tbuckley/cabot-search huggingface dataset:
Bivalent Chromatin Domains in Glioblastoma Reveal a Subtype-Specific Signature of Glioma Stem Cells
Authors: Amelia Weber Hall, Anna M. Battenhouse, Haridha Shivram, Adam R. Morris, Matthew C. Cowperthwaite, Max Shpak, Vishwanath R. Iyer
Journal: Cancer Research (2018)

Glioblastoma multiforme (GBM) can be clustered by gene expression into four main subtypes associated with prognosis and survival, but enhancers and other gene-regulatory elements have not yet been identified in primary tumors. Here, we profiled six histone modifications and CTCF binding as well as gene expression in primary gliomas and identified chromatin states that define distinct regulatory elements across the tumor genome. Enhancers in mesenchymal and classical tumor subtypes drove gene expression associated with cell migration and invasion, whereas enhancers in proneural tumors controlled genes associated with a less aggressive phenotype in GBM. We identified bivalent domains marked by activating and repressive chromatin modifications. Interestingly, the gene interaction network from common (subtype-independent) bivalent domains was highly enriched for homeobox genes and transcription factors and dominated by SHH and Wnt signaling pathways. This subtype-independent signature of early neural development may be indicative of poised dedifferentiation capacity in glioblastoma and could provide potential targets for therapy.Significance: Enhancers and bivalent domains in glioblastoma are regulated in a subtype-specific manner that resembles gene regulation in glioma stem cells. Cancer Res; 78(10); 2463-74. ©2018 AACR.
Brief Report: Cancer Immunotherapy in Patients With Preexisting Rheumatic Disease: The Mayo Clinic Experience
Authors: Michael D. Richter, Olga Pinkston, Lisa A. Kottschade, Heidi D. Finnes, Svetomir N. Markovic, Uma Thanarajasingam
Journal: Arthritis & Rheumatology (2018)

To determine the risk of rheumatic disease flare and adverse effects in patients with preexisting rheumatic disease who were receiving immune checkpoint inhibitor (ICI) therapy.A retrospective medical record review was performed to identify all patients who received ICI therapy at Mayo Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with a preexisting rheumatic disease were identified using specific diagnostic codes.Sixteen patients were identified (81% female, median age 68.5 years). The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia rheumatica (n = 5), Sjögren's syndrome (n = 2), and systemic lupus erythematosus (n = 2). Seven patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatic disease at the time of initiation of the ICI. The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or hematologic (n = 2). In most cases, ICIs were offered only after failure of several other therapies. Immune-related adverse effects (IRAEs) occurred in 6 patients, and all were treated successfully with glucocorticoids and discontinuation of the ICI therapy. There were no significant differences in time from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex between the patients with and those without IRAEs.To our knowledge, this represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE.
A comparison of nephrotoxicity between patients with a solitary-functioning kidney and those with bilateral-functioning kidneys in cisplatin-based chemotherapy for advanced urothelial carcinoma: A Japanese retrospective multi-institutional study.
Authors: Takamitsu Inoue, Jun Miyazaki, Daishi Ichioka, Shintaro Narita, Susumu Kageyama, Mikio Sugimoto, Koji Mitsuzuka, Hidefumi Kinoshita, Eiji Kikuchi, Yoshiyuki Matsui, Keiko Fujie, Tomonori Habuchi, Hiroyuki Nishiyama
Journal: Journal of Clinical Oncology (2018)

