tbuckley/cabot-search huggingface dataset:
Estimating the causal effect of body mass index on hay fever, asthma and lung function using Mendelian randomization
Authors: T. Skaaby, A. E. Taylor, B. H. Thuesen, R. K. Jacobsen, N. Friedrich, L. T. Møllehave, S. Hansen, S. C. Larsen, U. Völker, M. Nauck, H. Völzke, T. Hansen, O. Pedersen, T. Jørgensen, L. Paternoster, M. Munafò, N. Grarup, A. Linneberg
Journal: Allergy (2017)

Abstract Background Observational studies have shown that body mass index ( BMI ) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one‐second ( FEV 1) and forced vital capacity ( FVC ). Methods We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score ( GRS ) was created using 26 BMI ‐associated single nucleotide polymorphisms ( SNP s). Results were pooled in meta‐analyses and expressed as odds ratios ( OR s) or β‐estimates with 95% confidence interval ( CI ). Results The GRS was significantly associated with asthma ( OR =1.009; 95% CI : 1.004, 1.013), but not with hay fever ( OR = 0.998; 95% CI : 0.994, 1.002) or allergic sensitization ( OR =0.999; 95% CI : 0.986, 1.012) per BMI ‐increasing allele. The GRS was significantly associated with decrease in FEV 1: β=−0.0012 (95% CI : −0.0019, −0.0006) and FVC : β=−0.0022 (95% CI : −0.0031, −0.0014) per BMI ‐increasing allele. Effect sizes estimated by instrumental variable analyses were OR =1.07 (95% CI : 1.03, 1.10) for asthma, a 9 ml decrease in FEV 1 (95% CI : 2.0‐15 mL decrease) and a 16 ml decrease in FVC (95% CI : 7.0‐24 mL decrease) per 1 kg/m 2 higher BMI . Conclusions The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.
Differential clinical outcome according to KRAS, NRAS and BRAF genotype detected by massive parallel sequencing of metastatic colorectal cancer patients treated with first line FIr-B/FOx adding bevacizumab to triplet chemotherapy
Authors: Gemma Bruera, Francesco Pepe, Umberto Malapelle, Pasquale Pisapia, Antonella Dal Mas, Giuseppe Calvisi, Giancarlo Troncone, Enrico Ricevuto
Journal: Annals of Oncology (2017)
Evaluating for pseudoprogression in colorectal and pancreatic tumors treated with immunotherapy
Authors: Chistine Parseghian, Madhavi Patnana, Priya Bhosale, Kenneth Hess, Scott Kopetz, Michael Overman, Aung Naing, Sarina Piha-Paul, Vivek Subbiah, David Hong, Hung Le, Shubham Pant
Journal: Annals of Oncology (2017)
BMA annual meeting: GPs working at unsafe levels should issue “black alert”-style warnings, says BMA
Authors: Abi Rimmer
Journal: BMJ (2017)

GP clinics should use a system similar to hospital “black alerts” to indicate when they have reached their maximum capacity, the BMA has said.

Delegates at the BMA’s annual representative meeting in Bournemouth on 27 June voted in favour of a motion saying that a system similar to the “black alerts” issued by hospitals should be introduced for general practice. The motion called on the BMA to construct such a system “with or without government cooperation.”

The term “black alert” has been used by hospitals when demand outstripped their capacity and has usually meant having to divert patients elsewhere to receive emergency care. This type of alert has since been replaced by a new system, the Operational Pressures Escalation Levels (OPEL) …
Abstract LB-098: Sequential azacitidine and histone deacetylase inhibition induces a potent antitumor response in Kras G12D mouse model of NSCLC
Authors: Michael Topper, Michelle Vaz, Katherine Chiappinelli, Christina DeStefano Shields, Alyssa Wenzel, Cynthia Zahnow, Pam Strissel, Reiner Strick, Stephen Baylin
Journal: Cancer Research (2017)

