tbuckley/cabot-search huggingface dataset:
Calcineurin inhibitors impair neutrophil activity against Aspergillus fumigatus in allogeneic hematopoietic stem cell transplant recipients
Authors: Sébastien Imbert, Priscillia Bresler, Alexandre Boissonnas, Lauraine Gauthier, Laëtitia Souchet, Madalina Uzunov, Véronique Leblond, Dominique Mazier, Stéphanie Nguyen, Arnaud Fekkar
Journal: Journal of Allergy and Clinical Immunology (2016)
Authors’ reply to Toth
Authors: Timothy M Frayling, Jessica Tyrrell
Journal: BMJ (2016)

Toth raises an important point about our mendelian randomisation study on height, body mass index, and socioeconomic status.1 2 He is troubled that the genetic polymorphisms we used explained only 12. 3% of the variation in height and 1.5% of the variation in body mass index (BMI). He suggests that this apparently small amount of variation explained by genetics makes our conclusions uncertain.

We strongly disagree. …
OC-038 Effectiveness Of A Nurse-led Alcohol Liaison Team In Reducing Admissions At Lancashire Teaching Hospitals Nhs Foundation Trust
Authors: S Soteriadou, E Dermody, K Allan, K Anderson, A Platt, V Balachandrakumar, A Sharma
Journal: Gut (2014)

<h3>Introduction</h3> In 2010/11 alcohol related harm cost the NHS in Lancashire £141.92 million, with Preston having the highest rate of hospital admissions for alcohol related liver disease in the North West. At that time there was no alcohol liaison team within Lancashire Teaching Hospitals. In view of this, in April 2013, the Hospital Alcohol Liaison Service (HALS) was created providing a seven day service for both the Royal Preston Hospital and Chorley and South Ribble Hospital. <h3>Methods</h3> The HALS team comprises 4 senior nurses with experience in managing patients with alcohol and substance misuse. The referral criteria are patients scoring 8 or more on the Alcohol Use Disorders Identification Tool (AUDIT). A prospective database was created to include numbers of referrals, types of alcohol misuse, referring wards and departments, dates of admission and discharge, and the numbers of bed days saved. Data collected from April-October 2013 were analysed. <h3>Results</h3> 808 patients were reviewed with 68% being male. The majority referrals were acute admissions, with 23% referred from the Emergency Department and 47% from the Medical Assessment Unit. Patients were reviewed within an average of 12 h since referral time (range 3–36 h). Delayed discharges were frequently identified in patients on a reducing regime of Chlordiazepoxide. The majority of patients were being kept in to complete this regime, regardless of whether they planned to stop drinking or not. On discharge, patients were not being offered follow up in the community which often led to recidivism and re-attendance at hospital seeking further detoxification. The HALS team reviewed and assessed these patients with validated assessment tools including the Severity of Alcohol Dependency Questionnaire (SADQ) and Clinical Institute Withdrawal Assessment Score (CIWA). The level of misuse was calculated as low risk in 127 patients, dependent in 382, harmful in 126, hazardous in 166, detox in 1 and unknown in 6 patients. Existing treatment regimes were reviewed to ensure they were appropriate and timely, and patients were identified for safe and early discharge with early community follow up. A total of 641 bed days were saved over the time period analysed. <h3>Conclusion</h3> Implementation of a 7-day HALS team covering two acute hospital sites has significantly improved the quality of care provided to patients with alcohol-related disorders. In addition there has been a very positive impact on reducing length of stay and bed occupancy. Plans are in place to develop and audit the HALS team further and strengthen working relationships with community partners. <h3>Disclosure of Interest</h3> None Declared.
Abstract 606: Heat shock protein 90 inhibitors: New mode of therapy to overcome aromatase inhibitor resistance
Authors: Cynthie Wong, Shiuan Chen
Journal: Cancer Research (2010)

