tbuckley/cabot-search huggingface dataset:
Methotrexate and azathioprine for severe atopic dermatitis: a 5-year follow-up study of a randomized controlled trial
Authors: L.A.A. Gerbens, S.A.S Hamann, M.W.D. Brouwer, E. Roekevisch, M.M.G. Leeflang, P.I. Spuls
Journal: British Journal of Dermatology (2017)

Systemic treatment is indicated for moderate‐to‐severe atopic dermatitis (AD) refractory to topical treatment. Long‐term evidence, up to 5 years, of off‐label prescribed methotrexate (MTX) and azathioprine (AZA) is lacking. To investigate long‐term effectiveness, safety and drug survival of MTX and AZA. In an open‐label follow‐up phase of a clinical trial, patients were seen every 3 months for 5 years. MTX and AZA doses could be increased or decreased concurrent with daily clinical practice. Primary effectiveness outcomes were mean absolute and relative reduction in SCORing Atopic Dermatitis (SCORAD) index and Investigator's Global Assessment (IGA) after 5 years compared with baseline. To assess safety, the type, frequency, severity and relatedness to treatment of adverse events were investigated. Drug survival was analysed by Kaplan–Meier curves. Thirty‐five of 43 originally included patients participated, of whom 27 completed the follow‐up. At year 5, the mean relative reduction in SCORAD index was similar in the MTX and AZA groups: 53% and 54% using descriptive analysis. Twelve serious adverse events occurred in 5 years; for three there was a possible causal relationship. Drug survival demonstrated a longer survival for MTX, but survival in both groups was low after 5 years (MTXn = 5, AZAn = 1). Based on this relatively small pragmatic study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate‐to‐severe AD up to 5 years. Few patients in both groups survive on their originally allocated drug although some discontinued because of controlled AD.
Brexit is shifting drug industry’s focus away from UK, MPs hear
Authors: Adrian O’Dowd
Journal: BMJ (2017)

Drug companies seem to be looking to base future operations and processes outside the UK because of uncertainty caused by Brexit, MPs have been told.

During an evidence session of the parliamentary business, energy and industrial strategy committee’s inquiry into the implications for British business of leaving the EU, witnesses representing the drug industry said that changes in the sector were already evident.

Contingency plans were being drawn up in case the UK did not secure a Brexit deal that included “regulatory alignment” with Europe over medicines, they warned during the evidence session, held on 5 December. MPs asked whether any noticeable changes had occurred since the Brexit referendum in …
Tumor-infiltrating lymphocytes, tumor-associated macrophages and HLA class 1 expression in breast cancer patients treated with neoadjuvant chemotherapy with or without zoledronic acid: A sub study of the NEOZOTAC trial
Authors: A.F. de Groot, E.J. Blok, A. Charehbili, C.C. Engels, V T H B M Smit, N.G. Dekker-Ensink, H. Putter, C.J.H. van de Velde, G-J Liefers, J.W.R. Nortier, P.J.K. Kuppen, S.H. van der Burg, J.R. Kroep
Journal: Annals of Oncology (2017)
SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth
Authors: Hironari Tamiya, Hyungsoo Kim, Oleksiy Klymenko, Heejung Kim, Yongmei Feng, Tongwu Zhang, Ji Yun Han, Ayako Murao, Scott J. Snipas, Lucia Jilaveanu, Kevin Brown, Harriet Kluger, Hao Zhang, Kazuhiro Iwai, Ze’ev A. Ronai
Journal: Journal of Clinical Investigation (2017)

SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.
Pulmonary Vasodilator Therapy in Shock-associated Cardiac Arrest
Authors: Ryan W. Morgan, Robert M. Sutton, Michael Karlsson, Andrew J. Lautz, Constantine D. Mavroudis, William P. Landis, Yuxi Lin, Sejin Jeong, Nancy Craig, Vinay M. Nadkarni, Todd J. Kilbaugh, Robert A. Berg
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Many in-hospital cardiac arrests are precipitated by hypotension, often associated with systemic inflammation. These patients are less likely to be successfully resuscitated, and novel approaches to their treatment are needed.
Spontaneous communication and infant imitation
Authors: Ross Buck
Journal: Behavioral and Brain Sciences (2017)

