tbuckley/cabot-search huggingface dataset:
Transcriptome analysis of severely active chronic spontaneous urticaria shows an overall immunological skin involvement
Authors: A. Giménez‐Arnau, L. Curto‐Barredo, L. Nonell, E. Puigdecanet, J. Yelamos, R. Gimeno, S. Rüberg, L. Santamaria‐Babi, R.M. Pujol
Journal: Allergy (2017)

The knowledge about chronic spontaneous urticaria (CSU) phenotypes is based on its clinical characteristics, associated comorbidities, course of the disease, and its response to the available effective drugs. Genotype expression and its further correlation with CSU phenotypes are still unknown. We describe the cutaneous transcriptome of patients suffering a severely active CSU refractory to antihistamine treatment.Through the bioinformatic analysis of the whole Human Genome with Oligo Microarrays and quantitative real-time polymerase chain reaction (qPCR), relevant genes expressed in nonlesional (NLS-CSU) and lesional skin (LS-CSU) and peripheral blood were identified in 20 patients suffering from severely active CSU and 10 healthy controls (HCs).From 39 genes differentially expressed in NLS-CSU when compared with HCs, 31 (79.48%) were confirmed by qPCR corresponding to genes involved in epidermal homeostasis and dermal repair. From the analysis comparing LS-CSU with NLS-CSU, a selection of 142 genes was studied with qPCR, and 103 (72.53%) were confirmed. Differentially expressed genes in the phenomenon of wheal development are involved in a variety of biological functions as, epidermal differentiation, intracellular signal function, transcriptional factors cell cycle differentiation, inflammation, or coagulation. Differentially expressed genes that uniformly increase or decrease along the skin worsening until the wheal appearance is shown.The skin of CSU patients with a severely active disease shows an overall immunological skin involvement showing a peculiar gene profile.
Enhanced proangiogenic potential of mesenchymal stem cell-derived exosomes stimulated by a nitric oxide releasing polymer
Authors: Wei Du, Kaiyue Zhang, Shuaiqiang Zhang, Ran Wang, Yan Nie, Hongyan Tao, Zhibo Han, Lu Liang, Di Wang, Jianfeng Liu, Na Liu, Zhongchao Han, Deling Kong, Qiang Zhao, Zongjin Li
Journal: Biomaterials (2017)
Foods and beverages and colorectal cancer risk: a systematic review and meta-analysis of cohort studies, an update of the evidence of the WCRF-AICR Continuous Update Project
Authors: A.R. Vieira, L. Abar, D.S.M. Chan, S. Vingeliene, E. Polemiti, C. Stevens, D. Greenwood, T. Norat
Journal: Annals of Oncology (2017)
Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database
Authors: Lindsay A. Renfro, Richard M. Goldberg, Axel Grothey, Alberto Sobrero, Richard Adams, Matthew T. Seymour, Volker Heinemann, Hans-Joachim Schmoll, Jean-Yves Douillard, Herbert Hurwitz, Charles S. Fuchs, Eduardo Diaz-Rubio, Rainer Porschen, Christophe Tournigand, Benoist Chibaudel, Paulo M. Hoff, Fairooz F. Kabbinavar, Alfredo Falcone, Niall C. Tebbutt, Cornelis J.A. Punt, J. Randolph Hecht, John Souglakos, Carsten Bokemeyer, Eric Van Cutsem, Leonard Saltz, Aimery de Gramont, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2017)

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.
A phase 1 study to assess the food effect on the pharmacokinetics (PK) of entinostat.
Authors: Denise A. Yardley, Suzanne Fields Jones, Peter Ordentlich, Carol J Braun, Helen S Pentikis, Jeannette Lynne Hasapidis, Miranda Rees, Howard A. Burris
Journal: Journal of Clinical Oncology (2014)