Abstract Results from several major trials have revealed that aromatase inhibitors (AIs) are superior to tamoxifen with regard to disease progression, incidences of locoregional and distant relapses, and contralateral breast cancers. Although AIs are highly effective drugs (with outstanding specificity and potency), unfortunately, a significant number of AI-treated breast cancer patients will eventually develop disease progression due to acquired resistance. Hormone refractory breast cancers result from complex molecular changes and are challenging to cure. Recently, we examined whether the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) can inhibit the growth of AI-resistant breast cancers and the mechanisms by which 17-DMAG affects proliferation. AI-responsive MCF-7aro and AI-resistant LTEDaro breast epithelial cells were used in this study. We observed that 17-DMAG inhibited proliferation in both MCF-7aro and LTEDaro cells in a dose-dependent manner. 17-DMAG induced apoptosis and G2 cell cycle arrest in both cell lines. Although inhibition of HSP90 decreased the levels of ERα, the ERα transcriptional activity was not affected when cells were treated with 17-DMAG together with estradiol. Moreover, detailed mechanistic studies suggested that 17-DMAG inhibits cell growth via degradation of HSP90 client proteins AKT and HER2. Furthermore, our experiments using AI responsive MCF-7aro cells have revealed that HSP90 inhibitors such as 17-DMAG and AIs such as letrozole can suppress the proliferation of hormone-dependent breast cancer cells in a synergistic manner. To study de novo AI-resistance, our lab has generated MCF-7 cell models to overexpress both aromatase and either Akt (MCF-7Aktaro) or HER2 (MCF-7aroHER2). We have found that HSP90 inhibitor 17-DMAG is also effective on suppressing the proliferation of these de novo AI resistant cells. Collectively, results from this study provide data to support the theory that HSP90 inhibitors may be an effective therapy to delay and treat AI-resistant breast cancers (This research was supported by the NIH grant CA44735). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 606.
Abstract 3299: Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver
Authors: Xiao Qi Wang, Chung Mau Lo, Lin Chen, Cindy KY Cheung, Sheung Tat Fan
Journal: Cancer Research (2012)

Abstract Liver transplantation (LT) is a cure for many liver diseases. Blood chimerism of donor origin can develop after LT, which raises the possibility of existence of hematopoietic stem/progenitor cells (HSPCs) in liver. We characterized the blood chimerism in a large cohort of 226 LT patients and analyzed putative HSPCs in adult human livers. The overall incidence of chimerism was 6.19%, of which 10.3% was among short-term (one day to six months) and 3.6% was among long-term (six months to eight years) LT patients. Hematopoietic LinαCD34+CD38αCD90+ population has been demonstrated to generate long-term multipotent grafts in transplantations. In human adult livers, we detected LinαCD34+CD38αCD90+ population accounting for 0.056% ± 0.05% of the total single liver cells and for 0.06% ± 0.05% of CD45+ liver cells. Both LinαCD34+ and LinαCD45+ liver cells from extensive perfused human liver graft were capable of forming hematopoietic myeloid-lineage and erythroid-lineage methylcellulose colonies. More importantly, LinαCD45+ or CD45+ liver cells could be engrafted into hematopoietic cells in an immunodeficient mouse model. These results are the first evidence of presence of the putative HSPC population in adult human liver, where liver is a good ectopic niche. The discovery of existence of HSPCs in adult liver will have new implications for understanding of extra-marrow hematopoiesis, liver regeneration, mechanisms of tolerance in organ transplantation and de novo cancer recurrence in LT patients. Conclusion: Human adult liver contains small population of HSPCs. In LT patients, there are two types of chimerism: transient chimerism resulting from mature leucocytes and long-term chimerism deriving from putative HSPCs in the liver graft. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3299. doi:1538-7445.AM2012-3299
Screening for Chronic Obstructive Pulmonary Disease
Authors: David H. Au
Journal: JAMA Internal Medicine (2016)