420 Background: To compare the prevalence of nephrotoxicity between patients with a solitary-functioning kidney versus those with bilateral-functioning kidneys during the administration of cisplatin-based chemotherapy for advanced urothelial carcinoma. Methods: We retrospectively analyzed 244 advanced urothelial carcinoma patients treated with cisplatin-based chemotherapy between 2004 and 2010 at 17 institutes in Japan. The urinary tract function status was determined based on the data of nephroureterectomy, hydronephrosis, and relief of upper urinary tract obstruction. A total of 244 patients were divided into four groups according to their urinary tract functioning status and eGFR results, including bilateral-functioning kidneys with pretreatment eGFR≥60 mL/min/1.73 m 2 group (n = 83, 34.0%); a solitary-functioning kidney with pretreatment eGFR≥60 mL/min/1.73 m 2 group (n = 36, 14.8%); bilateral-functioning kidneys with pretreatment eGFR &lt; 60 mL/min/1.73 m 2 group (n = 45, 18.4%); and a solitary-functioning kidney with pretreatment eGFR &lt; 60 mL/min/1.73 m 2 group (n = 80, 32.8%). Results: The prevalence of nephrotoxicity with impaired eGFR of &gt; 10% and 30% from baseline in the post-third-course of chemotherapy was significantly higher in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney, among patients with pretreatment eGFR &lt; 60 mL/min/1.73 m 2 (p = 0.023 and p = 0.026). During all courses of chemotherapy, the prevalence of nephrotoxicity with impaired eGFR of &gt; 20% from baseline were significantly higher in patients with bilateral-functioning kidneys than those with a solitary-functioning kidney among patients with pretreatment eGFR &lt; 60 mL/min/1.73 m 2 (p = 0.034), whereas no significant difference was observed among patients with pretreatment eGFR ≥60 mL/min/1.73 m 2 . Conclusions: The results suggest that cisplatin-based chemotherapy may have more nephrotoxicity in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney.
Abstract P329: Prospective Association of Serum Uromodulin and Cardiovascular Disease in Chronic Kidney Transplant Receipents
Authors: Charles B Eaton, Dominik Steubl, Mary Roberts, Pranav Garimella, Theresa Shireman, Andreas Pasch, Joe Ix, Tuttle R Katherine, Anastasia Ivanova, Marc A Pfeffer, Andrew Bostom
Journal: Circulation (2018)

Serum levels of the exclusively renal-derived glycoprotein, uromodulin, a putative tubular function index, were recently associated with the development of fatal and non-fatal cardiovascular disease [CVD] outcomes during longitudinal surveillance of two cohorts undergoing diagnostic coronary angiography (Leiherer A et al. Int J Cardiol. 2017; 231:6-12; Delgado GE et al. 2017; 28: 2201-10). Using a case-cohort design (total n=685; random subcohort n=433) from the completed FAVORIT trial of chronic, stable kidney transplant recipients [KTRs], we examined the association between baseline serum uromodulin (mean ± standard deviation [SD]: 67.8 ±39.7 ng/mL), and the development of CVD (myocardial infarction, CVD death, stroke, &amp; major revascularization procedures, pooled, n=311 events), during a median 3.7 years of follow-up. Unadjusted, weighted Cox proportional hazards modeling, based upon the subcohort uromodulin level SD (±39.7), revealed that each SD higher was associated with a 23% decreased risk for CVD (hazards ratio [HR]= 0.77; 95% confidence interval [CI]=0.65-0.92). This association was attenuated after adjustment for age, sex, smoking status, graft type, prevalent diabetes &amp; CVD, systolic blood pressure gt140, diastolic blood pressure lt 70, estimated glomerular filtration rate [eGFR] gt=45 mL/min per 1.73m 2 , &amp; natural log urinary albumin/creatinine [UACR]: (HR=0.83; 95% CI=0.67-1.04). Comparing subcohort uromodulin [ng/mL] quartile ranges (Q1=5.6-39.1; Q2=39.2-58.8; Q3=58.9-82.9; Q4=83.0-309.6), with the lowest quartile as referent, unadjusted Cox models demonstrated that the risks for CVD were as follows: Q2 v. Q1 (HR=0.92; 95% CI=0.62-1.38); Q3 v. Q1 (HR=0.69; 95% CI= 0.46-1.03); Q4 v. Q1 (HR=0.56; 95% CI=0.37-0.85). Full adjustment yielded: Q2 v. Q1 (HR=1.16; 95% CI= 0.70-1.92); Q3 v. Q1 (HR= 0.77; 95% CI=0.44-1.37); Q4 v. Q1 (HR=0.76; 95% CI=0.44-1.31). Higher serum uromodulin, an ostensible indicator of better preserved tubular function, was associated with reduced risk for the development of CVD in a large cohort of chronic, stable KTRs, but this association did not persist upon adjustment for major CVD risk factors, eGFR, &amp; UACR.
Prediction of Overall Survival Based on Isocitrate Dehydrogenase 1 Mutation and 18F-FDG Uptake on PET/CT in Patients With Cerebral Gliomas
Authors: Dongwoo Kim, Soyoung Kim, Se Hoon Kim, Jong Hee Chang, Mijin Yun
Journal: Clinical Nuclear Medicine (2018)

