tbuckley/cabot-search huggingface dataset:
Correlation of T-cell inflamed phenotype with mesenchymal subtype, expression of PD-L1, and other immune checkpoints in head and neck cancer.
Authors: Vassiliki Saloura, Zhixiang Zuo, Hartmut Koeppen, Michaela K. Keck, Arun Khattri, Marigold Boe, Priti S. Hegde, Yuanyuan Xiao, Yusuke Nakamura, Everett E. Vokes, Jonas A. De Souza, Victoria Meucci Villaflor, Justin Paul Kline, Thomas Gajewski, Mark W. Lingen, Marcin Kowanetz, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2014)

6009 Background: Immunotherapy with checkpoint blockade has shown encouraging activity in squamous cell carcinomas including a case report in tongue cancer (Herbst 2013). PD-L1 expression is common in HNC (Lyford-Pike 2013). In melanoma a T cell-infiltrated phenotype is common and correlates with immune inhibitory pathways. We interrogated the immune microenvironment in a large cohort of HNC in order to identify molecular correlates of an inflamed tumor microenvironment that may predict benefit from checkpoint blockade. Methods: We evaluated the presence of a T cell-inflamed tumor microenvironment in a cohort of 134 (Chicago HNC Genomics (CHGC)) and 424 TCGA HNC samples using a melanoma expression signature (Harlin/Gajewksi 2009). We evaluated multiple immune-related markers by IHC in a subset of CHGC tumors including CD8 tumor infiltrating lymphocytes (TIL)(N=73) and PD-L1 (N=55). Results were correlated with genetic and clinical information. Results: 47% of CHGC and 33% of TCGA tumors showed a T cell-inflamed phenotype (TCIP) similar to melanoma based on a gene expression signature (Harlin 2009). 75% of HPV(+) tumors showed a TCIP compared to 23% of HPV(-) tumors in both cohorts. Mesenchymal subtype (Keck 2014) strongly correlated with TCIP (p<2.2x1016), and 90% of mesenchymal tumors showed TCIP including roughly equal numbers of HPV(+) and HPV(-) tumors in both cohorts. Basal and HPV-negative classical HNC tumors were TCIP negative. Based on IHC, 38% of CHCG tumors showed PD-L1 expression and 64% showed CD8+ TILs, both correlating with TCIP. Additional checkpoint molecules were universally co-expressed in the same TCIP tumors including CTLA4, LAG3, PDL-2, and IDO. Molecular processes enriched in non-TCIP tumors included EGFR/erbB signaling (p=0.09) characteristic of basal HNC, while multiple T-cell related signatures and the JAK/STAT pathway (p<0.05) characteristic of mesenchymal HNC were enriched in the TCIP tumors. Conclusions: 33-47% of HNC show a T cell-inflamed phenotype similar to melanoma. PD-L1 expression and TIL presence is common and strongly correlated with mesenchymal HNC in both HPV(+) and HPV(-) HNC and may benefit from immunotherapy.
Improving access to medical care
Authors: M. Reynolds, M. Doublet-Stewart
Journal: BMJ (1999)

Improving access to medical care General practice cooperatives are coping wellEditor-Cooperatives present patients with the easiest access to a doctor of any part of the NHS.We have led the way in modernising out of hours primary care, and we have been arguing for, and in many areas creating, a "whole systems approach" to access.It was therefore galling to read that "patients may have bypassed general practices and cooperatives as phone lines became overwhelmed; and accident and emergency staff often had no other options but to admit." 1 These unfounded assertions are damaging.The evidence set out in the report Winter Pressures on Primary Care by the Health Economics Consortium, which was commissioned by the Department of Health, showed that primary care, and cooperatives in particular, coped admirably.It is just as likely that patients would have phoned their cooperatives when faced with long delays in accident and emergency departments.Indeed, I triaged several calls made from Maidstone accident and emergency department last Boxing Day.About 1-2% of the population contacted primary care out of hours services between 24 December 1998 and 2 January 1999.It wasn't primary care that collapsed under the strain, but a secondary service that is always working almost flat out and therefore has no spare capacity.This is because we spend less on health as a percentage of gross national product than almost any other westernised nation.
Abstract 88: AMP-activated Protein Kinase Signaling Mediates the Cardioprotective effect of Antithrombin against Myocardial Ischemia and Reperfusion Injury
Authors: Ji Li, Yina Ma, Jinli Wang, Hui Yang, Yanqing Wang, Chandrashekhara Masnithody, Alireza R Rezaie
Journal: Circulation Research (2014)