Abstract Combination epigenetic treatment as a therapeutic approach holds much promise. However, to unlock the true potential of these combinatorial paradigms, further optimization is required. We have elucidated in our current study, a treatment schedule combining Azacitidine with Histone Deacetylase Inhibition (HDACi) which considers both schedule and isoform specificity. We have deployed a sequential schedule with HDACi administered post Azacitidine in a chronic low dose manner. This schedule takes advantage of two key parameters altered by Azacitidine: dsRNA induced immune signature and MYC depletion. In our system, HDACis amplify an existing immune signature and the MYC depleted environment acts as a potent sensitizer. HDACi induced augmentation of immune gene transcription seems driven predominantly through the inhibition of HDAC1/2 and HDAC6 isoforms, with broad spectrum HDACi inhibitors demonstrating the greatest potency. While the combination treatment induced perturbation of proliferation is driven by inhibition of HDAC1/2/3 isoforms. Applying this concept to a genetically engineered mouse model of NSCLC we observe a potent anti-tumor response as evidenced by a reduction in tumor burden, progression and proliferation. These phenotypic parameters are correlated with modification of both immune and proliferative gene signatures as well as alteration of key immune populations in the tumor microenvironment. We propose that this combinatorial alteration of both immune and proliferative parameters holds the promise to be a more robust treatment for NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Michael Topper, Michelle Vaz, Katherine Chiappinelli, Christina DeStefano Shields, Alyssa Wenzel, Cynthia Zahnow, Pam Strissel, Reiner Strick, Stephen Baylin. Sequential azacitidine and histone deacetylase inhibition induces a potent antitumor response in Kras G12D mouse model of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-098. doi:10.1158/1538-7445.AM2017-LB-098
UK emergency services need priority BMA urges reduction in drink driving limits NHS will claw back outstanding accident claims Data Protection Registrar will target GPs
Authors: Linda Beecham
Journal: BMJ (1997)

# UK emergency services need priority {#article-title-2}

The British government must continue to give emergency care services a high priority and make the best use of new technology.

In a joint report on dealing with the problems of the rise in emergency admissions the Royal College of Physicians (RCP) and the NHS Confederation say that “in the final analysis people judge the NHS by how well it responds when they are in the greatest need.”

The report comments that although emergency admissions have been increasing with sudden peaks in demand, particularly during the winter, there was now evidence that the winter pressures were extending into the rest of the year. There was a 9.9% increase in general and acute emergency admissions between 1991–2 and 1995-6—amounting to 920 new emergency admissions every day.

The RCP and the confederation set up a working group, chaired by Professor Michael Sheppard, professor of medicine at the University of Birmingham, to look at the implications of the rise in admissions and suggest possible solutions.

The report welcomes the additional non-recurring £300m in 1997–8 to help …
Knowledge, attitudes and practices in paediatricpediatric concussion: informing research, education and clinical care
Authors: Christine Provvidenza, Dayna Greenspoon, Phil Fait, Nick Reed
Journal: British Journal of Sports Medicine (2017)

Objective To assess knowledge, attitudes, and practices surrounding research, education and clinical care in paediatric concussion at One Voice: the 1st International Symposium on Paediatric Concussion. Design Quantitative, cross sectional, one-group survey design. Setting One Voice: the 1st International Symposium on Paediatric Concussion. Participants Sixty-two international paediatric concussion leaders representing a multi-stakeholder group. Intervention None. Outcome measures A survey was designed to assess self-reported knowledge, attitudes, and practices surrounding paediatric concussion research, education, and clinical care. Main results Participants identified knowledge gaps as an issue across different groups including athletes and coaches. Attitude towards concussion in the sport culture was recognised as a barrier to common issues such as under reporting and playing while symptomatic. Stakeholders also identified that healthcare professionals do not have adequate training to diagnose and manage paediatric concussion, and highlighted the need for additional knowledge and streamlined education to enhance clinical practices. Conclusions Knowledge, attitude and practice gaps in paediatric concussion exist across various stakeholder groups, leading to inconsistencies in concussion care and a lack of concussion recognition and reporting. Survey results align with outcomes identified in the literature. One Voice stakeholders underscored the value of education in enhancing knowledge, and its role in shifting attitude and optimising practices in paediatric concussion: identification, management and prevention. These outcomes will inform research, education and clinical initiatives to best meet the needs of the paediatric concussion community. Competing interests None.
Clinical and genomic alterations features of patients with advanced colitis associated cancers (CAC).
Authors: David Paul Kelsen, Vincent A. Miller, Laura H. Tang, Marinela Capanu, Sohail Balasubramanian, Jeffrey S. Ross, Philip J. Stephens, Rona Yaeger
Journal: Journal of Clinical Oncology (2017)