Purpose This retrospective study aimed to correlate 18 F-FDG uptake on PET/CT with isocitrate dehydrogenase enzyme isoform 1 ( IDH1 ) mutation in patients with cerebral gliomas. Hierarchical interactions between factors affecting overall survival (OS) were also examined. Methods In 59 patients with glioma, the ratio of the SUVmax of a glioma to the SUVmean of the contralateral cortex (G/C ratio) on 18 F-FDG PET/CT and the presence of IDH1 mutation were correlated. The prognostic value of clinicopathologic factors and G/C ratio for OS were assessed using a Cox proportional hazards model and classification and regression tree models. Results The mean G/C ratio of IDH1-mutant tumors was significantly lower than that of IDH1 wild-type tumors (0.73 vs 1.14, P = 0.004). In multivariate analysis, IDH1-mutant and G/C ratio were significant for OS. The classification and regression tree modeling identified 3 risk groups for OS (group 1: IDH1 mutant [hazard ratio, 0.2]; group 2: G/C ratio ≤0.8 with IDH1 wild type [hazard ratio, 0.83]; group 3: G/C ratio &gt;0.8 with IDH1 wild type [hazard ratio, 1.9]) (overall P &lt; 0.001). The mean OS was 37.0 months in group 1, 28.6 months in group 2, and 20.7 months in group 3, respectively, showing significant differences among the groups (group 1 vs group 2: P = 0.023, group 2 vs group 3: P = 0.049, group 1 vs group3: P &lt; 0.001). Conclusions 18 F-FDG uptake of IDH1-mutant gliomas was significantly lower than that of IDH1 wild-type gliomas. IDH1 mutation was the most important factor in identifying patients with the best prognosis, whereas increased 18 F-FDG uptake provided additional prognostic information for predicting poor OS among patients with IDH1 wild-type gliomas.
Overall survival in an orthotopic GBM model is significantly prolonged by neurosurgical delivery of PLGA/PEG interstitial chemotherapy
Authors: Stuart Smith, Toby Gould, Betty Tyler, Alison Ritchie, Gareth Veal, Kevin Shakesheff, Henry Brem, Richard Grundy, Ruman Rahman
Journal: Neuro-Oncology (2018)

The blood brain barrier is a critical limiting step to achieving therapeutic CNS drug concentrations. We have developed a poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG)-based platform technology to interstitially deliver multiple chemotherapy agents from a single thermo-setting biodegradable paste, achieving high local but low systemic concentrations and sustained delivery of cytotoxic drugs directly to the CNS. Here we evaluate mouldable PLGA/PEG paste for combined temozolomide (TMZ) and etoposide (ETOP) delivery in an orthotopic high grade glioma animal model. Drug release and preserved stability of the active TMZ molecule (AIC) was evaluated by fluoroscopic and LC-mass spectrometer based methods. In vitro cytotoxicity of released TMZ/ETOP was evaluated against high grade glioma cell lines and patient-derived primary cultures using metabolic assays. In vivo efficacy and overall survival were evaluated in the syngeneic orthotopic 9L glioma rat model of intra cavity chemotherapy. TMZ and ETOP were released from PLGA/PEG alone or in dual combinations over 2 weeks in vitro. Cytotoxicity of released drugs in vitro is comparable to directly applied agents, demonstrating the retained molecular integrity of TMZ/ETOP upon loading and releasing from PLGA/PEG. Both high (20% w/w TMZ / 50% w/w ETOP) and low (10% w/w TMZ / 25% w/w ETOP) doses were well tolerated in vivo, with no observable weight loss nor neurological deficits. Significant positive survival benefits from PLGA/PEG/TMZ/ETOP therapy were observed in vivo compared to surgery alone, surgery with blank paste (49 vs. 14 days; p < 0.001) or surgery plus oral TMZ (49 vs. 33 days; p < 0.004). This study demonstrates that localised dual release of TMZ/ETOP achieves a significant extension to overall survival in vivo. As such, PLGA/PEG paste applied to the post-surgical resection cavity offers a realistic opportunity for localised control of residual malignant glioma cells.
Dynamics of dual-fluorescent polymersomes with durable integrity in living cancer cells and zebrafish embryos
Authors: Sven H.C. Askes, Nelli Bossert, Jeroen Bussmann, Victorio Saez Talens, Michael S. Meijer, Roxanne E. Kieltyka, Alexander Kros, Sylvestre Bonnet, Doris Heinrich
Journal: Biomaterials (2018)
Abstract P1-08-05: A phase I trial of chemotherapy followed by infusions of activated T cells armed with anti-CD3 and anti-HER2 bispecific antibody for stage III, Her2+ or Her2- breast cancer
Authors: P Dillon, R Rathore, A Thakur, G Colvin, N Kouttab, L Lum
Journal: Cancer Research (2018)

