tbuckley/cabot-search huggingface dataset:
SLC/CCL21-mediated anti-tumor responses require IFNgamma, MIG/CXCL9 and IP-10/CXCL10.
Authors: Sherven Sharma, Seok-Chul Yang, Sven Hillinger, Li X Zhu, Min Huang, Raj K Batra, Jeff F Lin, Marie D Burdick, Robert M Strieter, Steven M Dubinett
Journal: Molecular Cancer (2003)

SLC/CCL21, normally expressed in high endothelial venules and in T cell zones of spleen and lymph nodes, strongly attracts T cells and dendritic cells (DC). We have previously shown that SLC/CCL21-mediated anti-tumor responses are accompanied by significant induction of IFNgamma and the CXC chemokines, monokine induced by IFNgamma (MIG/CXCL9) and IFNgamma-inducible protein-10 (IP-10/CXCL10).We assessed the importance of IFNgamma, IP-10/CXCL10 and MIG/CXCL9 in SLC/CCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9 or IFNgamma significantly reduced the anti-tumor efficacy of SLC/CCL21. Assessment of cytokine production at the tumor site showed an interdependence of IFNgamma, MIG/CXCL9 and IP-10/CXCL10; neutralization of any one of these cytokines caused a concomitant decrease in all three cytokines. Similarly, neutralization of any one of these cytokines led to a decrease in the frequency of CXCR3+ve T cells and CD11c+ve DC at the tumor site.These findings indicate that the full potency of SLC/CCL21-mediated anti-tumor responses require in part the induction of IFNgamma, MIG/CXCL9 and IP-10/CXCL10.
Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance)
Authors: Hope S. Rugo, William T. Barry, Alvaro Moreno-Aspitia, Alan P. Lyss, Constance Cirrincione, Eleanor Leung, Erica L. Mayer, Michael Naughton, Deborah Toppmeyer, Lisa A. Carey, Edith A. Perez, Clifford Hudis, Eric P. Winer
Journal: Journal of Clinical Oncology (2015)

Purpose We compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel. Patients and Methods Eligible patients were age ≥ 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m 2 (arm A), nab-paclitaxel 150 mg/m 2 (arm B), or ixabepilone 16 mg/m 2 (arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73. Results In all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P &lt; .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions. Conclusion In patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting.
Role of endoscopy and biopsy in the work up of dyspepsia
Authors: G N J Tytgat
Journal: Gut (2002)

Endoscopy is recommended as the first investigation in the work up of a patient with dyspeptic symptoms and is essential in the classification of the patient9s condition as organic or functional dyspepsia. Although the correlation between mucosal alterations and symptom pattern is difficult, endoscopy will remain the initial investigation of choice for clinically relevant abnormalities that need proper detection and biopsy.
SLC45A3-ELK4 Is a Novel and Frequent Erythroblast Transformation–Specific Fusion Transcript in Prostate Cancer
Authors: David S. Rickman, Dorothee Pflueger, Benjamin Moss, Vanessa E. VanDoren, Chen X. Chen, Alexandre de la Taille, Rainer Kuefer, Ashutosh K. Tewari, Sunita R. Setlur, Francesca Demichelis, Mark A. Rubin
Journal: Cancer Research (2009)

