tbuckley/cabot-search huggingface dataset:
Abstract IA14: Targeting Ras
Authors: Frank McCormick
Journal: Clinical Cancer Research (2017)

Abstract We are exploring multiple ways of targeting Ras proteins and Ras-driven cancers. We have identified compounds that covalently bind to cysteine-185 on K-Ras 4B, and to the G-domain of K-Ras 4A and 4B. We are also screening for compounds that bind directly to K-Ras using a new technique referred to as Second Harmonic Generation and are developing compounds that promote phosphorylation of K-Ras4B on serine-181. In addition, we are attempting to solve novel structures of oncogenic Ras proteins on their own, or complexed with effectors, regulators and chaperones, in an attempt to identify new targeting opportunities. For example, we have solved the structure of fully processed K-Ras 4B bound to PDE-delta. This co-structure suggests several new approaches to targeting K-Ras processing. In addition to targeting K-Ras directly, we are validating downstream dependencies that are specific for K-Ras cancers, including the cytokine LIF, which is expressed at high levels in K-Ras transformed cells and plays a major role in stem-like properties of K-Ras cancers. Suppressing LIF expression using shRNA, CRISPR or monoclonal antibodies has profound effects on K-Ras tumor initiation and maintenance, and suggests new therapeutic opportunities. We are also analyzing signaling pathways that differ between Ras mutants and between Ras isoforms. These results, and their opportunities for intervention, will be discussed. Citation Format: Frank McCormick. Targeting Ras. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA14.
What about the needs of health workers in developing countries?
Authors: Neil Pakenham-Walsh
Journal: BMJ (2007)

In their randomised trial showing reduced in-hospital mortality after improved management of children under 5 years with malaria, Biai et al concede that “we cannot distinguish between the effect of supervising the implementation of the guidelines and the effect of the financial incentive in reducing mortality.”1 But this crucial point was lost in the abstract—and in others' interpretations:
Sustained virological response in HCV patients treated with daclatasvir + sofosbuvir, with or without ribavirin: a multicenter, field-practice experience
Authors: R. Sacco, E. Salomoni, S. Parodi, E. Gianni, L. Gragnani, G. Andreotti, M.R. Brunetto, A.L. Zignego, R. Gattai, I. Vivaldi, A. De Luca, D. Bartolozzi, R. Cinelli, M. Pozzi, B. Coco, G. Tapete, P. Forte, R. Puntili, L. Ricciardi, S. Sani, S. Luchi, B. Valoriani, M.P. Riccardi, C. Nencioni, D. Aquilini, A. Nerli, F. Esperti, F. Mazzotta, G. Bresci, P. Colombatto
Journal: Journal of Hepatology (2017)
Favourable virological and clinical outcomes at 1 year after liver transplantation in hepatitis C virus-positive patients who received direct-acting antivirals on the waiting list
Authors: S. Martini, S. Strona, M. Sacco, F. Tandoi, A. Ottobrelli, D. Cocchis, S. Mirabella, M. Salizzoni, G.M. Saracco, R. Romagnoli
Journal: Journal of Hepatology (2017)
Efficient Trial Design — FDA Approval of Valbenazine for Tardive Dyskinesia
Authors: Michael C. Davis, Brian J. Miller, Jasmeet K. Kalsi, Thomas Birkner, Mitchell V. Mathis
Journal: New England Journal of Medicine (2017)

In the case of valbenazine, which was recently approved for tardive dyskinesia, a small company pursued thoughtful, efficient trial design and an unusual application of remote assessment in clinical trials, and the FDA took an engaged and flexible approach to review.
Assessment of differentiation and progression of benign and malignant hepatic tumors using array based comparative genomic hybridization
Authors: Britta Skawran, Steinemann Doris, Becker Thomas, Tauscher Marcel, Weigmann Anja, Wingen Luzie, Tauscher Sarah, Hinrichsen Tanja, Hertz Sabine, Flemming Peer, Flik Jacobus, Wiese Birgit, Kreipe Hans, Lichter Peter, Schlegelberger Brigitte, Wilkens Ludwig
Journal: Cancer Research (2006)