e15010 Background: CAC are a catastrophic complication of inflammatory bowel disease. The spectrum of genomic alterations (GA) in CAC is different than that of sporadic colorectal cancer (CRC) (Yaeger et al PMID 27063727). While the prognosis for CAC patients (pts) may be worse than that of sporadic CRC pts, there is little data regarding outcome for metastatic CAC pts treated with standard chemotherapy regimens. We reviewed demographic features and clinical outcome for pts with metastatic CAC in the context of somatic tumor GA. Methods: We identified small and large bowel CAC cases seen at Memorial Sloan Kettering between 2003 and 2015 with tissue available for study. Hybrid capture based next-generation sequencing analysis of over 300 cancer-related genes was used to comprehensively characterize GA. The electronic medical record of each patient was reviewed. Demographic and clinical data was extracted and outcome reviewed in the context of somatic tumor GA. Results: Clinical features for 17 pts with metastatic CAC are shown below. All pts with initial stage III CAC received FOLFOX adjuvant therapy. First-line treatment for metastatic disease included FOLFOX/FOLFIRINOX/FU-LV in 10 previously untreated pts and FOLFIRI after adjuvant therapy. Median duration of survival from time of metastatic disease was 14.8 months, (95% CI 5.7-24.3;range 2-68+ months), substantially less than that expected for pts with Stage IV CRC. Only 4 patients survived for &gt; 24 months. GA were identified in TP53 (87%) and KRAS (33%); potentially targetable alterations were found in 8 pts ( IDH1 (1), EML4-ALK(1), ERBB2 (1); FGFR1/2 (3); BRAF (1); PIK3CA(1). 2 pts received a targeted agent based on GA; 1 partial response to a FGFR inhibitor is ongoing. No patient had a hyper-mutated tumor. Conclusions: Metastatic CAC pts have an exceedingly poor prognosis, with survival well below that expected for sporadic CRC. BRAF mutations associated with poor outcome in sporadic CRC are rare in CAC. 47% of CAC pts had potentially targetable GA. [Table: see text]
Improving the Armamentarium of PI3K Inhibitors with Isoform-Selective Agents: A New Light in the Darkness
Authors: Jordi Rodon, Josep Tabernero
Journal: Cancer Discovery (2017)

Abstract Summary: Excitement and drug-development efforts aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway have declined due to the limited clinical performance of these inhibitors as monotherapies. New, more isoform-selective treatments, such as taselisib, promise to both expand the therapeutic window and increase efficacy. Cancer Discov; 7(7); 666–9. ©2017 AACR. See related article by Juric et al., p. 704.
Nuclear SET Domain (NSD) Protein Lysine Methyltransferases (KMT) Family Members Expression in Acute Myeloid Leukemia
Authors: Virginia Mara De Deus Wagatsuma, Luisa C A Koury, Silvia Elena Sánchez, Lorena Lobo Figueiredo Pontes, Fernanda Borges da Silva, Adriana Ines Dore, Ana Silvia Gouvêa de Lima, Antonio R. Lucena-Araujo, Luciana Yamamoto Almeida, Fabiola Traina, Felipe Saldanha-Araújo, Fabio Pittella-Silva, Eduardo Magalhães Rego
Journal: Blood (2016)
Proteomic profiling of the epithelial and stromal components of matched normal and colonic carcinomas using protein microarrays
Authors: KM Sheehan, C Gulmann, HL Barrett, EW Kay, LA Liotta, EF Petricoin
Journal: Endoscopy (2006)