Abstract Chromosomal rearrangements account for all erythroblast transformation–specific (ETS) family member gene fusions that have been reported in prostate cancer and have clinical, diagnostic, and prognostic implications. Androgen-regulated genes account for the majority of the 5′ genomic regulatory promoter elements fused with ETS genes. TMPRSS2-ERG, TMPRSS2-ETV1, and SLC45A3-ERG rearrangements account for roughly 90% of ETS fusion prostate cancer. ELK4, another ETS family member, is androgen regulated, involved in promoting cell growth, and highly expressed in a subset of prostate cancer, yet the mechanism of ELK4 overexpression is unknown. In this study, we identified a novel ETS family fusion transcript, SLC45A3-ELK4, and found it to be expressed in both benign prostate tissue and prostate cancer. We found high levels of SLC45A3-ELK4 mRNA restricted to a subset of prostate cancer samples. SLC45A3-ELK4 transcript can be detected at high levels in urine samples from men at risk for prostate cancer. Characterization of the fusion mRNA revealed a major variant in which SLC45A3 exon 1 is fused to ELK4 exon 2. Based on quantitative PCR analyses of DNA, unlike other ETS fusions described in prostate cancer, the expression of SLC45A3-ELK4 mRNA is not exclusive to cases harboring a chromosomal rearrangement. Treatment of LNCaP cancer cells with a synthetic androgen (R1881) revealed that SLC45A3-ELK4, and not endogenous ELK4, mRNA expression is androgen regulated. Altogether, our findings show that SLC45A3-ELK4 mRNA expression is heterogeneous, highly induced in a subset of prostate cancers, androgen regulated, and most commonly occurs through a mechanism other than chromosomal rearrangement (e.g., trans-splicing). [Cancer Res 2009;69(7):2734–8]
Neutrophil Extracellular Traps Are Pathogenic in Primary Graft Dysfunction after Lung Transplantation
Authors: David M. Sayah, Beñat Mallavia, Fengchun Liu, Guadalupe Ortiz-Muñoz, Axelle Caudrillier, Ariss DerHovanessian, David J. Ross, Joseph P. Lynch III, Rajan Saggar, Abbas Ardehali, Lorraine B. Ware, Jason D. Christie, John A. Belperio, Mark R. Looney
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Primary graft dysfunction (PGD) causes early mortality after lung transplantation and may contribute to late graft failure. No effective treatments exist. The pathogenesis of PGD is unclear, although both neutrophils and activated platelets have been implicated. We hypothesized that neutrophil extracellular traps (NETs) contribute to lung injury in PGD in a platelet-dependent manner.To study NETs in experimental models of PGD and in lung transplant patients.Two experimental murine PGD models were studied: hilar clamp and orthotopic lung transplantation after prolonged cold ischemia (OLT-PCI). NETs were assessed by immunofluorescence microscopy and ELISA. Platelet activation was inhibited with aspirin, and NETs were disrupted with DNaseI. NETs were also measured in bronchoalveolar lavage fluid and plasma from lung transplant patients with and without PGD.NETs were increased after either hilar clamp or OLT-PCI compared with surgical control subjects. Activation and intrapulmonary accumulation of platelets were increased in OLT-PCI, and platelet inhibition reduced NETs and lung injury, and improved oxygenation. Disruption of NETs by intrabronchial administration of DNaseI also reduced lung injury and improved oxygenation. In bronchoalveolar lavage fluid from human lung transplant recipients, NETs were more abundant in patients with PGD.NETs accumulate in the lung in both experimental and clinical PGD. In experimental PGD, NET formation is platelet-dependent, and disruption of NETs with DNaseI reduces lung injury. These data are the first description of a pathogenic role for NETs in solid organ transplantation and suggest that NETs are a promising therapeutic target in PGD.
Genome-wide meta-analysis identifies new susceptibility loci for migraine
Authors: Verneri Anttila, Bendik S Winsvold, Padhraig Gormley, Tobias Kurth, Francesco Bettella, George McMahon, Mikko Kallela, Rainer Malik, Boukje de Vries, Gisela Terwindt, Sarah E Medland, Unda Todt, Wendy L McArdle, Lydia Quaye, Markku Koiranen, M Arfan Ikram, Terho Lehtimäki, Anine H Stam, Lannie Ligthart, Juho Wedenoja, Ian Dunham, Benjamin M Neale, Priit Palta, Eija Hamalainen, Markus Schürks, Lynda M Rose, Julie E Buring, Paul M Ridker, Stacy Steinberg, Hreinn Stefansson, Finnbogi Jakobsson, Debbie A Lawlor, David M Evans, Susan M Ring, Markus Färkkilä, Ville Artto, Mari A Kaunisto, Tobias Freilinger, Jean Schoenen, Rune R Frants, Nadine Pelzer, Claudia M Weller, Ronald Zielman, Andrew C Heath, Pamela A F Madden, Grant W Montgomery, Nicholas G Martin, Guntram Borck, Hartmut Göbel, Axel Heinze, Katja Heinze-Kuhn, Frances M K Williams, Anna-Liisa Hartikainen, Anneli Pouta, Joyce van den Ende, Andre G Uitterlinden, Albert Hofman, Najaf Amin, Jouke-Jan Hottenga, Jacqueline M Vink, Kauko Heikkilä, Michael Alexander, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Heinz Erich Wichmann, Arpo Aromaa, Johan G Eriksson, Bryan J Traynor, Daniah Trabzuni, Elizabeth Rossin, Kasper Lage, Suzanne B R Jacobs, J Raphael Gibbs, Ewan Birney, Jaakko Kaprio, Brenda W Penninx, Dorret I Boomsma, Cornelia van Duijn, Olli Raitakari, Marjo-Riitta Jarvelin, John-Anker Zwart, Lynn Cherkas, David P Strachan, Christian Kubisch, Michel D Ferrari, Arn M J M van den Maagdenberg, Martin Dichgans, Maija Wessman, George Davey Smith, Kari Stefansson, Mark J Daly
Journal: Nature Genetics (2013)
From Integrative Genomics to Therapeutic Targets
Authors: Rachael Natrajan, Paul Wilkerson
Journal: Cancer Research (2013)