Background: Antithrombin (AT) is an endogenous protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. AT is known to exhibit anti-inflammatory and cardioprotective properties when it binds to distinct heparan sulfate proteoglycans (HSPGs) on vascular endothelial cells. The energy sensor AMP-activated protein kinase (AMPK) plays an important cardioprotective role during myocardial ischemia and reperfusion (I/R). The objective of this study was to investigate whether the cardioprotective signaling function of AT against I/R injury is mediated through the AMPK pathway. Methods and Results: The cardioprotective activities of wild-type (WT) AT and its two recombinant derivatives, one having high affinity and the other no affinity for heparin, were evaluated in an acute I/R (20 min/4 h) injury model in which the left anterior descending coronary artery (LAD) was occluded. The serpin derivatives were given 5 min before reperfusion. The results showed that AT-WT can activate the protective AMPK signaling pathway in both in vivo and ex vivo conditions. Blocking AMPK activity abolished the cardioprotective function of AT against I/R injury. The AT derivative having high affinity for heparin was more effective in activating AMPK, but the derivative lacking any affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. The activation of AMPK by AT inhibited the inflammatory c-Jun N-terminal protein kinase (JNK) pathway during I/R. Further studies revealed that the AMPK activity of AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R. Conclusions: These results suggest that AT binds to vascular HSPGs to invoke a cardioprotective function by triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signaling pathways and modulating substrate metabolism during I/R.
Can we Do Better with Our Current Therapies for Nsclc? the Spanish Lung Cancer Group Approach
Authors: R. Rosell, N. Karachaliou, M.A. Molina, J. Codony, J.L. Ramirez, I. Chaib, S. Garcia-Roman, D. Morales-Espinosa, R. Estrada, J. Bertran, C. Codony, A. Gimenez-Capitan, M. Gonzalez-Cao, B. Massuti Sureda, A. Vergnenegre, T. Moran, E. Carcereny, C. Teixido, A. Villanueva, M. Sanchez-Ronco
Journal: Annals of Oncology (2014)
Phase II study of sequential high-dose methotrexate (MTX) and 5-fluorouracil (F) alternated with epirubicin (E) and cisplatin (P) [FEMTX-P] in advanced gastric cancer
Authors: E.J.M. Roelofs, D.J.Th. Wagener, Th. Conroy, J. Wils, J.Th. Burghouts, M. Fickers, A. de Graeff, F. Lalisang, B. Paillot
Journal: Annals of Oncology (1993)
Intestinal Dilation and Platelet:Albumin Ratio Are Predictors of Surgery in Stricturing Small Bowel Crohn’s Disease
Authors: Ryan W. Stidham, Amanda S. Guentner, Julie L. Ruma, Shail M. Govani, Akbar K. Waljee, Peter D.R. Higgins
Journal: Clinical Gastroenterology and Hepatology (2016)
Combination therapy with voriconazole and caspofungin for fungal infections in patients with acute leukemia
Authors: N. Lamanna, M. A. Weiss
Journal: Journal of Clinical Oncology (2004)

6735 Background: In patients with hematologic malignancies, invasive fungal infections, particularly aspergillosis, is a leading cause of infection and associated mortality. The availability of new agents with different mechanisms of action has renewed interest in developing combination strategies for these infections. In patients with acute leukemia monotherapy for invasive aspergillosis fails in many if not most cases. We recently published (Cancer 2003) our experience using combination caspofungin and liposomal amphotericin in patients with invasive fungal infections who failed monotherapy with amphotericin. Overall, 60% had a favorable response to combination antifungal therapy. Voriconazole is a new triazole antifungal approved for the treatment of invasive aspergillosis in patients who are intolerant or refractory to other agents. Since its introduction in September 2002, a group of patients with resistant fungal pneumonias have been treated with a combination of voriconazole and caspofungin. To our knowledge this abstract represents the first clinical data to be reported for combination antifungal therapy with voriconazole. Methods: We conducted a retrospective evaluation of patients with leukemia and invasive fungal infection treated with combination voriconazole and caspofungin between 9/02–7/03. Response to therapy was graded as either favorable (required both clinical and radiographic improvement) or unfavorable. Results: On preliminary analysis we have identified 27 patients (19 with AML and 8 with other leukemias). Patients received combination therapy for a median of 12 days (range 5–82 days). Survival was highly associated with response to antifungal therapy. Fourteen patients (52%) had a favorable response to combination therapy and 11 (79%) remain alive. Thirteen patients (48%) had an unfavorable response and only 1 (8%) is still alive (P=0.0003). In general unexpected toxicities were not seen. Conclusions: We conclude that combination therapy with voriconazole and caspofungin is safe in patients with leukemia and invasive fungal infections and that this combination appears to successfully salvage some patients who fail antifungal monotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
Duodenal ulceration following gastroduodenal artery embolization with coils
Authors: Audrius Dulskas, Giedre Rudinskaite, Romualdas Maskelis, Zygimantas Kuliesius, Ricardo Escalante, Narimantas Samalavicius
Journal: Endoscopy (2015)

