tbuckley/cabot-search huggingface dataset:
Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan
Authors: Shumpei Yokota, Yasuhiko Itoh, Tomohiro Morio, Hideki Origasa, Naokata Sumitomo, Minako Tomobe, Kunihiko Tanaka, Seiji Minota
Journal: Annals of the Rheumatic Diseases (2015)

Objectives To evaluate the safety and effectiveness of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (sJIA) in real-world clinical settings in Japan. Methods Paediatric patients with sJIA initiating TCZ between April 2008 and February 2012 and those previously enrolled in clinical trials who initiated TCZ before April 2008 were enrolled in a Japanese registry surveillance programme. Safety and effectiveness parameters were collected for 52 weeks. Results Of 417 patients enrolled, mean age was 11.2 years and 48.0% were female. TCZ exposure was 407.0 patient-years (PYs). Baseline corticosteroid use was higher than in clinical trials. Rates of total adverse events (AEs) and serious AEs (SAEs) were 224.3/100 PYs and 54.5/100 PYs, respectively, with SAEs higher than previously reported. The most frequent AEs and SAEs were infections and infestations (69.8/100 PYs and 18.2/100 PYs, respectively). 74 serious infections occurred in 55 patients (18.2/100 PYs); higher than previously reported. 26 macrophage activation syndrome events were reported in 24 patients (6.4/100 PYs). Fever and rash symptoms improved from baseline to week 52 (54.6% to 5.6% and 43.0% to 5.6%, respectively). At 4 weeks, 8 weeks and 52 weeks, 90.5%, 96.2% and 99.0% of patients achieved normal C reactive protein levels (&lt;0.3 mg/dL), respectively. Conclusions These first real-world data demonstrated that TCZ was well tolerated, with acceptable safety and effectiveness in patients with sJIA. Higher incidences of SAEs and serious infections may be due to differences, such as corticosteroid use and concomitant diseases, between patient populations enrolled in previously reported clinical trials and this study.
CHD1L promotes lineage reversion of hepatocellular carcinoma through opening chromatin for key developmental transcription factors
Authors: Ming Liu, Leilei Chen, Ning‐Fang Ma, Raymond Kwok Kei Chow, Yan Li, Yangyang Song, Tim Hon Man Chan, Shuo Fang, Xiaodong Yang, Shaoyan Xi, Lingxi Jiang, Yun Li, Ting‐Ting Zeng, Yan Li, Yun‐Fei Yuan, Xin‐Yuan Guan
Journal: Hepatology (2016)

High‐grade tumors with poor differentiation usually show phenotypic resemblance to their developmental ancestral cells. Cancer cells that gain lineage precursor cell properties usually hijack developmental signaling pathways to promote tumor malignant progression. However, the molecular mechanisms underlying this process remain unclear. In this study, the chromatin remodeler chromodomain‐helicase‐DNA‐binding‐protein 1‐like (CHD1L) was found closely associated with liver development and hepatocellular carcinoma (HCC) tumor differentiation. Expression of CHD1L decreased during hepatocyte maturation and increased progressively from well‐differentiated HCCs to poorly differentiated HCCs. Chromatin immunoprecipitation followed by high‐throughput deep sequencing found that CHD1L could bind to the genomic sequences of genes related to development. Bioinformatics‐aided network analysis indicated that CHD1L‐binding targets might form networks associated with developmental transcription factor activation and histone modification. Overexpression of CHD1L conferred ancestral precursor‐like properties of HCC cells both in vitro and in vivo . Inhibition of CHD1L reversed tumor differentiation and sensitized HCC cells to sorafenib treatment. Mechanism studies revealed that overexpression of CHD1L could maintain an active “open chromatin” configuration at promoter regions of estrogen‐related receptor‐beta and transcription factor 4, both of which are important regulators of HCC self‐renewal and differentiation. In addition, we found a significant correlation of CHD1L with developmental transcriptional factors and lineage differentiation markers in clinical HCC patients. Conclusion: Genomic amplification of chromatin remodeler CHD1L might drive dedifferentiation of HCC toward an ancestral lineage through opening chromatin for key developmental transcriptional factors; further inhibition of CHD1L might “downgrade” poorly differentiated HCCs and provide novel therapeutic strategies. (H epatology 2016;63:1544‐1559)
High expression of PTPN21 in B-cell non-Hodgkin’s gastric lymphoma, a positive mediator of STAT5 activity
Authors: J H C Plani-Lam, T C Chow, Y-H Fan, B Garcia-Bloj, L Cheng, D Y Jin, W Hancock, S Fanayan, E Ingley, Y-Q Song
Journal: Blood Cancer Journal (2016)