152  Background The E2F transcription factor family is known to play a key role in the cell cycle progression and proliferation. But limited number of genes, which are transcriptionally regulated by this gene, has been identified. To clarify genome-wide screening of E2F1-binding DNA sequences at the promoter of putative E2F1-target genes in living human cells, we used a combination of chromatin immunoprecipitation (ChIP) and in-house human genome array (chip) composed of bacterial artificial chromosome clones (BACs). Materials and Methods In a manner of ChIP-on-chip, from a glioblastoma cell line, T98G, cross-linked protein-DNA complexes were precipitated with anti-E2F1 antibody, and total input DNA was obtained in the same manner without the antibody. Each of the DNAs was amplified by adaptor ligation-PCR and labeled with Cy3 and Cy5. The same volume of labeled DNA was competitively hybridized with BACs spotted on our custom-made BAC array. Results We detected many positive spots including BACs containing cyclinA2 and N-myc, which are well known as the transcriptional targets for E2F1. Among them we chose strongly positive BACs. These BACs contain known genes but not recognized as E2F1 targets, and these genes harbor E2F1 consensus recognition sequences within 2000 nucleotides spanning the transcription start site. Those three BACs contained 11 genes with E2F1 consensus sequences, and of them, only four genes were expressed in T98G cells. Conventional ChIP assay demonstrated in vivo binding of E2F1 to the consensus sequences of all four genes. One of them, ETG1 (lab. name) is known to be an apoptosis regulator. The transcriptional activity of the luciferase reporter constructs containing the consensus E2F1 binding site of ETG1 were elevated by co-transfection of E2F1. Exogeneously overexpressed E2F1 increased endogeneous ETG1 mRNA level. Conclusion The E2F1 pathway in a mechanism of ETG1 regulation may function within cancer cells to enhance tumor progression. Our “ChIP on chip” on BAC-array platform can facilitate to identify DNAs interacting with the specific proteins including transcription factors.
Development of autoimmune hepatitis in a psoriasis patient without immunosuppressive therapy
Authors: Wonyong Jo, Young-Sun Suh, Sang-Il Lee, Yun-Hong Cheon, Jeongmin Hong, Sang Su Lee, Ji Eun Kim, Gyung Hyuck Ko, Hyun-Ok Kim
Journal: Clinical and Molecular Hepatology (2017)

We present a case of a 65-year-old man with psoriasis who developed autoimmune hepatitis (AIH) without receiving immunosuppressive therapy with either anti-tumor necrosis factor-Î± or methotrexate. The AIH had completely resolved at 2 months after prednisolone and azathioprine therapy. This case confirms the need to consider AIH in psoriasis patients who experience new elevations in liver enzymes. To our knowledge, this is first description of the development of AIH in an immunosuppressant-naÃ¯ve patient with psoriasis. Keywords: Psoriasis; Autoimmune hepatitis
Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3k-Nrf2 signaling
Authors: Eun-Joo Joung, Mei-Hua Li, Hee Geum Lee, Nuntiya Somparn, Young-Nam Cha, Hye-Kyung Na, Young-Joon Surh
Journal: Cancer Research (2008)

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

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Capsaicin ( trans -8-methyl- N -vanillyl-6-nonenamide), a major pungent ingredient of red pepper, is reported to have anti-mutagenic and anti-carcinogenic properties. However, the mechanisms underlying its chemoprotective effects remain largely unresolved. In the present study, we found capsaicin induced expression of heme oxygenase-1 (HO-1) in HepG2 cells. Capsaicin treatment resulted in a transient increase in the phosphorylation of Akt and subsequently nuclear translocation of NF-E2-related factor 2 (Nrf2) and its binding to antioxidant response element (ARE). HepG2 cells treated with capsaicin exhibited increased production of reactive oxygen species (ROS). Prior exposure of cells with N -acetyl-L-cysteine (NAC) not only blocked the ROS production but also the Akt phosphorylation, nuclear translocation of Nrf2 and Nrf2-ARE binding, as well as HO-1 induction. Moreover, immunoblot analysis showed that while the level of HO-1 protein was elevated, that of NAD(P)H:quinone oxidoreductase (NQO1) was decreased with capsaicin or the inhibitor of NQO1, dicumarol. These results suggested that generation of reactive quinone metabolites of capsaicin that may bind covalently to NQO1 and thereby inhibit its activity may have been responsible for the overproduction of ROS. This, in turn, triggers the phosphorylation of Akt, increases the nuclear translocation of Nrf2 and its binding to ARE and upregulates the expression of HO-1.
What do NHS doctors think about their work?
Authors: John Appleby
Journal: BMJ (2017)

