tbuckley/cabot-search huggingface dataset:
Exploring the association between renal cell carcinoma (RCC) and myeloid malignancies.
Authors: Niraj Konchady Shenoy, Mythri Mudireddy, Nelson Leung, Brian Addis Costello, Bradley C. Leibovich, Robert Houston Thompson, Lance C. Pagliaro, Thomas E. Witzig, Fang-Shu Ou, Tamas Ordog, Mrinal Mahesh Patnaik, Ayalew Tefferi, Kebede Begna
Journal: Journal of Clinical Oncology (2017)

e13073 Background: We observed several patients with a personal history of both RCC and myeloid malignancy, and aimed to explore a possible association, especially given the similarity in their epigenetic landscape, with both being characterized by widespread aberrant hypermethylation (Hu C et al, CCR 2014; Jiang Y et al, Blood 2009). Methods: Mayo Clinic’s ‘Advanced Cohort Explorer’ database was used to identify patients with a history of both RCC and a myeloid malignancy - Acute Myelogenous Leukemia (AML), Myeloproliferative Neoplasms (MPN), Myelodysplastic syndromes (MDS) - and to determine the clinical characteristics. The incidence of MDS in patients ≥65 years with a history of RCC was compared to that in the general population ≥65 years (SEER- Medicare database) as well as the general patient population at Mayo Clinic, using one sample test of proportions. Results: A total of 59 patients were identified, with both biopsy proven RCC and a myeloid malignancy during their life time (12 AML, 9 MPN, 9 low risk MDS and 29 intermediate- high risk MDS). The cohort was characterized by marked male predominance (4.4: 1). Median age at RCC diagnosis was 64 years (range 37-87) and myeloid malignancy was 75 years (range 44-90). 46/59 patients had the RCC antecedent, 10/59 concurrent and 3/59 subsequent to the myeloid malignancy with a median time of myeloid malignancy diagnosis after RCC diagnosis of 7.7 years. For patients ≥65 years, the risk of developing MDS with a history of stage I/II RCC and nephrectomy was 5.26 times that of the general population based on the SEER-Medicare database (Cogle, Blood 2011)(395/100,000 vs 75/100,000; p value &lt; 0.001), and 3.07 times that of the general population at Mayo Clinic (395/100,000 vs 128.4/100,000; p value &lt; 0. 001). Conclusions: We observed an association between RCC and myeloid malignancies, particularly MDS; with a history of RCC conferring a substantially increased risk of developing MDS. We hypothesize that the perturbation of epigenetic landscape in the form of widespread hypermethylation may explain, in part, the association between the two malignancies; and aim to explore the potential aberrancy of epigenetic regulators in our patient cohort with a genomic, epigenomic and transcriptomic analysis.
Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double‐blind, phase <scp>III NAVIGATE</scp> trial
Authors: R.G. Langley, T.‐F. Tsai, S. Flavin, M. Song, B. Randazzo, Y. Wasfi, J. Jiang, S. Li, L. Puig
Journal: British Journal of Dermatology (2017)

Guselkumab, an anti-interleukin-23 monoclonal antibody, has demonstrated significant efficacy in phase III psoriasis trials.To evaluate the efficacy and safety of guselkumab in patients with moderate-to-severe plaque psoriasis who had an inadequate response to ustekinumab.In this phase III, randomized, double-blind study, 871 patients received open-label ustekinumab (45 mg or 90 mg) at weeks 0 and 4. At week 16, 268 patients with an inadequate response to ustekinumab [Investigator's Global Assessment (IGA) ≥ 2] were randomized (double-blind) to guselkumab 100 mg or to continue ustekinumab; 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open-label ustekinumab. The primary end point was the number of visits at which randomized patients achieved IGA 0/1 and at least a two-grade improvement (from week 16) from week 28 to week 40. Improvement ≥ 90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed.The mean number of visits at which patients achieved IGA 0/1 and at least a two-grade improvemen (week 28-40) was significantly greater in the guselkumab group vs. the randomized ustekinumab group (1·5 vs. 0·7; P < 0·001); greater proportions of patients in the guselkumab group achieved IGA 0/1 and at least a two-grade improvement at week 28 (31·1% vs. 14·3%; P = 0·001) and week 52 (36·3% vs. 17·3%; P < 0·001). Greater proportions of patients treated with guselkumab achieved PASI 90, PASI 100 and DLQI 0/1 at week 52. After week 16, 64·4% of patients in the guselkumab group and 55·6% in the ustekinumab group had at least one adverse event (AE); infections were the most frequent AE type. Overall, 6·7% (n = 9) of patients in the guselkumab group had at least one serious AE compared with 4·5% (n = 6) for the ustekinumab group.Patients treated with ustekinumab who did not achieve an IGA of 0/1 by week 16 derived significant benefit from switching to guselkumab.
Association of baseline plasma levels of 25OH vitamin D and breast cancer risk in a chemoprevention trial.
Authors: Bernardo Bonanni, Davide Serrano, Sara Gandini, Harriet Ann Johansson, Debora Macis, Valentina Aristarco, Aliana Guerrieri-Gonzaga, Andrea De Censi
Journal: Journal of Clinical Oncology (2017)