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ET-12 * PHASE II STUDY OF ONARTUZUMAB PLUS BEVACIZUMAB VERSUS PLACEBO PLUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: T. Cloughesy, G. Finocchiaro, C. Belda-Iniesta, L. Recht, A. A. Brandes, E. Pineda, T. Mikkelsen, O. Chinot, C. Balana, D. Macdonald, M. Westphal, K. Hopkins, M. Weller, J.-M. Bruey, B. Liu, W. Verret
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastomas are highly vascularized with elevated VEGF expression and have been shown to respond to the anti-VEGF antibody bevacizumab. High MET expression has been associated with shorter progression-free survival (PFS) in glioblastomas (Pierscianek, et al. Brain Pathol 2013). This phase II study investigated the monovalent MET inhibitor, onartuzumab, plus bevacizumab (Ona + Bev) versus placebo plus bevacizumab (Pl + Bev) in recurrent glioblastoma. METHODS: Bevacizumab-naïve patients with glioblastoma at first recurrence following chemoradiation were randomized 1:1 to receive Ona (15mg/kg, q3w) + Bev (15mg/kg, q3w) or Pl + Bev until disease progression. Enrollment onto a third arm, Ona + Pl, was put on hold during assessment of safety data and was subsequently closed due to study conduct concerns (data not presented). Primary endpoint: PFS by RANO criteria (ITT and MET biomarker-positive subpopulations). Secondary endpoints: overall survival, objective response rate, duration of response, and safety. RESULTS: In the 129 patients enrolled (Ona + Bev n = 64, Pl + Bev n = 65) baseline characteristics were balanced; median age was 57 years; 43.4% had Karnofsky performance status 90-100%; 87.6% had measurable disease at baseline. Median number of bevacizumab cycles: 5 for Ona + Bev, 6 for Pl + Bev; median onartuzumab cycles, 4; median placebo cycles, 6. Grade ≥3 adverse events (AEs) were reported in 38.5% of Ona + Bev and 35.9% of Pl + Bev patients; serious AEs were reported in 30.8% and 29.7%, respectively. Grade 5 AEs: Ona + Bev n = 2 intestinal perforation; Pl + Bev n = 1 intracranial hemorrhage. AEs leading to study drug withdrawal were seen in 10.8% of Ona + Bev and 6.3% of Pl + Bev patients. AEs (all grades) with a difference in incidence of ≥10% between arms included peripheral edema (44.6% Ona + Bev, 14.1% Pl + Bev), hypertension (12.3% Ona + Bev, 32.8% Pl + Bev) and hypoalbuminemia (12.3% Ona + Bev, 1.6% Pl + Bev). Efficacy data are pending. CONCLUSION: The AEs observed were consistent with previous safety profiles for onartuzumab and bevacizumab with no new safety signals. Efficacy data will be presented.
OPTIMAL MANAGEMENT OF NON-CULPRIT STENOSIS IN PATIENTS WITH MULTIVESSEL DISEASE PRESENTING WITH ST ELEVATION MYOCARDIAL INFARCTION: RESULTS OF A NETWORK META ANALYSIS
Authors: Sanjog Kalra, Hadi Khafaji, Kelvin K.W. Chan, Sami M.A. Alnasser, Inderbir Singh, Sierra Cheng, Mahin Qureshi, Akshay Bagai, Asim Cheema
Journal: Journal of the American College of Cardiology (2016)
Amputation and Adriamycin in Primary Osteosarcoma
Authors: Engracio P. Cortes, James F. Holland, Jaw J. Wang, Lucius F. Sinks, Johannes Blom, Hansjurg Senn, Arthur Bank, Oliver Glidewell
Journal: New England Journal of Medicine (1974)

Adriamycin has been found effective in metastatic osteogenic sarcoma. To determine its efficacy in osteosarcoma without detectable metastases, 21 patients were given adjuvant adriamycin therapy two weeks (median) after surgical amputation of the primary lesion. Six courses of adriamycin (30 mg per square meter daily for three days, repeated every four to six weeks) were administered. Nineteen of the 21 patients survived from more than one to more than 32 months (median, more than nine months) after operation. Five of the 21 relapsed (two with local and three with pulmonary metastases). At 18 months, 71 per cent of treated patients may be expected to be free of pulmonary metastases as determined by life-table analyses (95 per cent confidence limits, 100 to 43 per cent), in contrast to 30 per cent of the series of 145 patients analyzed by Marcove et al. The data demonstrate an effect of adriamycin in delaying gross metastases from osteosarcoma and are consistent with chemotherapeutic eradication of micrometastases. (N Engl J Med 291:998–1000, 1974)
HALLAZGOS ENDOSCÓPICOS ENCONTRADOS EN LA ENFERMEDAD CELÍACA Y SU ASOCIACIÓN CON EL GRADO HISTOLÓGICO DE LA ENFERMEDAD
Authors: PJ Rosón Rodríguez, E Toscano, M López López, M Vidal Díaz, B Quintero Barranco
Journal: Endoscopy (2010)

Introducción: La enfermedad celíaca constituye uno de los procesos autoinmunes más frecuentes. La prevalencia mundial se estima en 1/266, aunque puede llegar a afectar hasta el 1% de la población en algunos países occidentales (rango 1/100 a 1/250).
USO DE PROPOFOL MEDIANTE PERFUSION CONTINUA EN CPRE CONTROLADO POR ENDOSCOPISTA
Authors: R Acosta Materán, C Piñero Pérez, A Mora Soler, Y Jamanca Poma, J Umaña Mejía, C Revilla Morato, D Pérez Corte, H Marcos Prieto, A Alvárez Delgado, A Rodríguez Pérez
Journal: Endoscopy (2013)