Abstract Infant behavior is viewed in a social-communicative context centered on the phenomenon of spontaneous communication. Symbolic communication is learned and culturally structured, intentional, consists of symbols, and is propositional in content. In contrast, spontaneous communication is innate in both its sending (display) and receiving (preattunement) aspects, non-intentional, consists of signs, and is non-propositional or emotional in content. It underlies infant imitation, interactional synchrony, primary intersubjectivity, emotional empathy, and mirror neurons; and it is associated with oxytocin.
The FDA’s Expedited Programs and Clinical Development Times for Novel Therapeutics, 2012-2016
Authors: Thomas J. Hwang, Jonathan J. Darrow, Aaron S. Kesselheim
Journal: JAMA (2017)

The US Food and Drug Administration (FDA) has 4 expedited programs to speed the development and review of drugs treating serious diseases: (1) priority review leads to FDA review in 6 months (vs 10 months for standard review);(2) accelerated approval permits approval based on surrogate measures; and (3) fast-track and (4) breakthrough therapy programs are intended to reduce the duration of clinical trials (Table ). 1 Clinical development times for drugs in these expedited programs, particularly the newly created breakthrough program (enacted in 2012), have not been comprehensively assessed.We analyzed clinical development times within each of the 4 expedited programs separately and between drugs qualifying for any vs no expedited program.Because fast-track and breakthrough programs are intended to abbreviate the overall drug development process, we also examined development times for drugs receiving either or both of these 2 programs (regardless of other programs).
Microbial colonization of the periodontal pocket and its significance for periodontal therapy
Authors: Andrea Mombelli
Journal: Periodontology 2000 (2017)

Abstract The aim of this paper was to evaluate strategies for periodontal therapy from the perspective of periodontal disease being a consequence of microbial colonization of the periodontal pocket environment. In classic bacterial infections the diversity of the microbiota decreases as the disease develops. In most cases of periodontitis, however, the diversity of the flora increases. Most incriminating bacteria are thought to harm tissues significantly only if present in high numbers over prolonged periods of time. Clinical trials have repeatedly demonstrated that scaling and root planing, a procedure that aims to remove subgingival bacterial deposits by scraping on the tooth surface within the periodontal pocket, is effective. At present, for the therapy of any form of periodontal disease, there exists no protocol with proven superiority, in terms of efficiency or effectiveness, over scaling and root planing plus systemic amoxicillin and metronidazole. Some exponents advocate rationing these drugs for patients with a specific microbial profile. However, the evidence for any benefit of bacteriology‐assisted clinical protocols is unsatisfactory. Treated sites are subject to recolonization with a microbiota similar to that present before therapy. The degree and speed of recolonization depends on the treatment protocol, the distribution patterns of periodontal microorganisms elsewhere in the oral cavity and the quality of the patient's oral hygiene. To limit the use of antibiotics and to avoid accumulation of harmful effects by repeated therapy, further efforts must be made to optimize procedures addressing the microbial colonization and recolonization of the periodontal pocket.
Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction
Authors: Ahmed U. Fayyaz, William D. Edwards, Joseph J. Maleszewski, Ewa A. Konik, Hilary M. DuBrock, Barry A. Borlaug, Robert P. Frantz, Sarah M. Jenkins, Margaret M. Redfield
Journal: Circulation (2017)

Background: We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. Methods: Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ≥40 mm Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. Results: The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls ( P &lt;0.0001 for all) but lower than PVOD ( P ≤0.005 for all). PASP (mm Hg) was lower in HF-PH (median, 59 [interquartile range, 50–70]) than in PVOD (median, 91 [interquartile range, 82–103]). PASP correlated with arterial percent medial thickness ( r =0.41) and arterial %IT ( r =0.35) but more strongly with venous %IT ( r =0.49) and IV %IT ( r =0.55) ( P &lt;0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. Conclusions: In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.
Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling
Authors: Mingxiang Ye, Yong Zhang, Hongjun Gao, Yan Xu, Pengyu Jing, Jianxiong Wu, Xinxin Zhang, Jie Xiong, Chenfang Dong, Libo Yao, Jian Zhang, Jian Zhang
Journal: Clinical Cancer Research (2017)

Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified.Experimental Design: AhR expression in non-small cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms.Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacologic and molecular approaches rendered EGFR-mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2-Src interaction, which does not require the canonical transcriptional activity of AhR.Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC. Clin Cancer Res; 24(5); 1227-39. ©2017 AACR.
Abstract #884: Mechanism of action of PNC-27/-28 anti-cancer peptides
Authors: Ehsan Sarafraz-Yazdi, Victor Adler, Wilbur Bowne, Kelley Sookraj, Alison North, Patrick Niharny, William Oxberry, Matthew Pincus, Josef Michl
Journal: Cancer Research (2009)

In vivo and in vitro studies have shown the efficiency of anti-cancer peptides PNC-27 and PNC-28 in killing cancer cells by necrosis without affecting untransformed normal cells (Kanovsky et al., PNAS 2001; Do T et al., Oncogene 2002; Michl et al, IJC, 2006). The peptides were derived from the HDM2-binding domain of p53 (PNC-27: aa12-26 and PNC-28: aa17-26) and linked to a leader sequence from the Drosophila antennapedia homeodomain protein. In contrast, over-expression intra-cellularly of the aa17-26 sequence kills tumor cells by apoptosis but not by necrosis (Bowne et al., Ann. Surg. Onc. 2008). The critical role of HDM2 as the target molecule for PNC-27 in the tumor cells\#8217; plasma membrane was confirmed by successful competition of a hdm2-specific antibody against the binding of PNC-27 to intact tumor cells and prevention of cytotoxicity as evident by the absence of lactate dehydrogenase (LDH) release. We now show that PNC-27-induced cytotoxicity is temperature sensitive, since LDH is released from cells treated with PNC-27 (LD50 at 0.035\#956;M) at 37°C, with reduced efficiency from cells treated at 25°C, but not at all by cells expsoed to PNC-27 at or below 17°C. The sequence of cellular events following the exposure of tumor cells to PNC-27 was established with spinning disc confocal microscopy of human pancreatic cancer MIA-Paca-2 cells that were preloaded with mitotracker dye: Within   Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 884.
Profound Electrocardiogram Changes in a Patient With Liver Cirrhosis
Authors: Laszlo Littmann, Jennifer K. Potter, Jessica R. Hoglund
Journal: JAMA Internal Medicine (2017)

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Chemotherapy of ovarian cancer patients with metastases in the brain.
Authors: David Naskhletashvili, Vera A. Gorbunova, Mark Bychkov, Ali Bekyashev, Vladislav Karahan, Sevyan Nadejda, Vladimir Aloshin, Zoya Michina, Sergey Medvedev, Alla Markovich, Ekaterina A. Moskvina
Journal: Journal of Clinical Oncology (2014)