High expression of PTPN21 in B-cell non-Hodgkin’s gastric lymphoma, a positive mediator of STAT5 activity
Parent-Adolescent Sexual Communication and Adolescent Safer Sex Behavior
Authors: Laura Widman, Sophia Choukas-Bradley, Seth M. Noar, Jacqueline Nesi, Kyla Garrett
Journal: JAMA Pediatrics (2015)

Parent-adolescent sexual communication has received considerable attention as a factor that can positively affect safer sex behavior among youth; however, the evidence linking such communication to youth contraceptive and condom use has not been empirically synthesized.To examine the effect of parent-adolescent sexual communication on safer sex behavior among youth and explore potential moderators of this association.A systematic search of studies published from database inception through June 30, 2014, using the MEDLINE, PsycINFO, and Communication & Mass Media Complete databases and relevant review articles yielded 5098 studies, of which 52 studies with 25,314 adolescents met the study eligibility criteria. Analysis was conducted from July 1, 2014, to July 27, 2015.Studies were included if they sampled adolescents (mean sample age ≤18 years), included an adolescent report of sexual communication with one or both parents, measured safer sex behavior, and were published in English.Correlation coefficients (r) and 95% CIs were computed from studies and meta-analyzed using random-effects models.Safer sex behavior, including use of contraceptives or condoms.Fifty-two articles, including 71 independent effects representing more than 3 decades of research on 25,314 adolescents (weighted mean age, 15.2 years) were synthesized. Across studies, there was a significant weighted mean effect (r = 0.10; 95% CI, 0.08-0.13) linking parent-adolescent sexual communication with safer sex behavior, which was statistically heterogeneous (Q = 203.50, P < .001, I2 = 65.60). Moderation analyses revealed larger effects for communication with girls (r = 0.12) than boys (r = 0.04) and among youth who discussed sex with their mothers (r = 0.14) compared with their fathers (r = 0.03). Effects did not differ for contraceptive vs condom use or among longitudinal vs cross-sectional studies, indicating that parent sexual communication had a similar effect across study designs and outcomes. Several methodological issues were identified in the literature; future studies can improve on these issues by measuring parent-adolescent communication with robust, multi-item measures, clearly specifying the target parent, and applying multimethod longitudinal designs.Sexual communication with parents, particularly mothers, plays a small protective role in safer sex behavior among adolescents; this protective effect is more pronounced for girls than boys. We discuss the implications for practice and make suggestions for future research on parent-adolescent sexual communication.
Effect of Artesunate–Amodiaquine on Mortality Related to Ebola Virus Disease
Authors: Etienne Gignoux, Andrew S. Azman, Martin de Smet, Philippe Azuma, Moses Massaquoi, Dorian Job, Amanda Tiffany, Roberta Petrucci, Esther Sterk, Julien Potet, Motoi Suzuki, Andreas Kurth, Angela Cannas, Anne Bocquin, Thomas Strecker, Christopher Logue, Thomas Pottage, Constanze Yue, Jean-Clement Cabrol, Micaela Serafini, Iza Ciglenecki
Journal: New England Journal of Medicine (2016)

