tbuckley/cabot-search huggingface dataset:
Role of Cancer Treatment in Long-Term Overall and Cardiovascular Mortality After Childhood Cancer
Authors: Markhaba Tukenova, Catherine Guibout, Odile Oberlin, Françoise Doyon, Abdeddahir Mousannif, Nadia Haddy, Sylvie Guérin, Hélène Pacquement, Albertine Aouba, Mike Hawkins, Dave Winter, Jean Bourhis, Dimitri Lefkopoulos, Ibrahima Diallo, Florent de Vathaire
Journal: Journal of Clinical Oncology (2010)

The purpose of this study was to assess the role of treatment in long-term overall and cardiovascular mortality after childhood cancer.We studied 4,122 5-year survivors of a childhood cancer diagnosed before 1986 in France and the United Kingdom. Information on chemotherapy was collected, and the radiation dose delivered to the heart was estimated for 2,870 patients who had received radiotherapy.After 86,453 person-years of follow-up (average, 27 years), 603 deaths had occurred. The overall standardized mortality ratio (SMR) was 8.3-fold higher (95% CI, 7.6-fold to 9.0-fold higher) in relation to the general populations in France and the United Kingdom. Thirty-two patients had died as a result of cardiovascular diseases (ie, 5.0-fold [95% CI, 3.3-fold to 6.7-fold] more than expected). The risk of dying as a result of cardiac diseases (n = 21) was significantly higher in individuals who had received a cumulative anthracycline dose greater than 360 mg/m(2) (relative risk [RR], 4.4; 95% CI, 1.3 to 15.3) and in individuals who received an average radiation dose that exceeded 5 Gy (RR, 12.5 and 25.1 for 5 to 14.9 Gy and > 15 Gy, respectively) to the heart. A linear relationship was found between the average dose of radiation to the heart and the risk of cardiac mortality (estimated excess [corrected] RR at 1 Gy, 60%).This study is the first, to our knowledge, to establish a relationship between the radiation dose received by the heart during radiotherapy for a childhood cancer and long-term cardiac mortality. This study also confirms a significant excess risk of cardiac mortality associated with a high cumulative dose of anthracyclines.
Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti–Tim-3 antibody in vivo
Authors: Jennifer Kearley, Sarah J. McMillan, Clare M. Lloyd
Journal: The Journal of Experimental Medicine (2007)

T cell immunoglobulin and mucin domain–containing molecule-3 (Tim-3) is a surface molecule that is preferentially expressed on activated Th1 cells in comparison to Th2 cells. Blockade of Tim-3 has been shown to enhance Th1-driven pathology in vivo, suggesting that blockade of Tim-3 may improve the development of Th2-associated responses such as allergy. To examine the effects of Tim-3 blockade on the Th2 response in vivo, we administered anti–Tim-3 antibody during pulmonary inflammation induced by transfer of ovalbumin (OVA)-reactive Th2 cells, and subsequent aerosol challenge with OVA. In this model, anti–Tim-3 antibody treatment before each airway challenge significantly reduced airway hyperreactivity, with a concomitant decrease in eosinophils and Th2 cells in the lung. We examined Th1 and Th2 cytokine levels in the lung after allergen challenge and found that pulmonary expression of the Th2 cytokine IL-5 was significantly reduced, whereas IFN-γ levels were significantly increased by anti–Tim-3 antibody treatment. Thus, blocking Tim-3 function has a beneficial effect during pulmonary inflammation by skewing the Th2 response toward that of a Th1 type, suggesting an important role for Tim-3 in the regulation of allergic disease.
<i>COX10</i>Mutations Resulting in Complex Multisystem Mitochondrial Disease That Remains Stable Into Adulthood
Authors: Robert D. S. Pitceathly, Jan-Willem Taanman, Shamima Rahman, Brigitte Meunier, Michael Sadowski, Sebahattin Cirak, Iain Hargreaves, John M. Land, Tina Nanji, James M. Polke, Cathy E. Woodward, Mary G. Sweeney, Shyam Solanki, A. Reghan Foley, Matthew E. Hurles, Jim Stalker, Julian Blake, Janice L. Holton, Rahul Phadke, Francesco Muntoni, Mary M. Reilly, Michael G. Hanna
Journal: JAMA Neurology (2013)