e13027 Background: Metastases in the brain is a rare complication of the tumor process in patients (pts) with ovarian cancer. About 1–2% of all pts with ovarian cancer develop BM, leading to a poor prognosis and a median survival of <6 months after whole brain radiotherapy. The role of chemotherapy in the management of ovarian cancer pts with BM a little studied. This study was designed to evaluate the role of chemotherapy in the combined treatment in ovarian cancer pts with BM. Methods: Eligible pts had confirmed ovarian cancer and BM (≥1 lesion of ≥10mm diameter) aged >18 years with ECOG performanse status (PS) of 0–2. From November 2005 to January 2014, 10 pts with ovarian cancer and BM were enrolled in this study. 7 pts (70%) had extracranial lesions. We studied the effectiveness of various treatment regimens: 5 pts received paclitaxel + carboplatin, 2 pts received topotecan, 3 pts received cyclophosphan + carboplatin, until radiologically-verified progressive disease. The primary endpoints were objective response rate (ORR) - complete and partial response in the brain and in the extracranial lesions, progressive-free survival (PFS) and overall survival. Demographics were following: median age - 59 years (range 47–71 years); PS: 1 - 5 pts, 2 - 5 pts; previously treated - 10 pts; number of BM: ≤3 - 6 pts, >3 - 4 pts. Previous chemotherapy regarding primary ovarian tumors was held to 10 pts (100%). Local control of BM: previous neurosurgery – 3 pts (30%), previous radiotherapy – 3 pts (30%). Results: ORR in the brain was 80% (6 partial responses and 2 complete responses). All complete responses in the brain achieved in patients who received radiotherapy to finally chemotherapy (after chemotherapy were achieved partial regressions). Stable disease in the brain was 20% (2 pts). ORR in the extracranial lesions was 28,6% (1 partial response and 1 complete response). Stable disease in the extracranial lesions was 57,1% (4 pts). The median of PFS was 6 months. The median survival of patients not achieved (6 pts are alive). 5 pts are alive more than 12 months, 3 of them are alive more than 24 months. Conclusions: Previous results of our study indicate high effectiveness of chemotherapy in the treatment of metastases in the brain of patients with ovarian cancer.
Airway Inflammatory Response In Healthy Subjects Following Chamber Exposure To 100% Rme Biodiesel
Authors: Jamshid Pourazar, Annelie F. Behndig, Ragnberth Helleday, Ala Muala, Gregory Rankin, Maria Sehlstedt, Jon Unosson, J. P. Langrish, Anders Blomberg, Thomas Sandström, Jenny A. Bosson
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Airway Inflammatory Response In Healthy Subjects Following Chamber Exposure To 100% Rme Biodiesel
Breaking Down Barriers to Chemoresistance: Role of Chemotherapy-Induced Osteoblastic Jagged1
Authors: Khalid S. Mohammad, Theresa A. Guise
Journal: Cancer Cell (2017)

Bone metastases are incurable. The bone microenvironment has always been a suspect for this clinical enigma, but the exact mechanisms have been unclear. In this issue of <i>Cancer Cell</i>, Zheng and colleagues provide evidence that chemotherapy itself induces chemoresistance of bone metastases, mediated by osteoblast Jagged1-induced tumor Notch signaling.
Casos humanos de viruela de los monos en Kasai Oriental, Zaire (1996-1997)
Authors: P. T. Mwanbal, K F Tshioko, A Moudi, V Mukinda, G. N. Mwema, D Messinger, L Okito, D Barakymfyte, P Malfait, R G Pebody, M Szczeniowski, K Esteves, D Heymann, Y Hutin, R J Williams, A. S. Khan, J J Esposito
Journal: Eurosurveillance (1997)

La viruela de los monos es un Orthopoxvirus con circulacion enzootica en los bosques tropicales de Africa central y occidental; el virus puede transmitirse al hombre y causar un sindrome clinicamente similar a la viruela (erupcion pustulosa, fiebre, sintomas respiratorios y, en algunos casos, la muerte). Entre febrero y agosto de 1996, se registraron un total de 71 casos clinicos de viruela de los monos, incluidas 6 muertes, en 13 aldeas de Zaire situadas en el area de salud de Katako-Kombe (poblacion total en 1.996: 15.698 habitantes), subregion de Sankuru, region oriental de Kasai (figura 1) (1).
Abstract 15975: A Meta-analysis of Substrate Modification versus Clinical Ventricular Tachycardia Ablation in Structural Heart Disease
Authors: Mohit Turagam, Sandia Iskandar, Madhav Lavu, Donita Atkins, Sudharani Bommana, Dhanunjaya Lakkireddy, Madhu Reddy
Journal: Circulation (2016)

Background: Catheter ablation (CA) is an effective treatment strategy for ventricular tachycardia (VT) in structural heart disease. However, the most effective ablation strategy remains unknown. We...