John Appleby finds much variation among trusts in the latest NHS staff survey

All good organisations want to know how their staff feel about their work. Disgruntled and unhappy staff means poor service and inefficiency, which for healthcare businesses can have serious consequences for patients and their health. This is the reason the NHS in England has been carrying out a staff survey every year since 2003, with the latest survey results published earlier this year.1

Given the size of the NHS workforce, the task is immense. For the latest survey more than 982 000 directly employed staff (about 94% of staff, and excluding those in contracted services such as general practice) were invited to take part, and 423 000 (44%), from hundreds of NHS organisations, responded.2 The survey included questions about working patterns, health and wellbeing, patient care, and bullying and was large enough to provide details at organisational and occupation levels. So what do …
Re: Fatemeh Seyednasrollah, Mehrad Mahmoudian, Liisa Rautakorpi, et al. How Reliable are Trial-based Prognostic Models in Real-world Patients with Metastatic Castration-resistant Prostate Cancer? Eur Urol. 2017;71:838–40
Authors: Tuomas Mirtti, Tero Aittokallio
Journal: European Urology (2017)
Abstract 61: miRNA-21 Targets Left Ventricular Peroxisome Proliferator-activated Receptor Alpha in a Rat Model of Type 4 Cardiorenal Syndrome
Authors: Alison J Kriegel, Mingyu Liang, Yong Liu, Pengyuan Liu, Allen W Cowley, Marc C Casati, Sandra Chuppa
Journal: Circulation Research (2015)

Type 4 cardiorenal syndrome (CRS4) is a condition in which chronic kidney disease (CKD) contributes to cardiovascular pathology including cardiac dysfunction, left ventricular (LV) hypertrophy, atherosclerosis, and heart failure. We have used a rat model of CKD, the 5/6 nephrectomy (5/6 NX), to study molecular mechanisms that mediate the development of cardiac pathology in CRS4. We previously reported that the upregulation of microRNA miR-21-5p (miR-21) in the left ventricle (LV) was accompanied by pathological remodeling and a drop in fractional shortening in adult male Sprague Dawley rats 7 weeks after 5/6 NX. Systemic knockdown of miR-21 in 5/6 NX rats with LNA-modified anti-miR-21 improved cardiac function, however it did not reduce the modest fibrosis observed with our 5/6 NX model or upregulate miR-21 targets identified in other models of cardiac pathology, suggesting a novel cardiac target for miR-21 in this model. Through next-generation mRNA sequencing of LV tissues from anti-miR-21 treated rats, and subsequent Ingenuity Pathway Analysis, we have found cardioprotective alterations in genes related to cardiac hypertrophy, metabolism, immune and inflammatory signaling, and atherosclerosis. Suppression or reduction of miR-21 target peroxisome proliferator-activated receptor alpha (PPARa), a master regulator of fatty acid oxidation, has been reported to be involved in all of these processes. Translational suppression of PPARa through miR-21 has been confirmed in other tissues, but not in the myocardium. The average LV PPARa protein expression level was significantly reduced (-37.7 ± 5.4%) in the 5/6 NX model and restored by miR-21 knockdown (Western blot; n=5-6/group; mean ± SEM). Immunohistochemistry revealed that the pronounced alterations in PPARa expression occurred within cardiomyocytes (CMs) in these samples. Transfection of neonatal CMs with pre-miR-21, significantly reduced PPARa protein expression within 48 hours (-23.0 ± 0.9%; n=3/group). These data indicate that PPARa suppression by miR-21 occurs within LV in 5/6 NX model of CKD and that miR-21 can regulate PPARa in CMs. This regulation may be relevant in other models of chronic cardiac disease where increased miR-21 and suppression of PPARa have been independently reported.
Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2
Authors: Shihao Zhang, Qinghua Chen, Qingxu Liu, Yuxi Li, Xiufeng Sun, Lixin Hong, Suyuan Ji, Chengyan Liu, Jing Geng, Weiji Zhang, Zhonglei Lu, Zhen-Yu Yin, Yuanyuan Zeng, Kwang-Huei Lin, Qiao Wu, Qiyuan Li, Keiko Nakayama, Keiich I. Nakayama, Xianming Deng, Randy L. Johnson, Liang Zhu, Daming Gao, Lanfen Chen, Dawang Zhou
Journal: Cancer Cell (2017)
M tuberculosis drug resistance in AIDS (multiple letters) [15]
Authors: G. Di Perri, S. Bonora, S. Vento, B. Allegranzi, E. Concia, D. N. Durrheim, J. Levin, K. Weyer, W. Z. Bradford, P. C. Hopewell, P. N. Small
Journal: The Lancet (1997)
Neurological tests improve after Olympic-style boxing bouts: a pretournament and post-tournament study in the 2016 Women’s World Boxing Championships
Authors: David R Howell, William P Meehan, Michael P Loosemore, Joseph Cummiskey, Jean-Paul Grabner von Rosenberg, David McDonagh
Journal: British Journal of Sports Medicine (2017)

