tbuckley/cabot-search huggingface dataset:
Changes in outcomes for internal medicine inpatients after work-hour regulations. Commentary
Authors: Leora I. Horwitz, Mikhail Kosiborod, Zhenqiu Lin, Harlan M. Krumholz, Lee Goldman, Nicholas H. Fiebach
Journal: Annals of Internal Medicine (2007)

Background: Limits on resident work hours are intended to reduce fatigue-related errors, but may raise risk by increasing transfers of responsibility for patients. Objective: To examine changes in outcomes for internal medicine patients after the implementation of work-hour regulations. Design: Retrospective cohort study. Setting: Urban, academic medical center. Patients: 14 260 consecutive patients discharged from the teaching (housestaff) service and 6664 consecutive patients discharged from the nonteaching (hospitalist) service between 1 July 2002 and 30 June 2004. Measurements: Outcomes included intensive care unit utilization, length of stay, discharge disposition, 30-day readmission rate to the study institution, pharmacist interventions to prevent error, drug-drug interactions and in-hospital death. Results: The teaching service had net improvements in 3 outcomes. Relative to changes experienced by the nonteaching service, the rate of intensive care unit utilization decreased by 2.1% (95% Cl, -3.3% to -0.7%; P = 0.002), the rate of discharge to home or rehabilitation facility versus elsewhere improved by 5.3% (Cl, 2.6% to 7.6%; P< 0.001), and pharmacist interventions to prevent error were reduced by 1.92 interventions per 100 patient-days (Cl, -2.74 to -1.03 interventions per 100 patient-days; P< 0.001). Teaching and nonteaching services had similar changes over time in length of stay, 30-day readmission rate, and adverse drug-drug interactions. In-hospital death was uncommon in both groups, and change over time was similar in the 2 groups. Limitations: The study was a retrospective, nonrandomized design that assessed a limited number of outcomes. Teaching and nonteaching cohorts may not have been affected similarly by secular trends in patient care. Conclusions: After the implementation of work-hour regulations, 3 of 7 outcomes improved for patients in the teaching service relative to those in the nonteaching service. The authors found no evidence of adverse unintended consequences after the institution of work-hour regulations.
Coagulation factors bound to procoagulant platelets concentrate in cap structures to promote clotting
Authors: Nadezhda A. Podoplelova, Anastasia N. Sveshnikova, Yana N. Kotova, Anita Eckly, Nicolas Receveur, Dmitry Yu. Nechipurenko, Sergey I. Obydennyi, Igor I. Kireev, Christian Gachet, Fazly I. Ataullakhanov, Pierre H. Mangin, Mikhail A. Panteleev
Journal: Blood (2016)

Binding of coagulation factors to phosphatidylserine (PS)-exposing procoagulant-activated platelets followed by formation of the membrane-dependent enzyme complexes is critical for blood coagulation. Procoagulant platelets formed upon strong platelet stimulation, usually with thrombin plus collagen, are large "balloons" with a small (∼1 μm radius) "cap"-like convex region that is enriched with adhesive proteins. Spatial distribution of blood coagulation factors on the surface of procoagulant platelets was investigated using confocal microscopy. All of them, including factors IXa (FIXa), FXa/FX, FVa, FVIII, prothrombin, and PS-sensitive marker Annexin V were distributed nonhomogeneously: they were primarily localized in the "cap," where their mean concentration was by at least an order of magnitude, higher than on the "balloon." Assembly of intrinsic tenase on liposomes with various PS densities while keeping the PS content constant demonstrated that such enrichment can accelerate this reaction by 2 orders of magnitude. The mechanisms of such acceleration were investigated using a 3-dimensional computer simulation model of intrinsic tenase based on these data. Transmission electron microscopy and focal ion beam-scanning electron microscopy with Annexin V immunogold-labeling revealed a complex organization of the "caps." In platelet thrombi formed in whole blood on collagen under arterial shear conditions, ubiquitous "caps" with increased Annexin V, FX, and FXa binding were observed, indicating relevance of this mechanism for surface-attached platelets under physiological flow. These results reveal an essential heterogeneity in the surface distribution of major coagulation factors on the surface of procoagulant platelets and suggest its importance in promoting membrane-dependent coagulation reactions.
Decisional Algorithm to Incorporate Hematopoietic Stem Cell Transplantation in the Management of Adult Patients with Acute Myeloid Leukaemia.
Authors: Francesco Buccisano, Luca Maurillo, Maria Ilaria Del Principe, Giovanni Del Poeta, Paola Panetta, Emanuele Ammatuna, Licia Ottaviani, Chiara Sarlo, Micol Quaresima, Gottardo De Angelis, Manuela Rizzo, Selenia Campagna, Francesco Lo Coco, William Arcese, Sergio Amadori, Adriano Venditti
Journal: Blood (2008)
Clinicopathologic features and prognostic implications of epidermal growth factor receptor (EGFR) gene mutations detected by denaturing high-performance liquid chromatography (dHPLC) in non-small cell lung cancer (NSCLC)
Authors: V. Cohen, J. S. Agulnik, C. Ang, G. Kasymjanova, G. Chong, N. A. Tejada, C. Pepe, G. Batist, D. Small, W. H. Miller
Journal: Journal of Clinical Oncology (2007)