Abstract Background: The balance in the immune system between immune surveillance and tolerance is known to be associated with the prognosis of breast cancer patients. The aim of this phase I study was to assess the safety of anti-CD3 x anti-HER2Bi bispecific antibody targeted (BAT) activated T cells (TC) in high risk breast cancer patients. The BAT T-cells exhibit anti-HER2 cytotoxicity, proliferate, and secrete immunokines upon tumor engagement. Methods: High risk adjuvant breast cancer patients were recruited and completed standard adjuvant chemotherapy. BATs were produced by stimulating peripheral blood mononuclear cells (PBMC) obtained by leukapheresis; collected TC were then activated with anti-CD3 monoclonal antibody and expanded in IL-2 for 12-14 days. TC were armed with bispecific antibody and cryopreserved until used. Groups of 3 patients received 20, 40, 80 or 160 x 109 BATs per infusion twice a week for four weeks. All patients were treated at Roger Williams Medical Center. Results: Nine patients were accrued and all had N3 disease. Eight of 9 patients were ER positive; 2 of 9 were HER2 overexpressing. The median OS has not reached as five of nine patients are still alive. OS range from 14.3 to 154.7 months (as December 11, 2016). Five out of the five patients who are alive have no evidence of disease and 1 patient had a secondary primary that has been successfully treated and she has no evidence of disease. It was feasible to grow up to 160 x 109 BATs and this dose level was tolerable without any cell-based dose limiting toxicities. BATs persisted in the blood for at least a week. BAT infusions induce cellular anti-tumor responses and cytokine responses. Conclusion: Targeting HER2 positive and negative tumors induced cytotoxic anti-tumor responses, increases in Th1 cytokines and IL-12 serum levels. The prolonged survival in a high risk population suggests that BAT infusions provided a clinical benefit. These results are being confirmed in a phase II trial for metastatic breast cancer. Citation Format: Dillon P, Rathore R, Thakur A, Colvin G, Kouttab N, Lum L. A phase I trial of chemotherapy followed by infusions of activated T cells armed with anti-CD3 and anti-HER2 bispecific antibody for stage III, Her2+ or Her2- breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-08-05.
SMOKING AND OUTCOMES IN OLDER PATIENTS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION (HFPEF)
Authors: Amiya Ahmed, Evangelos I. Kanonidis, Markus Anker, Apostolos Tsimploulis, Phillip H. Lam, Helen Sheriff, Prakash Deedwania, Wilbert Aronow, Gregg C. Fonarow, Ali Ahmed
Journal: Journal of the American College of Cardiology (2018)
New consultant contract needs more flexibility for young doctors, senior leader says
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The new consultants’ contract should include new flexibilities to boost morale and retention of young doctors in England, including options for sabbaticals and extra annual leave for those who work unsociable hours, a senior medical leader has argued.

Clifford Mann, national clinical adviser to NHS England’s Accident and Emergency Improvement Plan and former president of the Royal College of Emergency Medicine, said that the proposed contract should be used as opportunity to re-engage demotivated staff. This would signal that national leaders had listened to the grievances underlying last year’s …
DEVELOPMENT AND VALIDATION OF A SIMPLE CLINICAL RISK PREDICTION MODEL FOR POSTOPERATIVE ATRIAL FIBRILLATION AFTER CARDIAC SURGERY
Authors: Lucrecia Burgos, Josefina B. Parodi, Juan Espinoza, Victoria Galizia Birto, Juan P. Costabel, Mariano Benzadon, Daniel Navia, Leonardo Seoane
Journal: Journal of the American College of Cardiology (2018)
Protease nexin-1 prevents growth of human B cell lymphoma via inhibition of sonic hedgehog signaling
Authors: Xiangke Xin, Yunchuan Ding, Ying Yang, Xing Fu, Jianfeng Zhou, Chad M. McKee, Ruth J. Muschel, Robert P. Gale, Jane F. Apperley, Danmei Xu
Journal: Blood Cancer Journal (2018)
Uptake of governmental social protection and financial hardship during drug-resistant tuberculosis treatment in Rio de Janeiro, Brazil
Authors: William E. Rudgard, Nancy S. das Chagas, Regina Gayoso, Mauricio L. Barreto, Delia Boccia, Liam Smeeth, Laura C. Rodrigues, Knut Lönnroth, Elizabeth Williamson, Ethel L.N. Maciel
Journal: European Respiratory Journal (2018)

