tbuckley/cabot-search huggingface dataset:
Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies
Authors: Chao Zeng, Jie Wei, Monica S M Persson, Aliya Sarmanova, Michael Doherty, Dongxing Xie, YiLun Wang, Xiaoxiao Li, Jiatian Li, Huizhong Long, Guanghua Lei, Weiya Zhang
Journal: British Journal of Sports Medicine (2018)

Objectives To compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA). Methods PubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies. Results 43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=−0.30, 95% CI −0.40 to –0.20) and improving function (SMD=−0.35, 95% CI −0.45 to –0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=−0.81, 95% CI −1.12 to –0.52) and piroxicam was most effective for functional improvement (SMD=−1.04, 95% CI −1.60 to –0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs. Conclusions Topical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study.
The Traf2 and Nck-Interacting Kinase Is a Conserved Regulator of Self-Renewal in Hematopoietic and Leukemia Stem Cells
Authors: Michael A Amrein, Elias D Bührer, Carla Ruckstuhl, Sabine Höpner, Carsten Riether, Adrian F Ochsenbein
Journal: Blood (2017)
PTU-093 Novel benzimidazole derivative bearing a pyrolidine side chain inhibits in-vivo liver cancer cells growth by downregulating akt/jnk signalling
Authors: C-Y Lee, C-Y Liu, Y-J Liao
Journal: Gut (2017)

Introduction  Hepatocellular carcinoma (HCC) is the 5th most common malignancy worldwide and the 3rd leading cause of cancer-related death. Currently, sorafenib is the only drug that has been approved by the U.S. FDA for patients with advanced HCC. However, its improvement on patient outcomes is modest, and the median survival time is only prolonged 2~3 months. Therefore, more effective novel agents are urgently needed for HCC therapy.  Method  A novel benzimidazole derivative bearing pyrolidine side chain was synthesised. The HuH7 xenograft model was used to examine the antitumor activity  in-vivo . Adverse effects (body weight, serum parameters, liver function and pathology) of mice were evaluated. Intratumoral signalling pathways were assessed by Western blot, Q-PCR and IHC staining.  Results  Administration of this novel benzimidazole derivative bearing pyrolidine side chain compound significantly decreased HCC markers c α-fetoprotein, glypican-3 and survivin expression and suppressed tumour growth. The phosphorylations of Akt and JNK in HuH7 xenograft tumour were also decreased. Meanwhile, there were no adverse effects in the liver and kidney of mice treated with this compound.  Conclusion  Administration of the novel benzimidazole derivative bearing a pyrolidine side chain compound exerted significant antitumor activity in preclinical HCC models, which potentially suggests its use as a novel therapeutic strategy for patients with HCC.  Disclosure of Interest  None Declared
Discovery of Potent and Selective MRCK Inhibitors with Therapeutic Effect on Skin Cancer
Authors: Mathieu Unbekandt, Simone Belshaw, Justin Bower, Maeve Clarke, Jacqueline Cordes, Diane Crighton, Daniel R. Croft, Martin J. Drysdale, Mathew J. Garnett, Kathryn Gill, Christopher Gray, David A. Greenhalgh, James A.M. Hall, Jennifer Konczal, Sergio Lilla, Duncan McArthur, Patricia McConnell, Laura McDonald, Lynn McGarry, Heather McKinnon, Carol McMenemy, Mokdad Mezna, Nicolas A. Morrice, June Munro, Gregory Naylor, Nicola Rath, Alexander W. Schüttelkopf, Mairi Sime, Michael F. Olson
Journal: Cancer Research (2018)

