tool for advanced cancer patients. The SNAQ had a limitation to predict impending weight loss in advanced cancer patients.
Hepatocellular carcinoma with hepatic vein invasion should not be considered a contraindication for liver resection
Authors: Xiu‐Ping Zhang, Kang Wang, Zhen‐Hua Chen, Shu‐Qun Cheng
Journal: Hepatology (2017)

Supported by grants from the National Key Basic Research Program “973 project” (2015CB554000), the Science Fund for Creative Research Groups (81521091), the China National Funds for Distinguished Young Scientists (81125018), the ChangJiang Scholars Program (2013) of the Chinese Ministry of Education, the Shanghai Science and Technology Committee (134119a0200, SHDC12015106), the National Natural Science Foundation of China (8160110271), and the SMMU Innovation Alliance for Liver Cancer Diagnosis and Treatment (2012). Potential conflict of interest: Nothing to report. To the editor: Because symptoms of hepatocellular carcinoma (HCC) often are imperceptible in earlier stages of this disease, most HCC patients with a portal vein tumor thrombus or hepatic vein tumor thrombus (HVTT) diagnosis have already reached an advanced stage, stage C according to the Barcelona Clinic for Liver Cancer staging system and treatment guidelines.1 Based on official guidelines in the United States and Europe, oral sorafenib was the only recommended treatment for HCC patients associated with macroscopic vascular invasion.2 However, liver resection (LR) should not be offered for patients with HVTT. Kokudo et al.3 compare the survival of 540 Child‐Pugh A HCC patients with HVTT without inferior vena cava invasion who underwent LR and 481 Japanese patients who received other treatments. The median survival time in the LR group was 2.89 years, significantly longer than that in the non‐LR group (P < 0.001). Similarly, they found that the median survival time was 1.61 years longer than that in the non‐LR group (P = 0.023) in a propensity score–matched cohort. However, there was no survival benefit between patients with HVTT in the peripheral hepatic vein and those with HVTT in the major hepatic vein. This is a great exploration with the largest number of HCC patients with HVTT to recommend LR for some select patients. Their recent findings echo a previous study published in the Journal of Hepatology in 2014 from the same group, indicating that LR was associated with a good prognosis in HCC patients with microscopic or major HVTT when R0 resection was feasible.4 Other studies from Asian countries equally confirmed that widening the surgical margins when technically possible may increase overall survival of patients with HCC and HVTT.5 From previous studies, official treatment guidelines should recognize that LR may be a therapeutic option for some select patients with advanced HCC with HVTT. Liver surgeons should not shy away from LR for select HVTT patients under recent advances in surgical techniques and perioperative management. Precision therapy and combined treatments should be applied to HCC patients with different types of HVTT. It is imperative to design multicenter randomized controlled trials to assess LR in some select HVTT patients.
Functional assessment of human enhancer activities using whole-genome STARR-sequencing
Authors: Yuwen Liu, Shan Yu, Vineet K. Dhiman, Tonya Brunetti, Heather Eckart, Kevin P. White
Journal: Genome biology (2017)

Genome-wide quantification of enhancer activity in the human genome has proven to be a challenging problem. Recent efforts have led to the development of powerful tools for enhancer quantification. However, because of genome size and complexity, these tools have yet to be applied to the whole human genome. In the current study, we use a human prostate cancer cell line, LNCaP as a model to perform whole human genome STARR-seq (WHG-STARR-seq) to reliably obtain an assessment of enhancer activity. This approach builds upon previously developed STARR-seq in the fly genome and CapSTARR-seq techniques in targeted human genomic regions. With an improved library preparation strategy, our approach greatly increases the library complexity per unit of starting material, which makes it feasible and cost-effective to explore the landscape of regulatory activity in the much larger human genome. In addition to our ability to identify active, accessible enhancers located in open chromatin regions, we can also detect sequences with the potential for enhancer activity that are located in inaccessible, closed chromatin regions. When treated with the histone deacetylase inhibitor, Trichostatin A, genes nearby this latter class of enhancers are up-regulated, demonstrating the potential for endogenous functionality of these regulatory elements.WHG-STARR-seq provides an improved approach to current pipelines for analysis of high complexity genomes to gain a better understanding of the intricacies of transcriptional regulation.
Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer
Authors: Anshuman Panda, Janice M Mehnert, Kim M Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Michael Kane, Levi Sokol, Mark N Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann W Silk, Joseph Aisner, Nancy Chan, Jyoti Malhotra, Melissa Frankel, Howard L Kaufman, Siraj Ali, Jeffrey S Ross, Eileen P White, Gyan Bhanot, Shridar Ganesan
Journal: JNCI Journal of the National Cancer Institute (2017)

Abstract Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti–programmed death–ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P &lt; 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P &lt; 10-4; log2 fold-change of CD8A = 1.85, P &lt; 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P &lt; 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P &lt; .001) compared with MSS tumors. These data suggest that EBV-positive low–mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.
Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies
Authors: James W Dear, Joanna I Clarke, Ben Francis, Lowri Allen, Jonathan Wraight, Jasmine Shen, Paul I Dargan, David Wood, Jamie Cooper, Simon H L Thomas, Andrea L Jorgensen, Munir Pirmohamed, B Kevin Park, Daniel J Antoine
Journal: The Lancet. Gastroenterology & hepatology (2017)

Paracetamol overdose is common but patient stratification is suboptimal. We investigated the usefulness of new biomarkers that have either enhanced liver specificity (microRNA-122 [miR-122]) or provide mechanistic insights (keratin-18 [K18], high mobility group box-1 [HMGB1], and glutamate dehydrogenase [GLDH]). The use of these biomarkers could help stratify patients for their risk of liver injury at hospital presentation.