1546 Background: Observational studies have shown a correlation of higher serum 25-hydroxyvitamin D (25OHD) concentrations and reduced cancer risk, including breast cancer (BC). We assessed the association of 25OHD and Vitamin D Receptor (VDR) polymorphisms (SNPs) with breast cancer events within a chemoprevention trial in premenopausal women at risk for BC. Methods: Premenopausal women with history of intraepithelial neoplasia (IEN) or at risk women according to the Gail model were included in a 4 arm phase II prevention trial (low dose tamoxifen vs fenrerinide vs their combination vs placebo). Level of 25OHD were measured at baseline. VDR SNPs ( FokI, BsmI, TaqI, ApaI, and Cdx2) were determined using the Applied Biosystems’ Taqman Allelic Discrimination Assay according to manufacturer’s instructions. Survival analysis for breast cancer events was performed using competing risk models, adjusted for BMI, age, season and risk strata. Results: Plasma samples were available for 228 subjects. At baseline the median plasma 25OHD concentrations were slightly higher in 53 unaffected women, 19.6 ng/ml (IQR 12.7-27.3 ng/mL) than in 175 women with IEN, 18.8 ng/ml (11.7-25.8). After a median follow up of 15 years, 79 women developed a breast cancer event, 12 had different neoplastic events. The median level of 25OHD was 19.7 ng/ml (IQR 12.8-26.1) in subjects free from oncological events and 17.8 ng/ml (9.7-23.9) in subjects with breast events. Women in the lowest 25OHD quartile (≤12 ng/ml) had an increased risk of breast cancer events: HR = 1.79 (95%CI, 1.07-2.99, p = 0.03). Considering all cancer events, the associations with 25OHD were confirmed (P = 0.005). Among the VDR SNPs the ApaI variant in homozygote or heterozygote versus wild type showed an HR of 1.83 (95%CI, 1.04-3.21 p = 0.03). Conclusions: Our results support a role of plasma vitamin D levels in breast cancer risk. Subjects in the lowest quartile had a two-fold increased risk of a cancer event. Our findings support trials of 25OHD supplementation to prevent breast cancer in 25OHD insufficient subjects.
Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes
Authors: Emmy D.G. Fleuren, Myrella Vlenterie, Winette T.A. van der Graaf, Melissa H.S. Hillebrandt-Roeffen, James Blackburn, Xiuquan Ma, Howard Chan, Mandy C. Magias, Anke van Erp, Laurens van Houdt, Sabri A.S. Cebeci, Amy van de Ven, Uta E. Flucke, Erin E. Heyer, David M. Thomas, Christopher J. Lord, Kieren D. Marini, Vijesh Vaghjiani, Tim R. Mercer, Jason E. Cain, Jianmin Wu, Yvonne M.H. Versleijen-Jonkers, Roger J. Daly
Journal: Cancer Research (2017)

Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry-based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALK
Platelet-to-hemoglobin ratio as a prognostic factor for hepatocellular carcinoma patients receiving transcatheter arterial chemoembolization.
Authors: Xing Li, Zhi-Huan Lin, Ying-fen Hong, Tian-tian Wang, Dong-hao Wu, Xiao-kun Ma, Yan-Fang Xing, Mingsheng Huang, Min Dong, Qu Lin, Xiang-yuan Wu
Journal: Journal of Clinical Oncology (2016)

e15591 Background: The prognosis of hepatocellular carcinoma (HCC) patients receiving transcatheter arterial chemoembolization (TACE) is far from being identified. The present study aimed to assess role of blood cell counts, routine liver function tests in predicting the progression-free survival (PFS) of these patients. Methods: A total of 243 HCC patients receiving TACE were analyzed retrospectively. The current staging systems of HCC were investigated about their performance of prediction. And then, the novel prognostic factors were integrated in to the best staging systems to determine their independency. Results: Cancer of the Liver Italian Program (CLIP) score system and advanced liver cancer prognostic system (ALCPS) stages were indentified to be the best score systems among current 12 staging systems for this patient subgroup according akaike information criterion (AIC) index and linear trend χ2. Then, the novel prognostic value of parameters was determined by integration into CLIP and ALCPS score systems. As a result, Platelet-to-Hemoglobin Ratio (PHR) were confirmed to an independent predictor for PFS of HCC patients receiving TACE when integrated into CLIP, BCLC and ALCPS score systems (p= 0.026 and 0.009, respectively) with the other parameters, including platelet and hemoglobin, failed to reach statistical significance. Moreover，PHR improved the performance of CLIP, BCLC and ALCPS score systems by adjusted into it, thus improved the discriminatory ability. Furthermore, PHR were defined value ≤ 1.26 as low level and > 1.26 as high level, according to which patients were dichotomized into two groups. HCC patients receiving TACE with low PHR presented better 1 year disease progress rate (24.0% vs 41%) and overall survival (62.5% vs 38.8%) compared with patients with high PHR level. Besides, PHR level was associated with prognostic factors such as international normalized ratio, incidence of ascites, serum albumin, serum α-fetoprotein, total bilirubin and portal vein thrombosis. Conclusions: In summary, the present study firstly indentified PHR as an independent prognostic factor in HCC patients receiving TACE.
Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study
Authors: Séverine Sabia, Aline Dugravot, Jean-François Dartigues, Jessica Abell, Alexis Elbaz, Mika Kivimäki, Archana Singh-Manoux
Journal: BMJ (2017)

<h3>Abstract</h3> <h3>Objective</h3> To test the hypotheses that physical activity in midlife is not associated with a reduced risk of dementia and that the preclinical phase of dementia is characterised by a decline in physical activity. <h3>Design</h3> Prospective cohort study with a mean follow-up of 27 years. <h3>Setting</h3> Civil service departments in London (Whitehall II study). <h3>Participants</h3> 10 308 participants aged 35-55 years at study inception (1985-88). Exposures included time spent in mild, moderate to vigorous, and total physical activity assessed seven times between 1985 and 2013 and categorised as “recommended” if duration of moderate to vigorous physical activity was 2.5 hours/week or more. <h3>Main outcome measures</h3> A battery of cognitive tests was administered up to four times from 1997 to 2013, and incident dementia cases (n=329) were identified through linkage to hospital, mental health services, and mortality registers until 2015. <h3>Results</h3> Mixed effects models showed no association between physical activity and subsequent 15 year cognitive decline. Similarly, Cox regression showed no association between physical activity and risk of dementia over an average 27 year follow-up (hazard ratio in the “recommended” physical activity category 1.00, 95% confidence interval 0.80 to 1.24). For trajectories of hours/week of total, mild, and moderate to vigorous physical activity in people with dementia compared with those without dementia (all others), no differences were observed between 28 and 10 years before diagnosis of dementia. However, physical activity in people with dementia began to decline up to nine years before diagnosis (difference in moderate to vigorous physical activity −0.39 hours/week; P=0.05), and the difference became more pronounced (−1.03 hours/week; P=0.005) at diagnosis. <h3>Conclusion</h3> This study found no evidence of a neuroprotective effect of physical activity. Previous findings showing a lower risk of dementia in physically active people may be attributable to reverse causation—that is, due to a decline in physical activity levels in the preclinical phase of dementia.
Lying flat after stroke achieves similar outcomes to sitting up, trial finds
Authors: Susan Mayor
Journal: BMJ (2017)

Positioning patients who have had an acute ischaemic stroke so that they lie flat does not improve outcomes more than sitting them up, a large randomised trial shows,1 after a debate about whether head position affects stroke recovery.

Previous studies have found that laying patients flat in the 24 hours after an acute ischaemic stroke may improve recovery and reduce disability by increasing blood flow through the main arteries to the brain. Concerns were raised, however, that this could increase the risk of pneumonia. This uncertainty has resulted in ambiguous guidelines and variations in clinical practice.