To prospectively examine the neurocognitive, postural, dual-task and visual abilities of female Olympic-style boxers before and after participation in a tournament.Sixty-one females completed the modified Balance Error Scoring System (mBESS), King-Devick test and 3 m timed-up-and-go test in single-task and dual-task conditions. A subset (n=31) completed the CogState computerised neurocognitive test. Initial testing was completed prior to the 2016 Women's World Boxing Championships; each participant repeated the testing protocol within a day of elimination. No participant sustained a concussion. Pretournament and post-tournament performance variables were compared using paired t-tests or Wilcoxon signed-rank tests.Participants completed a mean of 7.5±4.5 rounds of Olympic-style boxing over 2-8 days. Post-tournament scores were significantly lower than pretournament scores for total mBESS (2.2±1.9 errors vs 5.5±2.9 errors, p<0.001, d=1.23) and King-Devick time (14.2±3.9 s vs 18.0±8.3 s, p=0.002, d=0.53). Processing speed was significantly faster after the boxing tournament (maze chase task: 1.39±0.34 correct moves/second vs 1.17±0.44 correct moves/second, p=0.001, d=0.58). No significant changes across time were detected for the other obtained outcome variables.Female boxers demonstrated either improvement or no significant changes in test performance after competing in an Olympic-style boxing tournament, relative to pretournament performance. As many of the test tasks were novel for the boxers, practice effects may have contributed to improved performance. When there is a short time frame between assessments, clinicians should be aware of potential practice effects when using ringside neurological tests.
A multicommunity trial for primary prevention of adolescent drug abuse. Effects on drug use prevalence
Authors: M. A. Pentz
Journal: JAMA (1989)