An 84-year-old woman was admitted to our department with epigastric pain, nausea, and vomiting. The patient had been treated for upper gastrointestinal bleeding and hemorrhagic shock 2 months earlier, with a hemoglobin level of 6.3 g/dL. The source of the bleeding was not found during several upper gastrointestinal procedures (esophagogastroduodenoscopy [EGD]), and empiric embolization of the gastroduodenal artery was performed with four fibered 0.6 × 14-cm coils (Azur Hydrocoils; Terumo Interventional Systems, Tokyo, Japan) and eight 0.4 × 3.7-cm microcoils (VortX Diamond; Boston Scientific, Natick, Massachusetts, USA). In addition, the patient received a transfusion of 5 units of blood. The subsequent clinical course was uneventful.
The concept of treatment-free remission in chronic myeloid leukemia
Authors: S Saußele, J Richter, A Hochhaus, F-X Mahon
Journal: Leukemia (2016)

The advent of tyrosine kinase inhibitors (TKI) into the management of patients with chronic myeloid leukemia (CML) has profoundly improved prognosis. Survival of responders is approaching that of the general population but lifelong treatment is still recommended. In several trials, TKI treatment has been stopped successfully in approximately half of the patients with deep molecular response. This has prompted the development of a new concept in the evaluation of CML patients known as 'treatment-free remission'. The future in CML treatment will be to define criteria for the safe and most promising discontinuation of TKI on one hand, and, on the other, to increase the number of patients available for such an attempt. Until safe criteria have been defined, discontinuation of therapy is still experimental and should be restricted to clinical trials or registries. This review will provide an overview of current knowledge as well as an outlook on future challenges.
Are We What We Eat? Evidence of a Vegetarian Diet Permanently Shaping the Human Genome to Change Individual Risk of Cancer and Heart Disease
Authors: Joseph Caspermeyer
Journal: Molecular Biology and Evolution (2016)

University-led research team has released a new version of their popular MEGA (Molecular Evolutionary Genomics Analysis) software, one of the most highly downloaded and widely used tools used by scientists worldwide to harness large-scale DNA sets for comparative studies.At its core, MEGA is a powerful bioinformatics tool designed to help researchers identify key patterns among the diversity and complexity of life on Earth, and unravel the mysteries of human evolution, health, and disease coded within the genome.
Physostigmine and haloperidol treatment of acute phencyclidine intoxication
Authors: S Castellani, A J Giannini, P M Adams
Journal: American Journal of Psychiatry (1982)

Twenty-four patients with phencyclidine intoxication were treated with either physostigmine (2 mg i.m.) or haloperidol (5 mg i.m.) based on the presence of delusions and/or hallucinations. Several symptoms subsequently improved. Schizophreniform symptoms showed substantial improvement with haloperidol.
Physiological responses to the incremental shuttle walk test in healthy adults
Authors: Victor Dourado, Ricardo Guerra, Suzana Tanni, Letícia Antunes, Irma Godoy
Journal: European Respiratory Journal (2011)