Abstract The myotonic dystrophy–related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin–myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here, we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphologic changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent antiproliferative effects with greatest activity in hematologic cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy. Significance: The development of selective small-molecule inhibitors of the Cdc42-binding MRCK kinases reveals their essential roles in cancer cell viability, migration, and invasive character. Cancer Res; 78(8); 2096–114. ©2018 AACR.
More Than Estrogen: Puberty Switch Of Non-Sex Hormones In Allergic Disease
Authors: Sergio E. Chiarella, Lyda Cuervo-Pardo, Mackenzie E. Coden, Brian M. Jeong, Raul I. Rodriguez, Mahboobeh Mahdavinia, Anne M. Singh, Hiam Abdala-Valencia, Sergejs Berdnikovs
Journal: Journal of Allergy and Clinical Immunology (2018)
Gray Zone Lymphoma (GZL) with Features Intermediate between Diffuse Large B-Cell Lymphoma (DLBCL) and Classical Hodgkin Lymphoma (cHL): A Pathologic Consensus Study with Patient Outcomes and Prognostication across 15 North American Centers
Authors: Andrew M Evens, Monika Pilichowska, Stefania Pittaluga, Judith Ferry, Jessica Hemminger, Hong Chang, Jennifer A. Kanakry, Laurie H Sehn, Tatyana A Feldman, Francisco J. Hernandez-Ilizaliturri, Izidore S Lossos, Jeremy S. Abramson, Athena Kritharis, Oliver W. Press, Timothy S. Fenske, Jonathan W. Friedberg, Julie M Vose, Kristie A. Blum, Deepa Jagadeesh, Bruce Woda, Randy D. Gascoyne, Elaine S. Jaffe
Journal: Blood (2017)
Evaluation of quality of life at progression in patients with soft tissue sarcoma.
Authors: Stacie Hudgens, Anna Forsythe, Ilias Kontoudis, David R. D'Adamo, Ashley Bird, Hans Gelderblom
Journal: Journal of Clinical Oncology (2016)

11015 Background: Soft tissue sarcoma (STS) is a rare group of heterogeneous mesenchymal cancers with an annual incidence of 2 to 3 diagnoses for every 100,000 persons. Median survival time in patients with metastatic STS is usually less than 12 months, with only a small subgroup of these patients achieving long-term survival. Understanding quality of life and the detrimental impact of disease progression is critical for long-term care and survival. Methods: The objective of this study was to better understand treatment related differences comparing Eribulin to dacarbazine (DTIC) in quality of life among patients who experienced disease progression. Health-related Quality of life (HRQoL) was determined using the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30). Any change greater than 10-points was considered meaningful. Differences in HRQoL between treatment arms and histology type were compared using a multi-factor ANOVA. Statistically significant differences in QLQ-C30 scores between planned treatment arms were assessed using p-values reflecting the F-ratio statistic at alpha 0.05. Results: A total of 452 patients were randomized into this Phase 3 clinical trial. Of these, 400 patients with progressive disease were included in this evaluation (209 in the Eribulin arm and 191 in the DTIC arm). Baseline QOL scores were equivalent at baseline for the Eribulin and DTIC arms. Patients on DTIC had significantly lower global health status compared to those on Eribulin (56.1 vs 62.1; p=0.0083) and physical function (63.9 vs 73.3; p=0. 0022) as well as worse nausea/vomiting (p=0.0009) and appetite loss (p=0.001). Similar results were observed in the histology subpopulations (adipocytic and Leiomyosarcoma). Conclusions: Overall, results of this exploratory analysis indicate difference in HRQoL at time of disease progression between the DTIC and Eribulin treatment arms, with notable increases in symptom severity noted among DTIC patients relative to comparable patients in the Eribulin arm.
Preliminary Results of FDG-PET Scanning after GDP Chemotherapy Prior to Autologous Stem Cell Transplant (ASCT) for Relapsed/Refractory (RR) Lymphoma
Authors: Matthew D. Cooper, Umberto Falcone, Naom Tau, Eshetu G Atenafu, Richard Tsang, David C. Hodgson, Armand Keating, Ur Metser, Michael Crump, John G. Kuruvilla
Journal: Blood (2016)
T-cell protein tyrosine phosphatase (TC-PTP) regulates Stat3 signaling in mouse epidermis after UVB irradiation
Authors: Dae Kim, Michel Tremblay, John DiGiovanni
Journal: Cancer Research (2007)