The entire early adolescent population of the 15 communities that constitute the Kansas City (Kansas and Missouri) metropolitan area has participated in a community-based program for prevention of drug abuse since September 1984. The Kansas City area is the first of two major metropolitan sites being evaluated in the Midwestern Prevention Project, a longitudinal trial for primary prevention of cigarette, alcohol, and marijuana use in adolescents. The project includes mass media programming, a school-based educational program for youths, parent education and organization, community organization, and health policy components that are introduced sequentially into communities during a 6-year period. Effects of the program are determined through annual assessments of adolescent drug use in schools that are assigned to immediate intervention or delayed intervention control conditions. In the first 2 years of the project, 22 500 sixth- and seventh-grade adolescents received the school-based educational program component, with parental involvement in homework and mass media coverage. Analyses of 42 schools indicate that the prevalence rates of use for all three drugs are significantly lower at 1-year follow-up in the intervention condition relative to the delayed intervention condition, with or without controlling for race, grade, socioeconomic status, and urbanicity (17% vs 24% for cigarette smoking, 11% vs 16% for alcohol use, and 7% vs 10% for marijuana use in the last month), and the net increase in drug use prevalence among intervention schools is half that of delayed intervention schools. (<i>JAMA</i>. 1989;261:3259-3266)
Comparison of Efficacy and Safety of Two Types of E.coli Asparaginase (Native or Pegylated) for Treatment of Adult Patients with High-Risk (HR), Philadelphia (Ph) Chromosome-Negative ALL Included in the Prospective MRD-Oriented Protocol ALL-HR-11 from the Spanish Pethema Group
Authors: Josep-Maria Ribera, Mireia Morgades, Pau Montesinos, Irene García-Cadenas, Pere Barba, Beatriz Soria, Arancha Bermúdez, MªJosé Moreno, José González-Campos, Susana Vives, Cristina Gil, Eugenia Abella, Ramon Guàrdia, Teresa Bernal, Pilar Martínez-Sánchez, MªLuz Amigo, Santiago Mercadal, Alfons Serrano, Aurelio López-Martínez, Ferran Vall-llovera, MªJosé Sánchez-Sánchez, MªJesús Peñarrubia, María Calbacho, Jose-Angel Méndez, Juan Bergua, Antònia Cladera, Mar Tormo, Daniel García-Belmonte, Juana Ciudad, Evarist Feliu, Alberto Orfao
Journal: Blood (2016)
James Hector Macpherson
Authors: Jonathan Pywell
Journal: BMJ (2017)

Rarely in life are there truly gracious and sincere individuals. James Hector Macpherson was one of them. Known to all as Jamie, he devoted a lifetime of service to working as a general practitioner in the Coventry area. His kind and warm approach, coupled with an excellent clinical acumen, made him a firm favourite with all the patients at Springfield Medical Practice, where he practised for more than 33 years. He was exceptionally well regarded and loved by his patients. No doubt his own experiences of ill health gave him an ability truly to empathise with his patients.

Of Scottish descent, Jamie was raised and educated in Zambia, where he qualified as a medical …
The prevalence of food allergy and other allergic diseases in early childhood in a population-based study: HealthNuts age 4-year follow-up
Authors: Rachel L. Peters, Jennifer J. Koplin, Lyle C. Gurrin, Shyamali C. Dharmage, Melissa Wake, Anne-Louise Ponsonby, Mimi L.K. Tang, Adrian J. Lowe, Melanie Matheson, Terence Dwyer, Katrina J. Allen
Journal: Journal of Allergy and Clinical Immunology (2017)
Serious adverse events and the risk of stroke in patients with rheumatoid arthritis: results from the German RABBIT cohort
Authors: Y Meissner, A Richter, B Manger, HP Tony, E Wilden, J Listing, A Zink, A Strangfeld
Journal: Annals of the Rheumatic Diseases (2017)