Physiological responses to the incremental shuttle walk test (ISWT) have been increasingly evaluated in patients. However, previous studies did not include healthy individuals. The aim of this study was to evaluate age- and gender-related changes in physiological responses to the ISWT and to establish predictive equations for such variables. We evaluated 103 non-trained healthy adults (49 males, aged 60±10). After familiarization, ISWT was performed using a telemetric gas analyzer. Physiological responses including oxygen uptake at ventilatory threshold (VO2VT) were obtained. Maximum walking velocity (Vmax), lean (LBM) and fat (FM) body masses (impedance), and handgrip strength (HGS) were also measured. Participants were stratified in four age groups (40-49 to ≥70). A set of linear equations was provided for predicting physiological variables. The VO2VT was identified in all but one participant. Among peak variables, heart (HR) and respiratory (RR) rates, tidal volume (VT), and gas exchange ratio (R) were not affected by sex as well as VO2/HR, R, RR, and VT were not influenced by age. There were no effect of age and gender in VO2VT (% of peak VO2). Prediction equations adjusted by sex, age, height, weight, LBM, FM, HGS, and ISWT showed R2 values ranging 0.352 to 0.661 (VO2VT and peak VO2 respectively). The best predictors of peak VO2 were HGS, weight, FM and age (R2=0.661). Age, weight, height and gender explained 59.7% of Vmax variability. The results therefore might provide a more appropriate frame of reference for normalcy of physiologic responses to the ISWT in healthy older adults. Our results may be useful for better interpretation of walking performance in patients with cardiopulmonary disease.
Phospholipase A2 Receptor–Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency
Authors: Stéphane Bally, Hanna Debiec, Denise Ponard, Frédérique Dijoud, John Rendu, Julien Fauré, Pierre Ronco, Chantal Dumestre-Perard
Journal: Journal of the American Society of Nephrology (2016)

Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against phospholipase A2 receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at −550 (L/L) and −221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2 .
A comparative study of borderline patients in a psychiatric outpatient clinic
Authors: M Sheehy, L Goldsmith, E Charles
Journal: American Journal of Psychiatry (1980)

The authors applied a list of operational criteria to all new patients in a large psychiatric outpatient department over a one-year period. A randomly selected group of patients clinically diagnosed as having borderline personality disorder was compared with groups with the diagnoses of schizophrenia, neurosis, and nonborderline personality disorder. The group with borderline personality disorder was significantly different from the other groups according to the criteria, especially on items reflecting impulsivity, affectivity, and overvaluation/derogation of others. Impaired reality testing proved a useful distinguishing criterion as well and should be retained as part of the borderline concept.
Developmental Effects of the ToxCast™ Phase I and Phase II Chemicals in <i>Caenorhabditis elegans</i> and Corresponding Responses in Zebrafish, Rats, and Rabbits
Authors: Windy A. Boyd, Marjolein V. Smith, Caroll A. Co, Jason R. Pirone, Julie R. Rice, Keith R. Shockley, Jonathan H. Freedman
Journal: Environmental Health Perspectives (2015)

Modern toxicology is shifting from an observational to a mechanistic science. As part of this shift, high-throughput toxicity assays are being developed using alternative, nonmammalian species to prioritize chemicals and develop prediction models of human toxicity.The nematode Caenorhabditis elegans (C. elegans) was used to screen the U.S. Environmental Protection Agency's (EPA's) ToxCast™ Phase I and Phase II libraries, which contain 292 and 676 chemicals, respectively, for chemicals leading to decreased larval development and growth. Chemical toxicity was evaluated using three parameters: a biologically defined effect size threshold, half-maximal activity concentration (AC50), and lowest effective concentration (LEC).Across both the Phase I and Phase II libraries, 62% of the chemicals were classified as active ≤ 200 μM in the C. elegans assay. Chemical activities and potencies in C. elegans were compared with those from two zebrafish embryonic development toxicity studies and developmental toxicity data for rats and rabbits. Concordance of chemical activity was higher between C. elegans and one zebrafish assay across Phase I chemicals (79%) than with a second zebrafish assay (59%). Using C. elegans or zebrafish to predict rat or rabbit developmental toxicity resulted in balanced accuracies (the average value of the sensitivity and specificity for an assay) ranging from 45% to 53%, slightly lower than the concordance between rat and rabbit (58%).Here, we present an assay that quantitatively and reliably describes the effects of chemical toxicants on C. elegans growth and development. We found significant overlap in the activity of chemicals in the ToxCast™ libraries between C. elegans and zebrafish developmental screens. Incorporating C. elegans toxicological assays as part of a battery of in vitro and in vivo assays provides additional information for the development of models to predict a chemical's potential toxicity to humans.Boyd WA, Smith MV, Co CA, Pirone JR, Rice JR, Shockley KR, Freedman JH. 2016. Developmental effects of the ToxCast™ Phase I and II chemicals in Caenorhabditis elegans and corresponding responses in zebrafish, rats, and rabbits. Environ Health Perspect 124:586-593; http://dx.doi.org/10.1289/ehp.1409645.
ATPS-852-HYDROXYGLUTARATE DEPLETION IS NOT SUFFICIENT TO INHIBIT GROWTH OF SEVERAL PROGRESSIVE IDH1 MUTANT SOLID CANCER TYPES
Authors: Kensuke Tateishi, Hiroaki Wakimoto, Franziska Loebel, Nina Lelic, Dan Zhao, Tracy Batchelor, John Iafrate, Andrew Chi, Daniel Cahill
Journal: Neuro-Oncology (2015)