3920   Ultraviolet B radiation (UVB) can cause DNA damage, induce gene mutations and modulate intracellular signal transduction contributing to the development of skin cancer. Signal transducer and activator of transcription 3 (Stat3) modulates various physiological functions including apoptosis, cell cycle regulation, and tumor angiogenesis through regulation of gene expression, and its constitutive activation is associated with human epithelial cancers. Recent studies indicated that Stat3 was rapidly dephosphorylated in keratinocytes after UVB irradiation. Vanadate treatment desensitized keratinocytes to UVB-induced apoptosis with the recovery of phosphorylated Stat3 protein levels, implying that a tyrosine phosphatase is involved in this mechanism. In the current work, the mechanism whereby UVB exposure leads to rapid dephosphorylation of Stat3 was examined. Western blot analysis showed that the nuclear form of TC-PTP, which is known to dephosphorylate various signaling molecules, was constitutively expressed in cultured mouse keratinocytes. After UVB exposure, activated stat3 was rapidly reduced, whereas the level of TC-PTP was not changed. Further immunofluorescence and western blot analyses revealed that TC-PTP translocates from cytosol to nucleus in response to UVB irradiation. Dephosphorylation of Stat3 by TC-PTP was rapidly increased after UVB irradiation of cultured keratinocytes with nuclear accumulation of TC-PTP. Stat3 target genes, such as cyclin D1 and c-Myc, were also down-regulated early following UVB exposure. Consistent with these observations, RNAi studies showed that the level of phosphorylated Stat3 in keratinocytes transfected with TC-PTP siRNA was higher compared with control keratinoctyes upon UVB irradiation. In addition, Inhibition of importin β1 expression by siRNA knockdown of importin β1, which is known to transport TC-PTP in to the nucleus, did not prevent its translocation and dephosphorylatin of Stat3 in nucleus, indicating that UVB-induced transport of TC-PTP is independent of importin β1. In mouse epidermis in vivo, the level of phosphorylated Stat3 was initially decreased, following by a significant increase at later time points after UVB exposure. The expression patterns of cyclin D1 and c-Myc followed the changes in activated Stat3. Consistently, dephosphorylation of Stat3 by TC-PTP was initially increased, and then decreased in vivo after UVB exposure. These results suggest that TC-PTP is responsible for the rapid dephosphorylation of Stat3 following UVB and may serve as part of an initial protective mechanisms against UV skin carcinogenesis.
Staff shortages force mental health trusts to cancel patient activities and close wards, says King’s Fund
Authors: Abi Rimmer
Journal: BMJ (2018)

Problems with staffing have forced mental health providers around England to cancel patient activities and close wards, a report by the King’s Fund has warned.1

The research by the healthcare think tank found that mental health providers were struggling with high staff vacancy rates and turnover, a reliance on bank and agency staff, and an inappropriate skill mix. It said that this had led to patient activities being cancelled, wards being closed owing to safety concerns, and patients being …
Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4
Authors: Akihiro Shimba, Guangwei Cui, Shizue Tani-ichi, Makoto Ogawa, Shinya Abe, Fumie Okazaki, Satsuki Kitano, Hitoshi Miyachi, Hisakata Yamada, Takahiro Hara, Yasunobu Yoshikai, Takashi Nagasawa, Günther Schütz, Koichi Ikuta
Journal: Immunity (2018)
Risk of Pancreatic Cancer in Patients With Pancreatic Cysts and Family History of Pancreatic Cancer
Authors: Saurabh S. Mukewar, Ayush Sharma, Nissy Phillip, Ridhi Gupta, Anupama Aryal-Khanal, Nicolo de Pretis, Vincent Anani, Felicity T. Enders, Joseph J. Larson, Naoki Takahashi, Michael J. Levy, Mark Topazian, Randall K. Pearson, Santhi S. Vege, Suresh T. Chari
Journal: Clinical Gastroenterology and Hepatology (2018)
Repression of the spindle assembly checkpoint gene CDC20 by p53 upon DNA damage
Authors: Banerjee Taraswi, Somsubhra Nath, Susanta Roychoudhury
Journal: Cancer Research (2008)