Introducción: La experiencia del uso de propofol en perfusión continua guiada por endoscopista experto y personal de enfermería (un/a enfermera/o y un/a auxiliar) en colangiopancreatografía retrógrada endoscópica (CPRE) es escasa. Objetivo: Analizar las características y determinar las complicaciones de la sedación en pacientes sedados con propofol en perfusión continua en CPRE en nuestra unidad. Material y Método: Estudio prospectivo observacional. Se incluyeron 108 pacientes entre agosto 2012 y abril 2013. Se clasificaron según riesgo ASA. La administración del propofol consistió en dosis de inducción entre 0,5 – 1 mg/kg según edad y comorbilidades, seguido de perfusión 4 – 8 mg/kg/h. Durante el procedimiento se monitorizaron saturación de O2, presión arterial, frecuencia cardíaca y respiratoria. La sedación fue administrada por un/a enfermero/a entrenado en sedación con ayuda del endoscopista. Para el alta se utilizó la escala de Aldrete. Resultados: La edad media fue de 76 ± 15 años. El 53,7% eran hombres y 47,3% mujeres. El 7,4% eran ASA I, 59,3% ASA II, 28, 7% ASA III y el 4,6% ASA IV. La dosis media de inducción con propofol fue de 66,98 mg. La dosis total media de propofol fue de 308,14 mg. El tiempo medio por CPRE fue 28,67 minutos, se asoció midazolam en 3 casos (2,8%) y fentanilo en 4 pacientes (3,7%). El tiempo medio de recuperación fue de 12 ± 6 minutos). Complicaciones relacionadas con la sedación, todas autolimitadas: 6,5% taquicardia, 11,1% desaturación leve (85 – 91%), 8,3% hipotensión arterial y 37% hipertensión leve. No se interrumpió ninguna CPRE debido a la sedación. Sólo 2 pacientes requirieron permanecer en endoscopias más de 20' para alcanzar 9 en la escala de Aldrete. Conclusión: La sedación con propofol en perfusión continua en CPRE administrada por personal de enfermería (enfermero/a y auxiliar) experto en sedación y controlada por un endoscopista capacitado es segura y eficaz.
Impaired Glucose Tolerance as a Disorder of Insulin Action
Authors: Stephen Lillioja, David M. Mott, Barbara V. Howard, Peter H. Bennett, Hannele Yki-Järvinen, Daniel Freymond, Bulangu L. Nyomba, Francesco Zurlo, Boyd Swinburn, Clifton Bogardus
Journal: New England Journal of Medicine (1988)

Impaired glucose tolerance often presages the development of non-insulin-dependent diabetes mellitus. We have studied insulin action and secretion in 24 Pima Indians before and after the development of impaired glucose tolerance and in 254 other subjects representing the whole spectrum of glucose tolerance, including subjects with overt non-insulin-dependent diabetes. The transition from normal to impaired glucose tolerance was associated with a decrease in glucose uptake during hyperinsulinemia, from 0.018 to 0.016 mmol per minute (from 3.3 to 2.8 mg per kilogram of fat-free body mass per minute) (P less than 0.0003). Mean plasma insulin concentrations increased during an oral glucose-tolerance test, from 1200 to 1770 pmol per liter (from 167 to 247 microU per milliliter). In 151 subjects with normal glucose tolerance, the insulin concentration measured during an oral glucose-tolerance test correlated with the plasma glucose concentration (r = 0.48, P less than or equal to 0.0001). This relation was used to predict an insulin concentration of 1550 pmol per liter (216 microU per milliliter) in subjects with impaired glucose tolerance (actual value, 1590 pmol per liter [222 microU per milliliter]; P not significant), suggesting that these subjects had normal secretion of insulin. In contrast, plasma insulin concentrations in the diabetics decreased as glucose concentrations increased (r = -0.75, P less than or equal to 0.0001), suggesting deficient secretion of insulin. This relative insulin deficiency first appears at the lower end of the second (diabetic) mode seen in population frequency distributions of plasma glucose concentrations. Our data show that impaired glucose tolerance in our study population is primarily due to impaired insulin action. In patients with non-insulin-dependent diabetes mellitus, by contrast, impaired insulin action and insulin secretory failure are both present.
Abstract 5031: R-spondin potentiates Wnt/β-catenin signaling in Ewing sarcoma cells.
Authors: Elisabeth A. Pedersen, Christopher A. Scannell, Elizabeth R. Lawlor
Journal: Cancer Research (2013)