591 Background: Entinostat (ENT) is an oral, class 1 isoform selective histone deacetylase inhibitor shown to extend progression free and overall survival when combined with exemestane (EXE) in post-menopausal women with estrogen receptor positive (ER+) metastatic breast cancer (MBC) who have progressed on prior non-steroidal aromatase inhibitors (Yardley et al; JCO 31:2128;2013). Based on these results ENT was granted Breakthrough Therapy designation by the FDA for this indication. This Phase 1 study evaluated the effect of food on ENT PK in patients (pts) with MBC and advanced non-small cell lung cancer (NSCLC). Methods: A total of 17 pts (14 postmenopausal ER+ MBC and 3 NSCLC) were randomized 1:1 to receive ENT 10 mg administered Day 1 and 15 of a 28 day lead-in cycle, fasting and with food. Pts randomized to ENT with food on Cycle 1 Day 1 (C1D1) received ENT fasted on Cycle 1 Day 15 (C1D15); pts randomized to ENT fasted on C1D1 received ENT with food on C1D15. Blood samples were obtained pre-dose C1D1 and serially during C1 for PK and pharmacodynamic (PD) analysis. Following C1, ENT 10 mg was continued on D1 and 15 of a 28 day cycle in combination with daily EXE 25mg (MBC) or erlotinib 150 mg (NSCLC) until toxicity or disease progression. Tumor assessments (RECIST 1.1) were performed every 2 cycles. Results: Co-administration of ENT with food decreased its Cmax by 71% and overall exposure by 15-17%, as estimated by AUClast and AUCinf. The mean t1/2 of ENT was estimated at 140 hrs under fasted conditions and 178 hrs under fed conditions. Additional PK parameters along with protein lysine acetylation PD will be reported. ENT was well tolerated with no unexpected toxicities. 9 MBC pts experienced stable disease (n=8) or partial response (n=1) with 3 pts continuing beyond 10 cycles; one patient continues on study at cycle 19. Progressive disease was the best response in the 3 NSCLC pts. Conclusions: ENT Cmax and exposure as measured by AUClast and AUCinf were significantly reduced when co-administered with food, leading to recommended ENT dosing under fasted conditions. ENT 10 mg was well tolerated and clinical benefit was observed in MBC pts. A randomized, double blind, placebo-controlled phase 3 trial in ER+ advanced breast cancer is planned. Clinical trial information: NCT01594398.
Abstract 217: Anti-fibrotic Function of Relaxin
Authors: Diana Lindner, P. Moritz Becher, Svenja Hinrichs, Michael Schwarzl, Nina Fluschnik, Stefan Blankenberg, Dirk Westermann
Journal: Circulation Research (2015)

Introduction: The RELAX in Acute Heart Failure (RELAX-AHF) trial was done in patients admitted for acute decompensated heart failure to evaluate the efficacy of Serelaxin (human recombinant relaxin-2) on dyspnoea relief, as well as its safety and tolerability. Interestingly, the 180-day mortality was significantly better in the Serelaxin group compared to placebo. The pathophysiology of these beneficial effects remains elusive. Methods and results: To induce heart failure in mice, they were treated with Angiotensin II in absence or in presence of relaxin. After 21 days hemodynamic measurements revealed an improved hemodynamic function in relaxin treated animals with AngII-induced heart failure compared to mice without relaxin treatment. To further investigate the , cardiac fibroblasts were stimulated with pro-fibrotic TGF-β in the presence or in the absence of relaxin. Additionally as a control cardiac fibroblasts were treated with relaxin alone. The treatment with TGF-β induced an increased gene expression of connective tissue growth factor (CTGF) as well as monocyte chemotactic protein 1 (MCP-1) in cardiac fibroblasts, whereas treatment with relaxin alone decreased the gene expression level of CTGF as well as MCP-1 . To investigate a potential inhibitory function of relaxin during TGF-β induced pro-fibrotic gene expression regulation, cardiac fibroblasts were pre-incubated with relaxin 1 hour prior to TGF-β treatment. After the following 6 hours of TGF-β treatment no decreased gene expression was observed in relaxin pre-treated cardiac fibroblasts compared to TGF-β stimulated fibroblasts without relaxin treatment. Conclusion: In this study we could demonstrate no inhibitory effect of relaxin during the pro-fibrotic TGF-β-induced signaling pathway. Nevertheless, relaxin alone induced anti-fibrotic function. Therefore, we conclude that the anti-fibrotic function is not due to an influence on the TGF-β induced pro-fibrotic signaling.
PHF6 Somatic Mutations and Their Functional Role in the Pathophysiology of Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)
Authors: Bartlomiej P Przychodzen, Xiaorong Gu, Dewen You, Cassandra M. Hirsch, Michael J. Clemente, Mikkael A. Sekeres, Aziz Nazha, Hideki Makishima, Jaroslaw P Maciejewski
Journal: Blood (2016)
Differences in Cancer Education Between Patients with Hematologic Malignancies and Solid Tumor Malignancies: Lessons from a Large Multi-Disease Patient Education Symposium
Authors: Leslie Padrnos, Robert Bennett, Heidi E. Kosiorek, Joseph Mikhael, Amylou Constance Dueck, Donald W. Northfelt, Raoul Tibes, Nandita Khera, Ruben A. Mesa
Journal: Blood (2016)
Three doctors struck off for dishonesty are allowed back on medical register
Authors: Clare Dyer
Journal: BMJ (2017)