Targeted agents that inhibit 2-hydroxyglutarate (2-HG) production by mutant IDH1 have shown considerable promise in acute leukemia. To examine the potential effects of 2-HG reduction in IDH1 mutant solid cancers, we treated endogenous IDH1 mutant tumor cells from several tissue types with a well-characterized inhibitor of IDH1 R132H and R132C (IDH1i) in vitro and in vivo. We confirmed potent inhibition of 2-HG formation in vitro in IDH1R132H glioma tumorsphere lines and a fibrosarcoma line, HT1080 (IDH1R132C). Then, we broadly tested 8 endogenous IDH1 mutant cell lines, including 6 IDH1R132H gliomas, HT1080 and a melanoma line E232-2010 (IDH1R132C). IDH1i markedly reduced 2-HG, however did not inhibit in vitro growth of any cell line. We then assessed the effect of IDH1i treatment on mice bearing patient-derived, endogenous IDH1 mutant glioma orthotopic xenografts. Continuous daily oral administration of IDH1i (200 mg BID) achieved marked 2-HG reduction within the tumor. However, we found no significant difference in tumor size or survival of IDH1i-treated versus vehicle-treated mice. Furthermore, neither short-term nor prolonged (>6mo) in vitro IDH1i exposure significantly altered the global trimethylation or dimethylation of histone 3 lysine 9 (H3K9), global trimethylation of H3K27, genomewide distribution of DNA methylation or methylation of the O-6-methylguanine-DNA methyltransferase gene promoter. Paradoxically, long-term in vitro IDH1i incubation resulted in acceleration of cell proliferation and significantly shorter animal survival upon subsequent intracerebral implantation, compared to passage-matched IDH1 mutant glioma cells grown in the absence of IDH1i. Thus, 2-HG levels can be uncoupled from cell proliferation in several IDH1 mutant solid cancer types, and the epigenetic alterations induced by mutant IDH1 are not reversed solely by depletion of 2-HG, even after many cell divisions. Alternative combination therapeutic strategies may be needed for successful growth inhibition of progressive mutant IDH1 solid cancers.
Detection and Monitoring of the BRAF Mutation in Circulating Tumor Cells and Circulating Tumor DNA in BRAF -Mutated Lung Adenocarcinoma
Authors: Nicolas Guibert, Anne Pradines, Anne Casanova, Magali Farella, Laura Keller, Jean-Charles Soria, Gilles Favre, Julien Mazières
Journal: Journal of Thoracic Oncology (2016)
Catherine Provan Pike
Authors: William Pike, Elizabeth Mackenzie
Journal: BMJ (2016)

Catherine Provan Pike was one of three daughters of Edward Cathcart, a distinguished professor of physiology at Glasgow University, and Gertrude Bostock, an early science graduate. She was educated at Laurel Bank School for Girls, and all the daughters graduated in medicine in Glasgow, where Catherine was president of the students’ union. After qualifying she served in the Women’s Auxiliary Air Force (WAAF) at RAF Fighter Command Uxbridge.

She was demobilised in 1947 and worked at Winchester General Hospital, where she met her future, husband Andrew Hamilton Pike, a provincial commissioner in Tanganyika. They had been introduced by her cousin, Maurice Dorman, who was her husband’s deputy at the time. While in Tanzania, Catherine helped establish a family planning organisation and raised a family of four boys. On her …