The lead author, …
Clono-Specific Evaluation of Minimal Residual Disease in Acute Myeloid Leukemia
Authors: Pierre Hirsch, Ruoping Tang, Nassera Abermil, Pascale Flandrin, Hannah Moatti, Mohamad Mohty, Ollivier Legrand, Luc Douay, Chrystele bilhou Nabera, Francois Delhommeau
Journal: Blood (2016)
Immune-mediated effects targeting hepatitis C virus in a syngeneic replicon cell transplantation mouse model
Authors: Sepideh Levander, Fredrik Holmström, Lars Frelin, Gustaf Ahlén, Daniel Rupp, Gang Long, Ralf Bartenschlager, Matti Sällberg
Journal: Gut (2017)

Objective HCV is characterised by its ability to establish chronic infection in hepatocytes and to replicate in the presence of an inflammation. We mimicked this situation in vivo in immune-competent mice by syngeneic transplantation of HCV replicon-containing mouse hepatoma cells. Design A total of 5 million H-2 b positive Hep56.1D cells, carrying a subgenomic genotype (gt) 2a replicon (HCV replicon cells) or stably expressing comparable levels of the HCV NS3/4A protease/helicase complex (NS3/4A hepatoma cells), were injected subcutaneously into syngeneic H-2 b -restricted mice. Kinetics of tumour growth, HCV RNA replication levels and HCV-specific immune responses were monitored. For immune monitoring, new H-2 b -restricted cytotoxic T cell epitopes within the gt2a NS3/4A region were mapped. Immune mice were generated by DNA-based vaccination. Results HCV replicon and NS3/4A hepatoma cells generated solid tumours in vivo. Similar to what is seen in human HCV infection did HCV RNA replicate in the presence of inflammation. NS3/4A-specific CD8+ T cells seemed to transiently reduce HCV RNA levels. Both CD4+ and CD8+ T cells were required for protection against tumour growth. Vaccine-induced NS3/4A(gt2a)-specific T cells protected against HCV replicon tumours in wild-type, but not in HCV NS3/4A(gt1a)-transgenic mice with dysfunctional HCV-specific T cells. Importantly, as in human HCV infection, HCV replicon cells neither primed nor boosted a strong NS3/4A-specific T cell response. Conclusion Syngeneic transplantation of mouse HCV replicon cells into immune-competent animals mirrors many in vivo events in humans. This system is versatile and can be applied to any genetically modified H-2 b -restricted mouse strain.
Targeting psychologic stress signaling pathways in Alzheimer’s disease
Authors: Hunter S. Futch, Cara L. Croft, Van Q. Truong, Eric G. Krause, Todd E. Golde
Journal: Molecular Neurodegeneration (2017)

Alzheimer’s Disease (AD) is the most prevalent progressive neurodegenerative disease; to date, no AD therapy has proven effective in delaying or preventing the disease course. In the search for novel therapeutic targets in AD, it has been shown that increased chronic psychologic stress is associated with AD risk. Subsequently, biologic pathways underlying psychologic stress have been identified and shown to be able to exacerbate AD relevant pathologies. In this review, we summarize the literature relevant to the association between psychologic stress and AD, focusing on studies investigating the effects of stress paradigms on transgenic mouse models of Amyloid-β (Aβ) and tau pathologies. In recent years, a substantial amount of research has been done investigating a key stress-response mediator, corticotropin-releasing hormone (CRH), and its interactions with AD relevant processes. We highlight attempts to target the CRH signaling pathway as a therapeutic intervention in these transgenic mouse models and discuss how targeting this pathway is a promising avenue for further investigation.
Abstract 15634: Effect of Perioperative Atrial Fibrillation in Orthotopic Heart Transplant Recipients on Short and Long Term Mortality
Authors: Lori K Soni, Jeffrey Jiang, Matthew A Lippel, Neelofar Abdullah, Nasir Hussain, Stephen Cheung, Kenneth J Schaefle, Marvi Rizwan, Matthew Konigsberg, Donna M Mancini, Maryjane Farr, Michael Argenziano, Yoshifumi Naka, Hiroo Takayama, Paul C Schulze, Faisal H Cheema
Journal: Circulation (2011)