Combinatorial approaches that integrate conventional pathology with genomic profiling and functional genomics have begun to enhance our understanding of the genetic basis of breast cancer. These methods have identified key genotypic-phenotypic correlations in different breast cancer subtypes that have led to the discovery of genetic dependencies that drive their behavior. Moreover, this knowledge has been applied to define novel tailored therapies for these groups of patients with cancer. With the current emphasis on characterizing the mutational repertoire of breast cancers by next-generation sequencing, the question remains as to what constitutes a driver event. By focusing efforts on homogenous subgroups of breast cancer and integrating orthogonal data-types combined with functional approaches, we can begin to unravel the heterogeneity and identify aberrations that can be therapeutically targeted.
PCTs' grip and professionalism are crumbling in the face of NHS reforms
Authors: A. O'Dowd
Journal: BMJ (2010)

The ability of primary care trusts to operate professionally and keep a grip on money is starting to weaken, MPs have been told.

Trusts are receiving fewer tenders, failing to follow cooperation and competition rules, not encouraging innovation, and losing valuable staff, the parliamentary health select committee heard on 7 December as part of its inquiry into commissioning.

Witnesses told MPs that urgent efforts should be made to help the transition from the current system to new arrangements set out in the health white paper, which will abolish primary care trusts and create GP led commissioning consortiums to control most of the NHS budget.

David Worskett, director of NHS Partners Network, the network for …
PEF variability, bronchial responsiveness and their relation to allergy markers in a random population (20-70 yr).
Authors: H M Boezen, D S Postma, J P Schouten, H A Kerstjens, B Rijcken
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