Six doctors who were struck off the UK medical register for disciplinary reasons have been allowed back in practice in the first four months of 2017. The figures suggest that reinstatement, while still rare, is on the rise: just five doctors were reinstated in the previous two years.

Robert Scott Taylor, a junior doctor who was struck off in 2011, this month became the third doctor to win restoration to the register within a month.

The decisions by the medical practitioner tribunals were of note because all three cases involved doctors who were originally found to have acted dishonestly. In Taylor’s case, this had led to a crown court conviction for fraud. …
Active commuting is beneficial for health
Authors: Lars Bo Andersen
Journal: BMJ (2017)

Background/objectives  To maintain and optimise the quality of care provided by health professionals in rheumatology (HPRs), adequate educational offerings are needed. This task force (TF) aimed to develop evidence-based recommendations for the generic core competences of HPRs, with specific reference to nurses, physical therapists (PTs) and occupational therapists (OTs) to serve as a basis for their postgraduate education.  Methods  The EULAR standardised operating procedures for the development of recommendations were followed. A TF including rheumatologists, nurses, PTs, OTs, patient-representatives, an educationalist, methodologists and researchers from 12 countries met twice. In the first TF meeting, 13 research questions were defined to support a systematic literature review (SLR). In the second meeting, the SLR evidence was discussed and recommendations formulated. Subsequently, level of evidence and strength of recommendation were assigned and level of agreement (LoA) determined (0–10 rating scale).  Results  Three overarching principles were identified and 10 recommendations were developed for the generic core competences of HPRs. The SLR included 79 full-text papers, 20 of which addressed the competences, knowledge, skills, attitudes and/or educational needs of HPRs from multiple professions. The average LoA for each recommendation ranged from 9.42 to 9.79. Consensus was reached both on a research and educational agenda.  Conclusion  Evidence and expert opinion informed a set of recommendations providing guidance on the generic core competences of HPRs. Implementation of these recommendations in the postgraduate education of HPRs at the international and national level is advised, considering variation in healthcare systems and professional roles.
NHS thrombectomy plan needs more doctors, say stroke experts
Authors: Anne Gulland
Journal: BMJ (2017)

Stroke experts have warned that not enough doctors are trained to carry out mechanical thrombectomy, after NHS England announced that the procedure will be performed on all patients who have had acute ischaemic stroke.

NHS England said that the procedure, which involves removing a blood clot from the brain using a stent, would be introduced in 24 specialist neuroscience centres throughout the country from this year, eventually benefiting around 8000 patients a year.