Background: There has been considerable variance in the reported incidence of atrial fibrillation (AF) after orthotopic heart transplant (Htx). We sought to define the development of perioperative ...
Doctors who misuse alcohol need more support English health authorities must reduce costs Patients' voices must be heard in research Access to the specialist register amended There are doubts about merit awards for GPs GPs' leader warns of rationing in general practice Review body report 1998 Medical academics criticise research assessment exercise GPs given guidance on section 36 payments
Authors: Linda Beecham
Journal: BMJ (1998)

# Doctors who misuse alcohol need more support {#article-title-2}

A new report on the misuse of alcohol and other drugs by doctors recognises that the public is concerned about the issue of doctors' impairment and says that the profession must respond by monitoring progress and modifying policies.

The report, The Misuse of Alcohol and Other Drugs by Doctors , was produced by a working party, which included representatives of the BMA, the General Medical Council, the Medical Defence Union, the Medical Protection Society, the Academy of Medical Royal Colleges, the Medical Council on Alcoholism, and the Society of Occupational Medicine.

The report says that two thirds of all cases referred to the GMC health procedures involve the misuse of alcohol and other drugs and it estimates that one in 15 doctors in Britain may suffer some form of dependence. Misuse is found in all sectors of the profession, in men and women, and in all parts of Britain.

The report aims to prevent any risk to patients; to raise awareness of the problem; to highlight the need for education; and to ensure access to appropriate treatment and rehabilitation. It recommends that addiction must be recognised in undergraduate, postgraduate, and continuing education programmes; that all working doctors should have access to a comprehensive occupational health service; that there must be support for those who express concern about a colleague; that medical schools, employing authorities, and GP surgeries should have a drug and alcohol policy; that doctors should avoid self prescribing of any sort; and that all doctors should be encouraged to register with a GP.

At the launch press conference the president of the Royal College of Psychiatrists, Dr Robert Kendell, reported that the Academy of Medical Royal Colleges would recommend to the Department of Health and the NHS Confederation that NHS managers should have the right to impose random …
IPI-549-01-A phase 1/1b first in human study of IPI-549, a PI3K-γ inhibitor, as monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors.
Authors: Anthony W. Tolcher, David S. Hong, Ryan J. Sullivan, James Walter Mier, Geoffrey Shapiro, Joseph Pearlberg, Les H. Brail, Jahnavi Kharidia, Lixin Han, Claudio Dansky Ullmann, Howard Marvin Stern, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2016)

TPS3111 Background: IPI-549 is a potential first-in-class potent and selective PI3K-γ inhibitor being developed as a novel orally administered immuno-oncology therapeutic in multiple cancer indications. Preclinical studies demonstrate a role for PI3K-γ in polarization of immune suppressive myeloid cells in the tumor microenvironment. Inhibition of PI3K-γ by IPI-549 enhanced antitumor immune responses and inhibited tumor growth in syngeneic solid tumor preclinical models. In addition, IPI-549 in combination with immune checkpoint inhibitors showed increased tumor growth inhibition compared to each single agent in multiple pre-clinical models. These data served as the scientific foundation for initiating a clinical trial testing IPI-549 as a potential immuno-oncology therapy. This first-in-human clinical study will evaluate the safety and tolerability, and determine the recommended Phase 2 dose (RP2D) of IPI-549 when administered as a monotherapy and in combination with pembrolizumab (NCT02637531) in solid tumors. Methods: This multi-part Phase 1/1b open-label trial will initiate with monotherapy dose escalation cohorts consisting of an accelerated dose escalation phase followed by a standard phase with a 3+3 design. Evaluation of the PK, PD, and safety data in these cohorts will lead to the determination of the maximum tolerated dose (MTD) and RP2D of IPI-549 monotherapy. Subsequently, combination dose escalation cohorts will be initiated in which the combination of IPI-549 and pembrolizumab will be evaluated. Expansion cohorts evaluating the safety, PK, PD, and preliminary clinical activity of IPI-549 as a monotherapy and in combination with pembrolizumab will occur following the dose escalation phase. All subjects in the trial will have advanced and/or metastatic carcinoma or melanoma, and will have failed to respond to standard therapies. Combination expansion cohorts will recruit subjects with non-small cell lung cancer or melanoma who must have received an anti-PD-1 or anti-PD-L1 antibody as their most recent treatment. This trial is currently enrolling patients in the US. Clinical trial information: NCT02637531.