We investigated the coherence of bronchial hyperresponsiveness (BHR) and peak expiratory flow (PEF) variability in their relation to allergy markers and respiratory symptoms in 399 subjects (20-70 yr). Bronchial hyperresponsiveness to methacholine was defined by both the provocative dose causing a fall in FEV1 of 20%, and the dose-response slope. PEF variability was determined as diurnal PEF variation (amplitude percent mean) and between-day PEF variation. Skin tests positivity, serum total IgE, and specific IgE (RAST) for house-dust mite (HDM), cat, timothy grass, and birch ("pollen") were determined, as well as the number of peripheral blood eosinophils. Wheeze and nocturnal dyspnea were defined as asthma-like symptoms; dyspnea > or = grade 3, cough and phlegm as chronic obstructive pulmonary disease (COPD)-like symptoms. The reciprocal of the dose-response slope and PEF variability were significantly correlated (r = -0.39). Subjects with a positive skin test for HDM (odds ratio [OR] = 3.9), cat (OR = 8.3), or pollen (OR = 3.6), or specific IgE for HDM (OR = 2.3), cat (OR = 3.4), or pollen (OR = 1.9) had increased risk of BHR compared with the reference group (all p values < 0.05). Higher levels of serum total IgE were significantly associated with higher odds for BHR (OR = 2.5 per log unit). There was no significant association between skin test positivity, serum total IgE, or presence of specific IgE and PEF variability. Neither BHR nor PEF variability were associated with higher numbers of peripheral blood eosinophils. There are different associations of BHR and PEF variability with allergy markers. Although BHR and PEF variability are significantly correlated, they cannot be used interchangeably in epidemiologic settings.
Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis
Authors: Kazuhide Watanabe, Yasuhiro Hasegawa, Hiroshi Yamashita, Kazue Shimizu, Yuanying Ding, Mayumi Abe, Hideki Ohta, Keiichi Imagawa, Kanji Hojo, Hideo Maki, Hikaru Sonoda, Yasufumi Sato
Journal: Journal of Clinical Investigation (2004)

Negative feedback is a crucial physiological regulatory mechanism, but no such regulator of angiogenesis has been established. Here we report a novel angiogenesis inhibitor that is induced in endothelial cells (ECs) by angiogenic factors and inhibits angiogenesis in an autocrine manner. We have performed cDNA microarray analysis to survey VEGF-inducible genes in human ECs. We characterized one such gene, KIAA1036, whose function had been uncharacterized. The recombinant protein inhibited migration, proliferation, and network formation by ECs as well as angiogenesis in vivo. This inhibitory effect was selective to ECs, as the protein did not affect the migration of smooth muscle cells or fibroblasts. Specific elimination of the expression of KIAA1036 in ECs restored their responsiveness to a higher concentration of VEGF. The expression of KIAA1036 was selective to ECs, and hypoxia or TNF-α abrogated its inducible expression. As this molecule is preferentially expressed in ECs, we designated it “vasohibin.” Transfection of Lewis lung carcinoma cells with the vasohibin gene did not affect the proliferation of cancer cells in vitro, but did inhibit tumor growth and tumor angiogenesis in vivo. We propose vasohibin to be an endothelium-derived negative feedback regulator of angiogenesis.
Anti-graft-versus-host disease effect of DT390-anti-CD3sFv, a single- chain Fv fusion immunotoxin specifically targeting the CD3 epsilon moiety of the T-cell receptor
Authors: DA Vallera, A Panoskaltsis-Mortari, C Jost, S Ramakrishnan, CR Eide, RJ Kreitman, PJ Nicholls, C Pennell, BR Blazar
Journal: Blood (1996)
Induced Sputum Cellularity
Authors: ANTONIO SPANEVELLO, MARCO CONFALONIERI, FRANCA SULOTTO, FRANCESCO ROMANO, GIANNI BALZANO, GIOVANNI BATTISTA MIGLIORI, ACHILLE BIANCHI, GIOVANNI MICHETTI
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Sputum induction has recently been proposed as the only direct noninvasive method for measuring airway inflammatory indices. The reference values and the distribution of cells in induced sputum in a control population have not yet been well defined. We therefore evaluated data from a large number of healthy volunteers. One hundred fourteen healthy, nonatopic, nonsmoking volunteers without airway hyperreactivity were enrolled (age: 38 ± 13 yr [mean ± SD]; FEV1: 105 ± 10% predicted; provocative dose of methacholine inducing a 20% decrease FEV1 > 3,200 μ g). Ninety-six subjects (84%) produced adequate analysis samples. The subjects had a normal age distribution. Their induced sputum was rich in macrophages (69.2 ± 13%) and neutrophils (27.3 ± 13%), and poor in eosinophils (0.6 ± 0.8%), lymphocytes (1.0 ± 1.2%), and epithelial cells (1.5 ± 1.8%). Only macrophages and neutrophils showed a normal distribution; total and differential counts of other cells did not. We propose that these data be used in comparison of the induced sputum cells of normal subjects and those of patients with airway inflammation.
Long-Acting Insulin Analogs Versus Insulin Pump Therapy for the Treatment of Type 1 and Type 2 Diabetes
Authors: John C. Pickup, Eric Renard
Journal: Diabetes Care (2008)