The Royal College of Physicians first recommended mechanical thrombectomy for patients with acute ischaemic stroke in guidelines last year.1 A systematic review and meta-analysis …
Autochthonous Japanese Encephalitis with Yellow Fever Coinfection in Africa
Authors: Etienne Simon-Loriere, Ousmane Faye, Matthieu Prot, Isabelle Casademont, Gamou Fall, Maria D. Fernandez-Garcia, Moussa M. Diagne, Jean-Marie Kipela, Ibrahima S. Fall, Edward C. Holmes, Anavaj Sakuntabhai, Amadou A. Sall
Journal: New England Journal of Medicine (2017)

et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs
Authors: Shixin Ma, Xiaoling Wan, Zihou Deng, Lei Shi, Congfang Hao, Zhenyuan Zhou, Chun Zhou, Yiyuan Fang, Jinghua Liu, Jing Yang, Xia Chen, Tiantian Li, Aiping Zang, Shigang Yin, Bin Li, Joel Plumas, Laurence Chaperot, Xiaoming Zhang, Guoliang Xu, Lubin Jiang, Nan Shen, Sidong Xiong, Xiaoming Gao, Yan Zhang, Hui Xiao
Journal: The Journal of Experimental Medicine (2017)

TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs. Mechanistically, CXXC5 is responsible for the recruitment of DNA demethylase Tet2 to maintain the hypomethylation of a subset of CGIs, a process coincident with active histone modifications and constitutive transcription of these CGI-containing genes. Consequently, CXXC5-deficient mice had compromised early IFN response and became highly vulnerable to infection by herpes simplex virus and vesicular stomatitis virus. Together, our results identify CXXC5 as a novel epigenetic regulator for pDC-mediated antiviral response.
Phase II study of the anti-ganglioside GD3 mouse/human chimeric antibody KW2871 combined with high dose interferon-a2b in patients with metastatic melanoma.
Authors: Stergios J. Moschos, Ahmad A. Tarhini, Thomas Gajewski, Andrew Mark Scott, Yan Lin, Janice Shipe-Spotloe, Weiping Xu Deblasio, Cindy Sander, Karen Matijevich, Fiona Elizabeth Smyth, Zhanqi Liu, Eric W. Hoffman, Ralph Rudolph Venhaus, Linda S. Pan, Sinhan Tran, James Fiore, John M. Kirkwood
Journal: Journal of Clinical Oncology (2012)

8547 Background: Immunotherapy has demonstrated notable effects in metastatic melanoma (MM) with durable responses achieved by high-dose IL-2 and IFN α 2b, leading to approval of these therapies for treatment of melanoma. However, complete responses occur in only a minority of patients. KW2871 is a chimeric monoclonal antibody (mAb) targeting the G D3 ganglioside with demonstrated antitumor activity and enhancement of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). IFN α 2b has potent immunoregulatory, anti-proliferative, differentiation-inducing, pro-apoptotic, and anti-angiogenic properties against a variety of malignancies including melanoma. Combining high dose IFN α 2b (HDI) + KW2871 was hypothesized to have synergistic anti-tumor activity due to (1) the ability of HDI to enhance KW2871 induced ADCC in vitro (Liu, Cancer Immun 2002); (2) improved mAb targeting due to increased G D3 expression and induced inflammatory cytokines (TNF-α, IL-4 and IFN-γ) (Hoon, Cancer Res, 1991); (3) increased tumor-infiltrating immune cells (Kirkwood, Cancer 2002; Moschos, J Clin Oncol 2006). Methods: This is an open label, dose-escalation, phase II study of KW2871 plus HDI in patients with measurable MM. Primary objectives are progression-free survival (PFS) and safety. Secondary objectives include assessment for tumor response by RECIST, ADCC, CDC, pharmacokinetics, human antichimeric antibodies (HACA), tumor-infiltrating immune cells, biomarkers and OS. Patients with measurable disease by RECIST, stable brain metastases, and performance status ECOG 0 or 1 are eligible. Patients with severe comorbidities or autoimmune disease or prior exposure to anti-G D3 antibodies are excluded. Sequential enrollment to cohorts of KW2871 at 5, 10 , 20 mg/m 2 IV every 2 week in combination with HDI 20 MU/m 2 IV once daily x 5 Days for 4 weeks, then 10 MU/m 2 SC three times weekly until disease progression. Results: To date, Cohort 1 (5 mg/m 2 KW2871) and Cohort 2 (10 mg/m 2 KW2871) have been completed safely. Cohort 3 (20 mg/m 2 KW2871) has enrolled of 18 of 27 planned patients. Conclusions: Will be presented at study completion.
IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition
Authors: Miriam Gaggianesi, Alice Turdo, Aurora Chinnici, Elisa Lipari, Tiziana Apuzzo, Antonina Benfante, Isabella Sperduti, Simone Di Franco, Serena Meraviglia, Elena Lo Presti, Francesco Dieli, Valentina Caputo, Gabriella Militello, Salvatore Vieni, Giorgio Stassi, Matilde Todaro
Journal: Cancer Research (2017)