Despite most countries offering tuberculosis (TB) diagnosis and treatment free of charge, TB-related costs remain an important barrier for accessing TB care [1]. TB-related costs include direct medical expenses ( e.g. consultations), direct non-medical expenses ( e.g. transport and food for accessing health services) and lost income from time off work related to disability, discrimination and/or infection control laws [2]. With the treatment duration for drug-resistant TB lasting up to 24 months, affected households are especially vulnerable to TB-related costs [1]. In Cambodia, Ecuador, Ethiopia, Indonesia, Kazakhstan and Peru, average drug-resistant TB-related costs range between 75% and 223% of annual household income [3–7]. Governmental social protection contributes to preventing household financial hardship from drug-resistant tuberculosis in Brazil <http://ow.ly/jxZL30iPqOo> We would like to thank the World Health Organization patient cost task force for supplying their questionnaire; Maria da Conceição Souza e Souza (Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil) and Vilson Rodrigues Carneiro e Janine (Pontificia Universidade Católica do Rio de Janeiro, Rio de Janeiro, Brazil) for their help in collecting the data used in the paper; and Sanni Ali and Elizabeth Brickley (both London School of Hygiene and Tropical Medicine, London, UK) for their insightful comments and intellectual contribution to the content of the paper.
Doctors shouldn’t use personal profiles on social media to interact with patients, says GMC
Authors: Helen Jaques
Journal: BMJ (2012)

Doctors should steer clear of interacting with patients through their personal profiles on social media such as Twitter and Facebook, the General Medical Council has recommended.

Instead doctors should direct patients to their professional profile and review their privacy settings on social media to limit the availability of their personal information, the regulator says in its new draft guidance on social media for doctors.

Social media have blurred the boundaries between “public” and “private,” with risks for doctors when social and professional boundaries become unclear, says the GMC.

In its draft guidance, which is out to consultation until 13 June, the GMC makes recommendations about privacy online, interacting with patients through social media, behaving respectfully towards colleagues …
Leaving Against Medical Advice
Authors: David Dongkyung Kim
Journal: JAMA Neurology (2018)

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A multicentre, open, investigator-initiated phase IV clinical trial to evaluate the efficacy and safety of ingenol mebutate gel, 0·015% on the face and scalp, and 0·05% on the trunk and extremities, in Korean patients with actinic keratosis (PERFECT)
Authors: Y.C. Kim, J.Y. Yang, J.S. Yoon, S.J. Jo, H.H. Ahn, K.-H. Song, D.-Y. Lee, K.-Y. Chung, Y.-H. Won, I.-H. Kim
Journal: British Journal of Dermatology (2018)

Ingenol mebutate gel is a novel, field-directed topical treatment for actinic keratosis (AK). Most pivotal studies have targeted Western populations. No clinical study has been conducted to investigate its efficacy and safety in Asian populations.To evaluate the efficacy and safety of ingenol mebutate gel for treating AK of face/scalp and trunk/extremities in a large Asian (Korean) population.In this multicentre, open-label, interventional, parallel-group, prospective phase IV study (PERFECT, trial registration no.: NCT02716714), the eligible patients were allocated into either the face/scalp or the trunk/extremities group, according to their selected treatment area location. After application of ingenol mebutate gel, the participants were followed up for 6 months. The primary efficacy endpoint was complete clearance (CC) of AK lesions in the selected treatment area at day 57. Quality of life was evaluated using Skindex-29. Safety endpoints included local skin responses, scar, pigmentation, pain and adverse events.In total, 78·1% [95% confidence interval (CI) 66·86-86·92%] of subjects had CC at day 57, with 76·6% (95% CI 64·31-86·25%) in the face/scalp group and 88·9% (95% CI 51·75-99·72%) in the trunk/extremities group. Among them, CC was sustained in 88·9% (48 of 54, 95% CI 77·37-95·81%) at month 6. The local skin responses significantly increased 1 day after the treatment compared with baseline, and decreased afterwards. Among the total subjects, 7·8% (6 of 77) had hyperpigmentation on the application area. Scars were not reported.Ingenol mebutate is effective for the treatment of AK in Asians, with tolerable safety profiles.