Malaria treatment is recommended for patients with suspected Ebola virus disease (EVD) in West Africa, whether systeomatically or based on confirmed malaria diagnosis. At the Ebola treatment center in Foya, Lofa County, Liberia, the supply of artemether-lumefantrine, a first-line antimalarial combination drug, ran out for a 12-day period in August 2014. During this time, patients received the combination drug artesunate-amodiaquine; amodiaquine is a compound with anti-Ebola virus activity in vitro. No other obvious change in the care of patients occurred during this period.We fit unadjusted and adjusted regression models to standardized patient-level data to estimate the risk ratio for death among patients with confirmed EVD who were prescribed artesunate-amodiaquine (artesunate-amodiaquine group), as compared with those who were prescribed artemether-lumefantrine (artemether-lumefantrine group) and those who were not prescribed any antimalarial drug (no-antimalarial group).Between June 5 and October 24, 2014, a total of 382 patients with confirmed EVD were admitted to the Ebola treatment center in Foya. At admission, 194 patients were prescribed artemether-lumefantrine and 71 were prescribed artesunate-amodiaquine. The characteristics of the patients in the artesunate-amodiaquine group were similar to those in the artemether-lumefantrine group and those in the no-antimalarial group. A total of 125 of the 194 patients in the artemether-lumefantrine group (64.4%) died, as compared with 36 of the 71 patients in the artesunate-amodiaquine group (50.7%). In adjusted analyses, the artesunate-amodiaquine group had a 31% lower risk of death than the artemether-lumefantrine group (risk ratio, 0.69; 95% confidence interval, 0.54 to 0.89), with a stronger effect observed among patients without malaria.Patients who were prescribed artesunate-amodiaquine had a lower risk of death from EVD than did patients who were prescribed artemether-lumefantrine. However, our analyses cannot exclude the possibility that artemether-lumefantrine is associated with an increased risk of death or that the use of artesunate-amodiaquine was associated with unmeasured patient characteristics that directly altered the risk of death.
Gene expression signatures correlate with survival of patients with head and neck cancer treated with platinum-based regimens
Authors: Shama Buch, Michalis Karamouzis, Petr Pancoska, Shilong Zhong, Raja Seethala, Athanassios Argiris, Marjorie Romkes
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

4430 

Both the nucleotide excision repair (NER) pathway and glutathione S-transferase (GSTP1), a phase II metabolic enzyme, have independently been implicated as important predictors of responsiveness to platinum-based chemotherapy regimens and patient outcome in a variety of cancers. Here, we evaluated the association of mRNA expression profiles in both of these pathways as well as other DNA repair and cell cycle control pathways on survival in formalin-fixed paraffin embedded (FFPE) primary tumor and adjacent tissue samples from 96 patients with head and neck squamous cell carcinoma (HNSCC). All patients were treated with carboplatin or cisplatin, either alone or in combination with radiation or other agents. A panel of 128 genes was evaluated using a customized DASL assay on the Illumina Beadstation GX. The mean age of HNSCC diagnosis among these patients was 56.1 years, the median follow-up time was 834 days and a total of 25 deaths due to disease progression were observed.    An important aspect of expression profile analysis is the characterization of relationships among multiple profiles on the basis of similarities. Using a graph-theoretic approach to identify patterns of gene expression, several interesting associations were observed. A common over-expressed gene profile consisting of 16 genes was detected in a subset of cases (n=21). These simultaneously most highly expressed genes in cancers of the oral cavity and pharynx were associated with a reduced survival of <500 days. The 16 genes associated with this reduced survival profile were from the NER, base excision repair and mismatch repair families. GSTP1 as well as three cell cycle control genes were also predictive of reduced survival. Interestingly, males were overrepresented in this subgroup of cases compared to the overall study population (7:1 vs. 4:1). Additionally, the presence or absence of this over-expressed gene panel was able to differentiate short and long term survival in oral cavity and pharyngeal cancer cases with 64% sensitivity and 80% specificity.    The identification of gene expression profiles that can predict survival outcomes associated with platinum-based therapies provides an opportunity to evaluate the role of genes involved in DNA repair and response to treatment as well as to predict and potentially improve the efficacy of therapeutic approaches. Supported in part by NIH 1P50 CA097190.
Incidence of Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified As High-Risk in Guidelines for Myeloid Growth Factor Use: Importance of “Risk Factor Stacking”
Authors: Derek Weycker, Xiaoyan Li, Rich Barron, Hongsheng Wu, Phuong Khanh Morrow, Hairong Xu, Maureen Reiner, Jacob Garcia, Shivani Mhatre, Gary H. Lyman
Journal: Blood (2014)
BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis
Authors: J. Banuelos, S. Shin, Y. Cao, B. S. Bochner, L. Morales-Nebreda, G. R. S. Budinger, L. Zhou, S. Li, J. Xin, M. W. Lingen, C. Dong, R. P. Schleimer, N. Z. Lu
Journal: Allergy (2016)

Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis.Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo.Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids.Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma.
Timing of antiretroviral therapy initiation after diagnosis of recent human immunodeficiency virus infection and CD4+ T-cell recovery
Authors: Y. Ding, S. Duan, Z. Wu, R. Ye, Y. Yang, S. Yao, J. Wang, L. Xiang, Y. Jiang, L. Lu, M. Jia, R. Detels, N. He
Journal: Clinical Microbiology and Infection (2015)
Risk of CNS Relapse with Diffuse Large B-Cell Lymphoma (DLBCL) in the Rituximab Era: Results from the UK NCRI R-CHOP 14 v 21 Trial
Authors: Mary Gleeson, David Cunningham, Eliza A Hawkes, Wendi Qian, Paul Smith, Nick Chadwick, Paul Mouncey, Andrew Jack, Christopher Pocock, Kirit M Ardeshna, John Radford, Andrew McMillan, John Davies, Deborah Turner, Anton Kruger, Peter W.M. Johnson, Joanna Gambell, David C Linch
Journal: Blood (2014)
Abstract 16047: Clinical Difference Between Extended and Pure Apical Type of Apical Hypertrophic Cardiomyopathy
Authors: Sangchol Lee, Sung-Ah Chang, Sungji Park, Jin Oh Choi, Seung Woo Park, Eun Kyung Kim, Ga Yeon Lee, Sung Mok Kim, Eun Jeong Cho, Yeon Hyeon Choe, Jae K Oh
Journal: Circulation (2014)

Introduction:  Apical hypertrophic cardiomyopathy (HCM) is a type of hypertrophic cardiomyopathy that is considered to show favorable prognosis compared to other types in general. With the increase in use of cardiac magnetic resonance imaging (CMR), it has been able to evaluate the extent of apical hypertrophy among the patients with apical HCM.   Hypothesis:  We sought to find out the difference between the extended type and the pure apical type of apical HCM.   Methods:  Sixty-nine consecutive subjects who received CMR at our institute under the diagnosis of apical HCM by echocardiography were included in this study. The subjects were divided into two groups. When the hypertrophy was confined only to the 4 left ventricular apical segments, the subject was included in the pure apical group (N=32). The second group consisted of subjects whose apical hypertrophy was extended to at least one of the midventricular 6 segments, hence extended apical group (N=37). Clinical and CMR parameters were evaluated and compared between the two groups.   Results:  There were no significant differences in age, gender, history of syncope, NYHA class, presence of atrial fibrillation, or family history of sudden cardiac death or HCM. There were no differences in non-sustained ventricular tachycardia on 24-hour ECG or abnormal hemodynamic response to exercise either. In the extended apical group, the frequency of presence of late Gadolinium enhancement, (35 (94.6%) vs. 23 (71.9%), p = 0.02), left ventricular mass index, (78.90±19.78 vs. 69.24±12.71, p = 0.03) and presence of dynamic left ventricular cavity obstruction (18 (48.6%) vs. 3 (9.4%), p =0.001) were significantly higher compared to the pure apical group. Notably, there were 14 cases of apical pouching or aneurysmal change (20.3%) which were found only in the extended apical group.   Conclusions:  The extended type of apical hypertrophy in apical HCM demonstrates a higher rate of potentially serious findings for the prognosis of the disease compared to the pure apical type. This group should be considered separately among the apical HCM patients and may need special attention.
Punjab Medical Council investigates doctors for alleged payments from drug companies
Authors: Priyanka Pulla
Journal: BMJ (2015)

The Punjab Medical Council has sent notices to 10 doctors for receiving funds from pharmaceutical and allied healthcare companies, alleging that the doctors violated the code of ethics of the Medical Council of India. 