Objective In the general population, the incidence of stroke is increased following other serious events and hospitalisation. We investigated the impact of serious adverse events on the risk of stroke in patients with rheumatoid arthritis (RA), taking risk factors and treatment into account. Methods Using data of the German biologics register RABBIT (Rheumatoid Arthritis: Observation of Biologic Therapy) with 12354 patients with RA, incidence rates (IRs) and risk factors for stroke were investigated using multi-state and Cox proportional hazard models. In addition, in a nested case–control study, all patients with stroke were matched 1:2 to patients with identical baseline risk profile and analysed using a shared frailty model. Results During follow-up, 166 strokes were reported. The overall IR was 3.2/1000 patient-years (PY) (95% CI 2.7 to 3.7). It was higher after a serious adverse event (IR: 9.0 (7.3 to 11.0)), particularly within 30 days after the event (IR: 94.9 (72.6 to 121.9)). The adjusted Cox model showed increased risks of age per 5 years (HR: 1.4 (1.3 to 1.5)), hyperlipoproteinaemia (HR: 1.6 (1.0 to 2.5)) and smoking (HR: 1.9 (1.3 to 2.6)). The risk decreased with better physical function (HR: 0.9 (0.8 to 0.96)). In the case–control study, 163 patients were matched to 326 controls. Major risk factors for stroke were untreated cardiovascular disease (HR: 3.3 (1.5 to 7.2)) and serious infections (HR:4.4 (1.6 to 12.5)) or other serious adverse events (HR: 2.6 (1.4 to 4.8)). Conclusions Incident adverse events, in particular serious infections, and insufficient treatment of cardiovascular diseases are independent drivers of the risk of stroke. Physicians should be aware that patients who experience a serious event are at increased risk of subsequent stroke.
Beraprost sodium, a prostacyclin analogue, reduces fructose-induced hepatocellular steatosis in mice and in vitro via the microRNA-200a and SIRT1 signaling pathway
Authors: Pengyuan Zhang, Lijuan Xu, Hongyu Guan, Liehua Liu, Juan Liu, Zhimin Huang, Xiaopei Cao, Zhihong Liao, Haipeng Xiao, Yanbing Li
Journal: Metabolism (2017)
A randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapy (EORTC/ETOP 1416-PEARLS)
Authors: L. Paz-Ares, B. Hasan, U. Dafni, J. Menis, E. De Maio, K. Oselin, I. Albert, M. Faehling, P. Van Schil, M.E.R. O'Brien
Journal: Annals of Oncology (2017)
Landscape of Subclonal Mutations in Myelodysplastic Syndromes (MDS) Allows for a Novel Hierarchy of Clonal Advantage By Combining Germline and Somatic Mutations
Authors: Yasunobu Nagata, Hideki Makishima, Tomas Radivoyevitch, Cassandra M. Hirsch, Bartlomiej P Przychodzen, Teodora Kuzmanovic, Samuel Li, Kenichi Yoshida, Tetsuichi Yoshizato, Vera Adema, Eiju Negoro, Michael J. Clemente, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Sudipto Mukherjee, Aziz Nazha, Francesc Sole, Hetty E. Carraway, Satoru Miyano, Thomas LaFramboise, Mikkael A. Sekeres, Seishi Ogawa, Jaroslaw P. Maciejewski
Journal: Blood (2016)
Multicenter External Validation of Risk Stratification Criteria for Patients With Variceal Bleeding
Authors: Irene Conejo, Maria Anna Guardascione, Puneeta Tandon, Alba Cachero, Josep Castellote, Juan G. Abraldes, Lucio Amitrano, Joan Genescà, Salvador Augustin
Journal: Clinical Gastroenterology and Hepatology (2017)
Antifibrotic effects of 8-hydroxydeoxyguanosine through the inhibition of NADPH oxidase-derived oxidative stress in vitro and in vivo model of liver fibrosis
Authors: S.K. Shin, O.S. Kwon, J.J. Lee, D.J. Choi, Y.S. Kim, J.H. Kim
Journal: Journal of Hepatology (2017)
A framework for hepatitis C virus treatment as prevention in the prison setting: the SToP-C implementation toolkit
Authors: M. Byrne, B. Hajarizadeh, G.J. Dore, C. Treloar, P. Marks, A. Milat, J. Bowman, C. McGrath, N. Bath, I. Calder, K. Lagios, J. Grebely, A. Lloyd
Journal: Journal of Hepatology (2017)
The effect of elafibranor and obeticholic acid on NAFLD Activity score and fibrosis stage in a novel metabolic rat model of diet-induced and biopsy-confirmed NASH
Authors: N. Vrang, K.S. Tølbøl, M. Illemann, S.S. Veidal, L.D. Fensholdt, M. Feigh
Journal: Journal of Hepatology (2017)