7594 Background: Somatic mutations of the EGFR gene predict sensitivity to erlotinib and gefitinib and confer a favorable prognosis in patients (pts) with NSCLC. We have recently shown that dHPLC is an efficient and more sensitive method for mutation screening compared with DNA sequencing. The goal of this study was to describe the relationship between EGFR status (mutation status and type) and clinicopathologic factors. Methods: Tumor samples were analysed for EGFR exon 19 deletions and exon 21 L858R point mutations. DNA was extracted from paraffin-embedded tumor specimens and genotyped using dHPLC. The results were correlated with gender, smoking status, pathologic subtype, disease stage, and overall survival. Results: 215 NSCLC pts were genotyped. Mutations were present in 25% of cases (54 of 215). Among pts with mutations, 70% (38 of 54) had an exon 19 mutation whereas 30% had EGFR L858R. EGFR mutations were more common in women (31% vs 14%; p=0.008), in nonsmokers than ever-smokers (54% vs 17%; p&lt;0.001), in adenocarcinomas/BAC than with other NSCLC histologies (31% vs 11%; p=0.004) and more frequently detected in advanced-stage than in early-stage disease (36% vs 15%; p=0.001). Median survival times of pts with stage IIIB-IV disease with and without EGFR mutations were 20 and 14 months, respectively. Those with exon 19 deletion mutations had a longer median survival than pts with L858R point mutations. Data describing the impact of tyrosine kinase inhibitor therapy on survival outcomes are pending and will be presented. Conclusion: dHPLC is a reliable tool for EGFR mutation detection. Mutations were preferentially observed in women, nonsmokers, adenocarcinomas/BAC and in patients with advanced disease. Pts with mutations experienced improved survival and those harboring deletions fared better than those with point mutations. These observations warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types. No significant financial relationships to disclose.
Vascular endothelial growth factor expression and survival in node positive breast cancer patients treated with adjuvant therapy
Authors: S. E. Rivkin, A. M. Gown, J. A. Malmgren, R. J. Tickman, M. Atwood, D. Iriarte
Journal: Journal of Clinical Oncology (2004)

653 Background: Vascular endothelial growth factor (VEGF) expression may affect tumor angiogenesis, with most studies finding worse survival associated with VEGF positivity. Methods: An immunohistochemical analysis for VEGF expression was performed on a cohort of 125 primary breast cancer patients diagnosed between 1989 and 1998 with 4 or more positive axillary lymph nodes, treated with adjuvant therapy. Patients were followed via registry for treatment, recurrence, and vital status current as of 2003. VEGF immunostaining, using the C1 clone on deparaffinized, formalin fixed tissue, was scored via a semi-quantitative system based on the intensity of immunostaining signal. Correlations were measured with factors associated with better and worse outcomes such as tumor size, number of positive lymph nodes, estrogen/progesterone receptor status, and HER-2/neu over expression. Log rank test for survival differences by VEGF status were calculated using Kaplan Meier plots. Results: 37% of the sample tested positive (2+) for VEGF (n=46). Fifty seven percent of the cases were over 50 years of age, 65% had 4–9 positive lymph nodes and 35%>=10, and median follow up was six years. VEGF positive patients had worse breast cancer survival (log rank test = 8.93, p = .003), overall survival (log rank test = 7.54, p = .006), and relapse free survival (log rank test = 5.61, p = .018). Patients who had 4–9 versus 10 or more positive lymph nodes, were estrogen receptor positive, or were HER-2/neu negative had significantly worse disease specific survival if they were VEGF positive. ER+/VEGF+ patients had significantly worse survival that ER+/VEGF- patients. Conclusions: In this study high levels of expression of VEGF were associated with significantly worse survival in breast cancer patients, even in subgroups expected to have a better prognosis. No significant financial relationships to disclose.
Concurrent chemoradiation (CRT) with conventional fractionation for limited disease small cell lung cancer (SCLC-LD): a retrospective analysis in a single institution
Authors: Elke Vandenbroucke, Ans Pelgrims, Yolande Lievens, Johnny Moons, Johan Vansteenkiste, Kristiaan Nackaerts
Journal: Journal of Thoracic Oncology (2009)
Randomized phase II study of the efficacy and safety of gemcitabine plus TH-302 versus gemcitabine alone in previously untreated patients with advanced pancreatic cancer.
Authors: M. J. Borad, D. Sigal, H. Uronis, J. Stephenson, N. Bahary, M. U. Rarick, L. C. DeMarco, T. J. Finnegan, E. G. Chiorean, D. P. Ryan, A. L. Cohn, B. K. Ulrich, V. C. Harish, E. N. Anderes, W. W. Ma, P. P. Yu, F. Sinicrope, C. Eng, U. K. Sunkara, S. G. Reddy
Journal: Journal of Clinical Oncology (2011)