The code forbids doctors from accepting funds directly from drug firms, and any payments for services such as clinical research must be routed through institutions.1 

The Punjab Medical Council’s president, G S Grewal, said that the doctors named in its order to show cause had received funds through their personal bank accounts from drug companies, thus violating the national rules. 

The doctors have until 28 October to explain the payments. If the council is not satisfied it can begin proceedings against the doctors, which could result in a penalty such as the suspension of their licences.

The show cause notice named 21 companies, including Merck, MSD Pharmaceuticals, Sanofi India, Bayer Zydus Pharma, and Novartis Healthcare and the India based companies Glenmark Pharmaceuticals, Ranbaxy Laboratories (now a part of Sun Pharmaceuticals), Intas Pharmaceuticals, Eris Life Sciences, and Lupin. The notice also named three cord blood banking companies and two insurance third party administrators.

Grewal told The BMJ that his council identified the 10 doctors after scrutinising the tax records of a longer list of doctors who had previously been questioned for other ethical violations.

In March this year the council began investigating 164 doctors for being “ghost faculty,” a term for doctors who misrepresent themselves as full time teaching staff at medical colleges, in return for a payment.2 This misrepresentation allows these medical colleges to notch up their staff numbers and meet the requirements of the Medical Council …
Abstract 116: Door-to-Implantation Time of Percutaneous Circulatory Support Systems Predicts Mortality in Patients with Out-of-Hospital Cardiac Arrest
Authors: Juergen Leick, Christoph Liebetrau, Sebastian Szardien, Arnaud Van Linden, Holger Nef, Andreas Rolf, Matthias Arlt, Thomas Walther, Christian Hamm, Helge Mollmann
Journal: Circulation (2012)

Background: Cardiopulmonary resuscitation (CPR) is associated with low success rates and high variability in outcomes. Extracorporeal life support systems (ECLS) provide hemodynamic stabilization a...
Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated ΔNp73 Inhibition and p73 Activation
Authors: Varun V. Prabhu, Bo Hong, Joshua E. Allen, Shengliang Zhang, Amriti R. Lulla, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2016)

Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer. In contrast, p53 family member p73 is rarely mutated in colorectal cancer and p73 activation elicits p53-like tumor suppression. Colorectal cancer stem cells (CRCSC) comprise a rare self-renewing subpopulation that contributes to tumor maintenance and chemoresistance. p53 restoration is known to target CRCSCs, but p73 restoration in CRCSCs has not been examined. In this study, we investigated the effects of the small-molecule prodigiosin, which restores the p53 pathway in tumor cells via p73 activation, on CRCSCs in vitro and in vivo Prodigiosin prevented colonosphere formation independent of p53 status and reduced the viability of self-renewing, 5-fluorouracil-resistant Aldefluor positive [Aldefluor(+)] CRCSCs in vitro Furthermore, prodigiosin inhibited the growth of xenograft tumors initiated with Aldefluor+ cells without toxic effects and limited the tumorigenic potential of these cells. Consistently, prodigiosin induced activation of a p53-responsive luciferase reporter in colonospheres, Aldefluor(+) cells, and tumor xenografts. Mechanistic studies revealed that prodigiosin increased the levels of p73 and reduced levels of the oncogenic N-terminally truncated isoform ΔNp73 in Aldefluor(+) cells. Accordingly, p73 knockdown or ΔNp73 overexpression suppressed prodigiosin-mediated inhibition of colonosphere formation. Moreover, prodigiosin increased levels of the transcription factor c-Jun, a regulator of p73 and ΔNp73, in both the cytoplasm and nucleus. c-Jun knockdown attenuated prodigiosin-mediated p53-reporter activation, ΔNp73 downregulation, p73 activation, and cell death. Collectively, our findings highlight the previously uncharacterized use of p73-activating therapeutics to target CRCSCs. Cancer Res; 76(7); 1989-99. ©2016 AACR.