Abstract Proper regulation of Wnt signaling is highly context-dependent and critical for growth and cellular maintenance. It is well-established that dysregulation of the canonical Wnt/β-catenin pathway contributes to the development and progression of numerous malignancies. Despite this, there has been little evidence to support a role for canonical Wnt signaling in Ewing sarcoma (ES) pathogenesis. Recent studies have shown that when members of the leucine-rich G-protein coupled receptor (LGR) family, namely LGR4 and LGR5, are bound by their ligands, R-spondins, they potentiate Wnt/β-catenin activity. Importantly, recent studies from our lab have shown that some ES tumors and cell lines express high levels of LGR5. In addition, R-spondin is highly expressed in the developing bone, which is the primary site of ES in children. Since ES cells do not exhibit canonical Wnt/β-catenin activity in standard culture conditions, we hypothesized that cues from the tumor microenvironment may be required for activation of this pathway. In particular, we hypothesized that R-spondins would potentiate Wnt activity in LGR-expressing ES cells. To test this hypothesis, ES cells were cultured in the presence of WNT3A and/or R-spondin 2 (Rspo2). Immunocytochemistry was used to determine β-catenin nuclear localization, and Wnt transcriptional activity was determined by flow cytometry and luciferase activity using cell lines transduced with lentiviral 7xTCF-GFP and 7xTCF-luciferase reporters, respectively. qRT-PCR was used to confirm transcription of the Wnt target gene AXIN2. Our results show that exogenous WNT3A induces β-catenin nuclear localization in ES cells and is associated with induction of TCF-mediated transcriptional activity and AXIN2 expression. Furthermore, Wnt/β-catenin activation is potentiated in the presence of Rspo2, and ES cells lines with the highest expression of LGRs show the strongest potentiation. Interestingly, however, exogenous WNT3A and Rspo2 did not induce Wnt activity in all cells. Together these data confirm that in the presence of exogenous ligand, Wnt/β-catenin signaling can be robustly activated in a subpopulation of ES cells and that signaling is potently enhanced in the presence of Rspo2 and LGRs. To our knowledge, this is the first evidence of R-spondins influencing Wnt activity in a non-epithelial cancer. These studies support the concept that R-spondin expression in the tumor microenvironment may contribute to ES pathogenesis by modulating Wnt/β-catenin signaling. Citation Format: Elisabeth A. Pedersen, Christopher A. Scannell, Elizabeth R. Lawlor. R-spondin potentiates Wnt/β-catenin signaling in Ewing sarcoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5031. doi:10.1158/1538-7445.AM2013-5031
Abstract 1554: Inducible B-Raf and c-Src models as tools for drug development.
Authors: Jan E. Ehlert, Bettina Mutschler, Melanie Mueller, Andreas Lingnau, Steffen Hoffmann, Holger Weber, Michael H. G. Kubbutat
Journal: Cancer Research (2013)

Abstract C-Src and B-Raf are critical kinases in signal transduction often involved in the onset of cancer and therefore representing promising targets for drug development. In order to assess the kinase-specific inhibitory effect in cellular and in-vivo models, we have generated cell lines exogenously expressing either c-Src or the commonly found mutant B-RafV600E in a regulatable manner, either by Doxicyclin-suppression or Hydroxy-Tamoxifen activation, respectively. Despite moderate kinase expression levels we observe significantly increased kinase activity in the activated state which can be monitored by substrate specific phospho-ELISAs as well as by analysis of phenotypic responses such as soft agar growth. Moreover, these cellular models are applicable for in-vivo analyses, showing strong in vivo growth in the activated state while no tumor growth occurs in the unactivated state. The applicability of these models in drug development is exemplified using c-Src inhibitor Dasatinib and B-Raf inhibitor Sorafenib. Citation Format: Jan E. Ehlert, Bettina Mutschler, Melanie Mueller, Andreas Lingnau, Steffen Hoffmann, Holger Weber, Michael H. G. Kubbutat. Inducible B-Raf and c-Src models as tools for drug development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1554. doi:10.1158/1538-7445.AM2013-1554