Introduction: Colorectal carcinoma does not have a single specific biomarker that can detect and predict disease behaviour. Consequently, combinations of expression markers may be useful in diagnostics and prognostics. Moreover, it is likely that the complex interaction between tumour epithelium and stroma is a key facilitator in sustaining tumor growth.
Rechallenge with cetuximab + irinotecan in 3rd-line in RAS and BRAF wild-type metastatic colorectal cancer (mCRC) patients with acquired resistance to 1st-line cetuximab+irinotecan: The phase II CRICKET study by GONO.
Authors: Daniele Rossini, Daniele Santini, Chiara Cremolini, Lisa Salvatore, Sara Lonardi, Emanuela Dell' Aquila, Giuseppe Aprile, Fotios Loupakis, Bruno Vincenzi, Francesca Battaglin, Vanessa Buoro, Emiliano Tamburini, Deborah Basile, Domenico Corsi, Iacopo Fioroni, Gianluca Masi, Carlotta Antoniotti, Beatrice Borelli, Marzia Del Re, Giuseppe Tonini, Alfredo Falcone
Journal: Annals of Oncology (2017)
Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma
Authors: Jennifer M. Kalish, Leslie Doros, Lee J. Helman, Raoul C. Hennekam, Roland P. Kuiper, Saskia M. Maas, Eamonn R. Maher, Kim E. Nichols, Sharon E. Plon, Christopher C. Porter, Surya Rednam, Kris Ann P. Schultz, Lisa J. States, Gail E. Tomlinson, Kristin Zelley, Todd E. Druley
Journal: Clinical Cancer Research (2017)

Abstract A number of genetic syndromes have been linked to increased risk for Wilms tumor (WT), hepatoblastoma (HB), and other embryonal tumors. Here, we outline these rare syndromes with at least a 1% risk to develop these tumors and recommend uniform tumor screening recommendations for North America. Specifically, for syndromes with increased risk for WT, we recommend renal ultrasounds every 3 months from birth (or the time of diagnosis) through the seventh birthday. For HB, we recommend screening with full abdominal ultrasound and alpha-fetoprotein serum measurements every 3 months from birth (or the time of diagnosis) through the fourth birthday. We recommend that when possible, these patients be evaluated and monitored by cancer predisposition specialists. At this time, these recommendations are not based on the differential risk between different genetic or epigenetic causes for each syndrome, which some European centers have implemented. This differentiated approach largely represents distinct practice environments between the United States and Europe, and these guidelines are designed to be a broad framework within which physicians and families can work together to implement specific screening. Further study is expected to lead to modifications of these recommendations. Clin Cancer Res; 23(13); e115–e22. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.
Laparoscopic Resection of Ileocaecal Crohn's Disease
Authors: I Heaslip, E Carton, D O'Donoghue, J Hyland
Journal: Endoscopy (2006)

Methods: 53 patients with ileocolic Crohns disease were referred for resection between Sept 2002 and Sept 2005. Laparoscopic ileocaecal resections were performed in 23 patients. The mean age was 29 years (range18–44 years). Stenosing ileocaecal disease was confirmed radiologically by either small bowel follow through or CT scanning. In the same period 30 open resections were performed, as laparoscopic surgery was not appropriate due to complex fistulae, multiple previous surgeries or deep abscesses.
Synergistic vs protective activity of cerium oxide nanoparticles (CNP) in gastrointestinal tumoral and non-tumoral cell cultures respectively when combined with cytotoxic drugs
Authors: Jose Vazquez Villa, Amador Garcia Fuente, Daniel Martinez Perez, Rebeca Fernandez Fernandez, García Alonso Francisco J, Martin Carbajo Jose I, Paula Fonseca, Jaime Ferrer, de Prado Jose Maria Vieitez
Journal: Annals of Oncology (2017)
Allergic Reactions to Drugs and Biologic Agents
Authors: Richard D. deShazo
Journal: JAMA (1997)