2597   CDC20 is a crucial player in the Spindle Assembly Checkpoint (SAC), which activates the Anaphase Promoting Complex (APC) and helps the cell proceed from metaphase towards anaphase. Even in the presence of a single unattached kinetochore to the spindle fibers during metaphase, CDC20 is sequestered by the mitotic checkpoint complex to activate the SAC. Hence, anaphase cannot be initiated and cell division is arrested. We already showed that overexpression of CDC20 results in chromosomal instability, a hallmark of cancer. We know that in response to DNA damage, cell cycle checkpoints, like those at G1/S and G2/M are activated by the p53 tumor suppressor protein. However, little is known about the DNA damage-induced effect of p53 on the SAC. In this study, we investigated transcriptional regulation of CDC20 by p53.  We observed a dose-dependent decrease in endogenous CDC20 mRNA and protein in HeLa cells upon transfection with a wt.p53 expression vector. We validated this observation under physiological conditions by treating HepG2 cells with increasing concentrations of 5-fluorouracil (5-FU), a DNA damaging drug, to stabilize endogenous p53. To establish that the downregulation of CDC20 by p53 occurs at the transcriptional level, we performed the following experiments. First, ectopic expression of p53 in HCT  p53-/-  cells dose-dependently inhibited luciferase activity from a CDC20 promoter-luciferase vector. We also showed that the proteasome inhibitor, MG132 has no effect on p53-mediated CDC20 expression in HepG2 cells. Next, HeLa cells co-transfected with CDC20 promoter-luciferase and p53-expressing plasmids were treated with Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, in a dose-dependent manner. With increasing dose of TSA, we observed decreasing repression of the CDC20 promoter by p53, suggesting involvement of HDACs in the repression mechanism. Currently, we are investigating which HDAC and co-repressor are involved in this inhibitory process. Previous reports showed an indirect role of p53 in CDC20 repression via a series of signal transduction cascades working through the NFY and E2F response elements in the CDC20 promoter. However, using a bioinformatics approach, we identified a putative p53 binding site within the 1 kb promoter of CDC20 that we used in the promoter-reporter assay. This led us to hypothesize that in addition to the indirect role, p53 might directly inhibit the CDC20 promoter. Towards this end, we showed that p53 can still inhibit the CDC20 promoter containing mutated NFY and E2F binding sites both individually and in combination. A chromatin immunoprecipitation (ChIP) assay showed the presence of p53 in the transcription complex on the CDC20 promoter both in p53 overexpressed HCT  p53-/-  cells and in 5FU-treated HepG2 cells. Finally, we are also investigating the effect of this DNA damage-triggered repression of CDC20 on the SAC.
Usefulness of ß-D-glucan for diagnosis and follow-up of invasive candidiasis in onco-haematological patients
Authors: J. Guitard, F. Isnard, M.-D. Tabone, M. Antignac, E. Brissot, Y. Senghor, A. Petit, G. Leverger, C. Hennequin
Journal: Journal of Infection (2018)
Unapologetically patriotic – SMA shines the BJSM spotlight on Australian Research
Authors: Liam Richard West, Julie Pham
Journal: British Journal of Sports Medicine (2018)

As we write this Warm Up for the Sports Medicine Australia (SMA) issue of the  British Journal of Sports Medicine ( BJSM ), elite sport dominates both front and back pages of Australian newspapers. We have international cricket, tennis and both Women’s and Men’s Australian Football League (AFL) is around the corner. Along side elite sport, participation is rising in community level sport and this puts demands on clinicians who treat these weekend warriors.

SMA draws together under one banner all sports medicine, sports science and healthcare professionals who work in elite and community sports settings. SMA plays an active role in educating healthcare professionals and sports-minded community members to help individuals benefit from exercise, activity and competition. To reflect SMA’s membership, this BJSM edition includes papers from a broad range of disciplines on topics within both sport and physical activity from Australian authors and institutions.