TPS176 Background: A hypoxic microenvironment is believed to be a characteristic of solid tumors including pancreatic adenocarcinoma (PAC) and is associated with resistance to chemotherapy. The hypoxia-activated prodrug, TH-302, is designed to specifically target the hypoxic microenvironment. Combining gemcitabine (G) with TH-302 may enable the targeting of both the normoxic and hypoxic regions of PAC. TH-302 was investigated in combination with full-dose G as part of a phase I/II study and the efficacy of the combination was higher than generally reported with single agent G (Burris, JCO 1997). 43 PAC patients received 1000 mg/m2 G in combination with 240 – 575 mg/m2 TH-302. By RECIST tumor response criteria, 1 (2%) had a CR, 8 (19%) had a PR, 39 (91%) patients had SD or better. Median PFS and OS were 5.95 and 8.5 months, respectively. Based upon these data, an ongoing randomized study (NCT01144455) is being conducted to assess the benefit of adding TH-302 to the standard dose G regimen for first-line therapy of PAC. Methods: An open-label multi-center Phase II study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone was initiated in June 2010. Patients are randomized at a ratio of 1:1:1. TH-302 is administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. G (1000 mg/m2) is administered IV over 30 minutes on Days 1, 8 and 15 starting 2 hours after completion of the TH-302 infusion when used in combination. Patients on the G arm who discontinue for disease progression and meet eligibility may crossover and be randomized to a TH-302 plus G arm. Key eligibility criteria: locally advanced unresectable or metastatic PAC untreated with chemotherapy, ECOG status 0 or 1, measurable disease by RECIST and adequate hematologic, hepatic and renal function. The primary efficacy endpoint is a progression-free (PFS)/event-free (EFS) comparison of the combination arms vs G alone. Interim analyses for efficacy and safety are scheduled after approximately 50, 75 and 100 PFS or EFS events. Additional analyses comparing each of the two TH-302 dose levels with G versus the G alone arm will also be conducted. Over 90 of 165 planned patients have been enrolled.
High Response Rate of Moxetumomab Pasudotox in Relapsed/Refractory Hairy Cell Leukemia Includes Eradication of Minimal Residual Disease: Potential Importance for Outcome
Authors: Robert J. Kreitman, Evgeny Arons, Martin S Tallman, Robak Tadeusz, Steven Coutre, Wyndham H Wilson, Maryalice Stetler-Stevenson, Constance M. Yuan, Mark Lanasa, David JP FitzGerald, Ira Pastan
Journal: Blood (2015)
Deletion of IKZF1 (Ikaros) Predicts Poor Outcome and Impaired Maturation in B-Progenitor Acute Lymphoblastic Leukemia
Authors: Charles G. Mullighan, Xiaoping Su, Jinghui Zhang, Ina Radtke, Letha A Phillips, Christopher B Miller, Jing Ma, Wei Liu, Cheng Cheng, Richard C. Harvey, I-Ming Chen, Robert Clifford, William L. Carroll, Gregory Reaman, Meenakshi Devidas, Daniela S. Gerhard, Wenjian Yang, W. Paul Bowman, Sheila A. Shurtleff, Mary V. Relling, Malcolm Smith, Stephen P. Hunger, Cheryl L. Willman, James R. Downing
Journal: Blood (2008)
Protein C receptor (PROCR) is a negative regulator of Th17 pathogenicity
Authors: Yasuhiro Kishi, Takaaki Kondo, Sheng Xiao, Nir Yosef, Jellert Gaublomme, Chuan Wu, Chao Wang, Norio Chihara, Aviv Regev, Nicole Joller, Vijay K. Kuchroo
Journal: The Journal of Experimental Medicine (2016)

Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on single-cell RNA-seq profiling of pathogenic versus nonpathogenic Th17 cells, we identified protein C receptor (PROCR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PROCR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PROCR negatively regulated Th17 differentiation. CD4+ T cells from PROCR low expressor mutant mice readily differentiated into Th17 cells, whereas addition of the PROCR ligand, activated protein C, inhibited Th17 differentiation in vitro. In addition, PROCR acted as a negative regulator of Th17 pathogenicity in that it down-regulated expression of several pathogenic signature genes, including IL-1 and IL-23 receptors. Furthermore, T cell–specific deficiency of PROCR resulted in the exacerbation of experimental autoimmune encephalomyelitis (EAE) and higher frequencies of Th17 cell in vivo, indicating that PROCR also inhibits pathogenicity of Th17 cells in vivo. PROCR thus does not globally inhibit Th17 responses but could be targeted to selectively inhibit proinflammatory Th17 cells.
Corrigendum to “Short-range cytokine gradients to mimic paracrine cell interactions in vitro” [J. Control. Release 224 (2016) 59–68]
Authors: Michael Ansorge, Nadine Rastig, Ralph Steinborn, Tina König, Lars Baumann, Stephanie Möller, Matthias Schnabelrauch, Michael Cross, Carsten Werner, Annette G. Beck-Sickinger, Tilo Pompe
Journal: Journal of Controlled Release (2016)
Effectiveness of the live attenuated and the inactivated influenza vaccine in two-year-olds – a nationwide cohort study Finland, influenza season 2015/16
Authors: Hanna Nohynek, Ulrike Baum, Ritva Syrjänen, Niina Ikonen, Jonas Sundman, Jukka Jokinen
Journal: Eurosurveillance (2016)

Although widely recommended, influenza vaccination of children is part of the national vaccination programme only in few countries. In addition to Canada and the United States (US), in Europe Finland and the United Kingdom have introduced live attenuated influenza vaccine (LAIV) for healthy children in their programmes. On 22 June 2016, the US Advisory Committee on Immunizations Practices, voted against further use of LAIV due to no observed vaccine effectiveness (VE) over three consecutive influenza seasons (2013/14 to 2015/16). We summarise the results of a nationwide, register-based cohort study (N=55,258 of whom 8,086 received LAIV and 4,297 TIV); all outcome (laboratory-confirmed influenza), exposure (vaccination) and confounding variable data were retrieved from four computerised national health registers, which were linked via a unique personal identity code assigned to all permanent Finnish residents regardless of nationality. Our study provides evidence of moderate effectiveness against any laboratory-confirmed influenza of the quadrivalent LAIV vaccine (VE: 51%; 95% confidence interval (CI): 28-66%) as well as the inactivated trivalent vaccine (VE: 61%; 95% CI: 31-78%) among two-year-olds during the influenza season 2015/16 in Finland. Based on these data, Finland will continue using LAIV for young children in its National Immunisation Programme this coming influenza season.
Rescue of a Terminally Ill Patient with Chemo-Refractory Acute Lymphoblastic Leukemia Carrying Bcr/Abl and TP53 Mutations Based on a 4th Generation CD19 Chimeric Antigen Receptor-Engineered T (CAR-T) Therapy
Authors: Ting Niu, Lung-Ji Chang, Jinrong Yang, Yuchen Liu, Lujia Dong, Wei Wang, Ting Liu
Journal: Blood (2015)
Development of a mobile application (app) for improving symptoms and adherence to oral chemotherapy in patients with cancer.
Authors: Lauren Nisotel, Nicole Amoyal, Joel Fishbein, James MacDonald, William F. Pirl, Jennifer S. Temel, Inga Tolin Lennes, Steven A. Safren, Joanne S. Buzaglo, Kamal Jethwani, Joseph A. Greer
Journal: Journal of Clinical Oncology (2015)