Insulin pump therapy (continuous subcutaneous insulin infusion [CSII]) is now an established form of intensive insulin treatment. It is pertinent to ask, however, if multiple daily injection (MDI) regimens based on new long-acting insulin analogs such as glargine and detemir have now replaced the need for CSII. In type 1 diabetes, CSII reduces the frequency of severe hypoglycemia compared with isophane-based MDIs, but the rate of severe hypoglycemia is usually similar on glargine- or detemir-based MDIs compared with isophane-based MDIs. CSII reduces A1C and glycemic variability compared with isophane-based MDIs; but glargine and detemir do not improve A1C or variability in many patients, particularly those who are prone to hypoglycemia. Head-to-head comparisons of CSII with MDI based on glargine indicate lower A1C, fructosamine, or glucose levels on CSII. It can be concluded that long-acting insulin analogs have not yet replaced the need for insulin pump therapy in type 1 diabetes, and CSII is the best current therapeutic option for some type 1 diabetic subjects. In type 2 diabetes, CSII and MDI produce similar glycemic control, although there is little study of MDI based on long-acting analogs compared with pumps. It is possible that CSII will be beneficial in selected patient groups with type 2 diabetes, but this requires further study.
Depression and Survival in Metastatic Non–Small-Cell Lung Cancer: Effects of Early Palliative Care
Authors: William F. Pirl, Joseph A. Greer, Lara Traeger, Vicki Jackson, Inga T. Lennes, Emily R. Gallagher, Pedro Perez-Cruz, Rebecca S. Heist, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2012)

In a randomized trial, early palliative care (EPC) in patients with metastatic non-small-cell lung cancer (NSCLC) was observed to improve survival. In a secondary analysis, we explored the hypothesis that the survival benefit resulted from improving depression.In total, 151 patients with newly diagnosed metastatic NSCLC participated in a randomized trial of EPC integrated with standard oncology care versus standard oncology care alone. Depression was assessed at baseline and at 12 weeks with the Patient Health Questionnaire-9 (PHQ-9) and was scored diagnostically by using Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria for major depression syndrome (MDS). Depression response was considered ≥ 50% reduction in PHQ-9 scores at 12 weeks. Survival differences were tested with log-rank and Cox proportional hazards models.At baseline, 21 patients (14%) met MDS criteria. MDS significantly predicted worse survival (hazard ratio, 1.82; P = .02). Patients assigned to EPC had greater improvements in PHQ-9 scores at 12 weeks (P < .001); among patients with MDS, those receiving EPC had greater rates of depression response at 12 weeks (P = .04). However, improvement in PHQ-9 scores was not associated with improved survival, except in a sensitivity analysis in which patients who died before 12 weeks were modeled to have worse depression. The group randomly assigned to EPC remained independently associated with survival after adding improvement in PHQ-9 scores to the survival model.Depression predicted worse survival in patients with newly diagnosed metastatic NSCLC. Although EPC was associated with greater improvement in depression at 12 weeks, the data do not support the hypothesis that treatment of depression mediated the observed survival benefit from EPC.
Molecular Chemotherapy and Chemotherapy: A New Front against Late-Stage Hormone-Refractory Prostate Cancer
Authors: Preetiner Pal Singh, Swapna Joshi, Pamela J. Russell, Nirupama D. Verma, Xiaochun Wang, Aparajita Khatri
Journal: Clinical Cancer Research (2011)

Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase-mediated, gene-directed enzyme-prodrug therapy (PNP-GDEPT) with docetaxel against CRPC has superior efficacy in comparison with individual treatments.The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment.The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the individual modalities, a combination of the 2 led to a marked reduction in "local and distant" tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T-helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy.PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings; these outcomes have implications of translational potential for improved treatment and management of CRPC patients.