Graduated and balanced …
HO-1hi patrolling monocytes protect against vaso-occlusion in sickle cell disease
Authors: Yunfeng Liu, Fangmiao Jing, Woelsung Yi, Avital Mendelson, Patricia Shi, Ronald Walsh, David F. Friedman, Caterina Minniti, Deepa Manwani, Stella T. Chou, Karina Yazdanbakhsh
Journal: Blood (2018)
Government postpones first ACOs to allow further consultation
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The government will delay the formation of the first accountable care organisations in England while further consultation takes place, the health and social care secretary has said.

In a letter to Sarah Wollaston, chair of the House of Commons Health Committee, Jeremy Hunt said that the ACO contract that was published in draft form last year would not be implemented in any area of the country until NHS England had concluded a national public consultation this spring.1

The commitment followed Wollaston’s request for Hunt to delay the introduction of the new ACO contract until after the Health Committee had heard evidence on the issue as part of an ongoing inquiry into the NHS’s sustainability and transformation partnerships (STPs), which aims to report after …
Abstract 14041: Caring for Infants With Complex Single Ventricle: Impact on Families
Authors: Karen Uzark, Janaki Sagi, Sunkyung Yu, Janet Donohue, Alicia Valentini, Veronica Zitterman, Sarah Gelehrter
Journal: Circulation (2015)

Objective: Outcomes for infants with single ventricle (SV) heart defects have steadily improved in recent decades, but there is still significant mortality and morbidity during the interstage period between stage 1 Norwood hospitalization discharge and stage 2 palliation at 4-6 months of age. The impact on families during this period of infant home surveillance is unknown. The aim of this study was to evaluate parental quality of life (QOL) and family functioning among parents of infants with SV during the interstage period. Methods: Parents (n= 32) completed the PedsQL Family Impact Module (FIM) via a web link or by telephone at 6 weeks post Norwood discharge and again prior to Stage 2 surgery. Higher scores indicate less negative impact. Data were compared to published norms for a Midwestern community sample of parents. Results: Median age at Norwood was 5 days (range 1-50) with a median hospital length of stay (LOS) of 28.5 days (range 14-102). Total FIM, family functioning, and parental QOL scores were not significantly lower than community norms. Across scales however, the SV parents had significantly worse scores related to worry (64.4 ± 20.6 vs 78.1 ± 20.1, p&lt;.001), communication (74.0 ± 23.5 vs 81.9 ± 17.7, p=0.01) and daily activities (53.6 ± 30.2 vs 63.2 ± 22.5, p=0.02) at 6 wks. Interestingly, the mean scale score for family relationships was significantly higher in the SV parents than community norms at 6 wks (82.7 ± 14.4 vs 67.0 ± 19.4, p&lt;.001) and pre-Stage 2 (76.3 ± 21.6 vs 67.0 ± 19.4, p=0.01). There was no significant change in any FIM scale scores between 6 wk and pre-Stage 2 assessments except parental physical functioning scores declined (p=0.004).Total FIM, including parental QOL and family functioning scores, were not significantly associated with Norwood hospital LOS. Most parents (97%) reported daily monitoring of their infant’s oxygen saturation at home was helpful and 22% felt monitoring decreased their stress. Conclusion: Care of an infant with SV has a significant impact on families throughout the interstage period with improved outcomes related to supportive family relationships. Home monitoring by parents with ongoing assessment of family concerns by healthcare providers may further support families caring for infants with single ventricle.
Sexual Health in Patients with Hemophilia; The Insights from the Patient Reported Outcomes, Burdens and Experiences (PROBE) Study
Authors: Chatree Chai-Adisaksopha, Mark Skinner, Randall Curtis, Neil Frick, Michael B. Nichol, Declan Noone, Brian O'Mahony, David Page, Jeffrey Stonebraker, Alfonso Iorio
Journal: Blood (2017)