Drug allergies are adverse reactions resulting from immunologic responses to drugs or their metabolites. These reactions result in predictable patterns of organ-specific or systemic hypersensitivity that usually recur on subsequent exposure to the same drug. Although diagnostic testing for drug allergy is available for only a few drugs, protocols have been developed to assist in management of allergic reactions to many drugs and biologic agents. Other protocols assist in the management of patients who develop drug reactions while undergoing multiple drug therapy or those with a history of adverse drug reactions who again require treatment for the same condition.
Impact of Gender on Outcome after Chemoimmunotherapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) or Bendamustine Plus Rituximab (BR) in Patients with Chronic Lymphocytic Leukemia (CLL): A Meta-Analysis of Three Phase II/III Studies of the German CLL Study Group (GCLLSG)
Authors: Othman Al-Sawaf, Sandra Robrecht, Jasmin Bahlo, Anna Maria Fink, Paula Cramer, Christian Maurer, Manuela A. Bergmann, Martin H. Dreyling, Elisabeth Lange, Michael Kneba, Stephan Stilgenbauer, Hartmut Döhner, Michael G Kiehl, Ulrich Jäger, Clemens-Martin Wendtner, Kirsten Fischer, Michael Hallek, Barbara F. Eichhorst, Georg Hopfinger
Journal: Blood (2016)
Knock-Down of the NFAT2 Long and Intermediate Isoforms Leads to CLL Acceleration
Authors: Jonas S Heitmann, Melanie Märklin, Posdorowkin Anastasia, Alexander R Fuchs, Felicia M Truckenmüller, Hans-Georg Kopp, Lothar Kanz, Anjana Rao, Stefan Wirths, Martin R Mueller
Journal: Blood (2016)
Detecting protein variants by mass spectrometry: a comprehensive study in cancer cell-lines
Authors: Javier A. Alfaro, Alexandr Ignatchenko, Vladimir Ignatchenko, Ankit Sinha, Paul C. Boutros, Thomas Kislinger
Journal: Genome Medicine (2017)

Onco-proteogenomics aims to understand how changes in a cancer's genome influences its proteome. One challenge in integrating these molecular data is the identification of aberrant protein products from mass-spectrometry (MS) datasets, as traditional proteomic analyses only identify proteins from a reference sequence database.We established proteomic workflows to detect peptide variants within MS datasets. We used a combination of publicly available population variants (dbSNP and UniProt) and somatic variations in cancer (COSMIC) along with sample-specific genomic and transcriptomic data to examine proteome variation within and across 59 cancer cell-lines.We developed a set of recommendations for the detection of variants using three search algorithms, a split target-decoy approach for FDR estimation, and multiple post-search filters. We examined 7.3 million unique variant tryptic peptides not found within any reference proteome and identified 4771 mutations corresponding to somatic and germline deviations from reference proteomes in 2200 genes among the NCI60 cell-line proteomes.We discuss in detail the technical and computational challenges in identifying variant peptides by MS and show that uncovering these variants allows the identification of druggable mutations within important cancer genes.
Abstract 20581: Population Based Characterization of the Definition, Prevalence and Associated Mortality of Pulmonary Hypertension in the Setting of Left Heart Disease
Authors: Rebecca R Vanderpool, Melissa I Saul, Seyed Mehdi Nouraie, Mark T Gladwin, Marc A Simon
Journal: Circulation (2016)

Purpose:  Patients with left heart disease can develop pre-capillary pulmonary vascular remodeling, resulting in elevations of pulmonary vascular resistance (PVR). Pre-capillary pulmonary vascular disease has been variably defined by elevations in the transpulmonary or diastolic pulmonary pressure gradients (TPG or DPG) or PVR, but the optimal hemodynamic definition and predictor of mortality remains uncertain.   Methods and Results:  We retrospectively analyzed a large cohort of 10,023 subjects who had a right heart catheterization at our institution between 2005 and 2012, with linkage of catheterization data to electronic health records with natural language-based search and social security death index. Pulmonary hypertension in the setting of heart failure with preserved ejection fraction (PH-HFpEF) was defined as mPAP ≥25 mmHg, PCWP ≥15 mmHg and LVEF ≥ 45%, with variable TPG, PVR and DPG cut-off values to quantify severity of PH. Cox proportional hazard regression analysis was used. In cases of non-linear associations with mortality (PVR and DPG), hazard ratios were calculated based on spline models fit to a parameter.  Of the 10,023 subjects, 21.4% have PH-HFpEF and 10.4%, 7.4% and 2.9% have PH-HFpEF with an elevated TPG (>12), PVR (≥3) and DPG (≥7), with 5-year survival rates of 50%, 46% and 45%, respectively (Figure 1). Predictive value was confirmed over a wide range of values by spline-modeled Cox analysis: TPG HR 1.02 (95%CI 1.01-1.02; P   1 (91% of observations); DPG HR 1.03 (95%CI 1.02-1.04; P    Conclusions:  PH-HFpEF is highly prevalent in patients referred for right heart catheterization. TPG, PVR and DPG are highly predictive of mortality by standard cut-offs and as continuous variables in a large PH-HFpEF cohort.