Abstract The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor–positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24− cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268–79. ©2017 AACR.
Role of endoscopy in primary sclerosing cholangitis: European Society of Gastrointestinal Endoscopy (ESGE) and European Association for the Study of the Liver (EASL) Clinical Guideline
Authors: Lars Aabakken, Tom Karlsen, Jörg Albert, Marianna Arvanitakis, Olivier Chazouilleres, Jean-Marc Dumonceau, Martti Färkkilä, Peter Fickert, Gideon Hirschfield, Andrea Laghi, Marco Marzioni, Michael Fernandez, Stephen Pereira, Jürgen Pohl, Jan-Werner Poley, Cyriel Ponsioen, Christoph Schramm, Fredrik Swahn, Andrea Tringali, Cesare Hassan
Journal: Endoscopy (2017)

MAIN RECOMMENDATIONS 1 ESGE/EASL recommend that, as the primary diagnostic modality for PSC, magnetic resonance cholangiography (MRC) should be preferred over endoscopic retrograde cholangiopancreatography (ERCP). Moderate quality evidence, strong recommendation. 2 ESGE/EASL suggest that ERCP can be considered if MRC plus liver biopsy is equivocal or contraindicated in patients with persisting clinical suspicion of PSC. The risks of ERCP have to be weighed against the potential benefit with regard to surveillance and treatment recommendations. Low quality evidence, weak recommendation. 6 ESGE/EASL suggest that, in patients with an established diagnosis of PSC, MRC should be considered before therapeutic ERCP. Weak recommendation, low quality evidence. 7 ESGE/EASL suggest performing endoscopic treatment with concomitant ductal sampling (brush cytology, endobiliary biopsies) of suspected significant strictures identified at MRC in PSC patients who present with symptoms likely to improve following endoscopic treatment. Strong recommendation, low quality evidence. 9 ESGE/EASL recommend weighing the anticipated benefits of biliary papillotomy/sphincterotomy against its risks on a case-by-case basis. Strong recommendation, moderate quality evidence. Biliary papillotomy/sphincterotomy should be considered especially after difficult cannulation. Strong recommendation, low quality evidence. 16 ESGE/EASL suggest routine administration of prophylactic antibiotics before ERCP in patients with PSC. Strong recommendation, low quality evidence. 17 EASL/ESGE recommend that cholangiocarcinoma (CCA) should be suspected in any patient with worsening cholestasis, weight loss, raised serum CA19-9, and/or new or progressive dominant stricture, particularly with an associated enhancing mass lesion. Strong recommendation, moderate quality evidence. 19 ESGE/EASL recommend ductal sampling (brush cytology, endobiliary biopsies) as part of the initial investigation for the diagnosis and staging of suspected CCA in patients with PSC. Strong recommendation, high quality evidence.
Response to Comment on O’Brien et al. Hormonal Contraception and Risk of Thromboembolism in Women With Diabetes. Diabetes Care 2017;40:233–238
Authors: Sarah H. O’Brien, Sara K. Vesely, Eleanor Bimla Schwarz
Journal: Diabetes Care (2017)

We would like to thank Dr. Braillon for his thoughtful letter (1) and for his enthusiasm regarding our work (2). His point is well taken that the incidence of thromboembolism among women with diabetes using the contraceptive patch was greater than 1 per 100 woman-years and would therefore meet the European …