189 Background: An advantage of oral chemotherapy is ease of administration, yet patients and family caregivers receive less support for adherence and monitoring of side effects. Effective interventions should support adherence to oral chemotherapy. We conducted qualitative interviews with patients, clinicians, and relevant stakeholders to inform the development of a proposed mobile app intervention to improve adherence and symptoms to oral chemotherapy. Methods: We conducted qualitative interviews and focus groups with multiple stakeholder groups (18 oncology physicians, 8 healthcare representatives, 8 cancer practice administrators, 18 patients and family members). Eligible patients had a diagnosis of cancer, a prescription for oral chemotherapy, cancer care at the MGH Cancer Center, and access to a smart phone. Stakeholders and clinicians evaluated the study approach, patient engagement, and intervention implementation. Patients reviewed wireframes of the mobile app to evaluate the components, usability, feasibility, and acceptability. Results: The app features include a treatment plan, medication reminders, symptom reporting, and cancer-specific resources. The themes from the qualitative interviews suggest that this mobile app would be helpful in improving adherence to oral chemotherapy and symptom management. Patients reported the wireframes to be acceptable and potentially user-friendly. Clinicians found that ongoing symptom reports would be helpful for proactively managing patients’ symptoms. Stakeholders recognized the importance of an app with functional tools to aid adherence and symptom management. All parties agreed that app features should remain simple, avoid undue burden, and thus enhance usability. Conclusions: Our findings suggest that a mobile app could be helpful for adherence and improving symptoms to oral chemotherapy in patients with cancer. Patients and clinicians rated the wireframe content favorably and commended the different features. We refined and finalized the mobile app based on feedback from the qualitative interviews. These findings support our plan to test the efficacy of this intervention in a randomized controlled trial. Clinical trial information: NCT02157519.
VALUE OF MEASUREMENT OF CENTRAL VENOUS-PRESSURE CHANGES (DELTA-PCV) VS ESOPHAGEAL PRESSURE CHANGES (DELTA-PES) FOR CALCULATION OF LUNG COMPLIANCE DURING MECHANICAL VENTILATION (MV)
Authors: Bs Hylkema, P Barkmeijerdegenhart, Tw Vandermark, Wj Snoek, R Peset, Hj Sluiter
Journal: Intensive Care Medicine (1980)
Biomarker discovery in psoriasis using a multiparameter flow cytometry platform
Authors: F. Villanova, P. Di Meglio, M. Inokuma, S. Heck, E. Perucha, R. Brinkman, M. Hernandez Fuentes, G. Lord, S. V. Maino, F. O. Nestle
Journal: British Journal of Dermatology (2012)
Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis
Authors: Tianli Xia, Hiroyasu Konno, Glen N. Barber
Journal: Cancer Research (2016)

The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity. Here, we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically, STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase, which generates STING-activating cyclic dinucleotides after binding cytosolic DNA species. Loss of STING function rendered melanoma cells unable to produce type I IFN and other immune cytokines after exposure to cytosolic DNA species. Consequently, such cells were highly susceptible to infection with DNA viruses including HSV1, a variant of which is being developed presently as a therapeutic oncolytic virus [talimogene laherparepvec (T-VEC)]. Our findings provide insight into the basis for susceptibility to viral oncolysis by agents such as HSV1. Cancer Res; 76(22); 6747-59. ©2016 AACR.
Combination of Farnesyl Transferase Inhibition (Lonafarnib) and Proteasome Inhibition (Bortezomib) Results in Rapid Caspase Activation and down Regulation of p-AKT in Myeloma cell Lines and Primary Myeloma Cells.
Authors: Ebenezer David, Shi-Yong Sun, Fadlo R. Khuri, Sagar Lonial
Journal: Blood (2004)
O-0021 Randomised Phase III Study of Bevacizumab + Chemotherapy Beyond Progression in Bevacizumab-Treated Patients with Metastatic Colorectal Cancer: TML Study Kras Subgroup Findings
Authors: Eric Van Cutsem, Jose Maria Vieitez, Olivier Bouché, Pia Österlund, Jaafar Bennouna, Thierry André, Javier Sastre, Vicente Alonso-Orduna, Stefan Kubicka, Richard Greil, Roger von Moos, Irmarie Reyes-Rivera, Stefan Scherer, Belguendouz Bendahmane, Dirk Arnold
Journal: Annals of Oncology (2012)
Proteinases, Their Extracellular Targets, and Inflammatory Signaling
Authors: Rithwik Ramachandran, Christophe Altier, Katerina Oikonomopoulou, Morley D. Hollenberg
Journal: Pharmacological Reviews (2016)

Given that over 2% of the human genome codes for proteolytic enzymes and their inhibitors, it is not surprising that proteinases serve many physiologic-pathophysiological roles. In this context, we provide an overview of proteolytic mechanisms regulating inflammation, with a focus on cell signaling stimulated by the generation of inflammatory peptides; activation of the proteinase-activated receptor (PAR) family of G protein-coupled receptors (GPCR), with a mechanism in common with adhesion-triggered GPCRs (ADGRs); and by proteolytic ion channel regulation. These mechanisms are considered in the much wider context that proteolytic mechanisms serve, including the processing of growth factors and their receptors, the regulation of matrix-integrin signaling, and the generation and release of membrane-tethered receptor ligands. These signaling mechanisms are relevant for inflammatory, neurodegenerative, and cardiovascular diseases as well as for cancer. We propose that the inflammation-triggering proteinases and their proteolytically generated substrates represent attractive therapeutic targets and we discuss appropriate targeting strategies.