Isolated cytochrome-c oxidase (COX) deficiency is one of the most frequent respiratory chain defects seen in human mitochondrial disease. Typically, patients present with severe neonatal multisystem disease and have an early fatal outcome. We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.Whole-exome sequencing detected 1 known pathogenic and 1 novel COX10 mutation: c.1007A>T; p.Asp336Val, previously associated with fatal infantile COX deficiency, and c.1015C>T; p.Arg339Trp. Muscle COX holoenzyme and subassemblies were undetectable on immunoblots of blue-native gels, whereas denaturing gels and immunocytochemistry showed reduced core subunit MTCO1. Heme absorption spectra revealed low heme aa3 compatible with heme A:farnesyltransferase deficiency due to COX10 dysfunction. Both mutations demonstrated respiratory deficiency in yeast, confirming pathogenicity. A COX10 protein model was used to predict the structural consequences of the novel Arg339Trp and all previously reported substitutions.These findings establish that COX10 mutations cause adult mitochondrial disease. Nuclear modifiers, epigenetic phenomenon, and/or environmental factors may influence the disease phenotype caused by reduced COX activity and contribute to the variable clinical severity related to COX10 dysfunction.
CD8+ T cells specific for a single nonamer epitope of Listeria monocytogenes are protective in vivo.
Authors: J T Harty, M J Bevan
Journal: The Journal of Experimental Medicine (1992)

Class I major histocompatibility complex (MHC)-restricted CD8+ T cells have been demonstrated to be effective mediators of both acquired and adoptive immunity to the intracellular bacterium Listeria monocytogenes. We have recently determined that L. monocytogenes-infected H-2d mice recognize a nonamer peptide, residues 91-99, of the secreted protein listeriolysin O (LLO), in a H-2Kd-restricted fashion. In this report we have generated CD8+ T cell lines with specificity for LLO 91-99 in the context of H-2Kd by in vitro stimulation with P815 (H-2d) cells transfected with LLO. These CD8+ lines have been generated from immune donors after sublethal infection with L. monocytogenes, or after in vivo immunization with syngeneic spleen cells coated with synthetic LLO 91-99 peptide. LLO-specific CD8+ T cells derived from either protocol were capable of significant protection against L. monocytogenes infection. The in vivo protection by these CD8+ T cell lines has been shown to be solely due to recognition of LLO 91-99 in the context of H-2Kd. These studies demonstrate that CD8+ T cell immunity to a single, naturally produced peptide epitope has the potential for significant protection in a bacterial infection. Thus, the allele-specific motif approach to epitope prediction has identified a naturally produced bacterial epitope with biological relevance.
Once-Weekly Exenatide Versus Once- or Twice-Daily Insulin Detemir
Authors: Melanie Davies, Simon Heller, Seamus Sreenan, Hélène Sapin, Omolara Adetunji, Arash Tahbaz, Jiten Vora
Journal: Diabetes Care (2012)

This multicenter, open-label, parallel-arm study compared the efficacy and safety of exenatide once weekly (EQW) with titrated insulin detemir in patients with type 2 diabetes inadequately controlled with metformin (with or without sulfonylureas).
Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice
Authors: Marie-Luise Berres, Rory R. Koenen, Anna Rueland, Mirko Moreno Zaldivar, Daniel Heinrichs, Hacer Sahin, Petra Schmitz, Konrad L. Streetz, Thomas Berg, Nikolaus Gassler, Ralf Weiskirchen, Amanda Proudfoot, Christian Weber, Christian Trautwein, Hermann E. Wasmuth
Journal: Journal of Clinical Investigation (2010)

Activation of hepatic stellate cells in response to chronic inflammation represents a crucial step in the development of liver fibrosis. However, the molecules involved in the interaction between immune cells and stellate cells remain obscure. Herein, we identify the chemokine CCL5 (also known as RANTES), which is induced in murine and human liver after injury, as a central mediator of this interaction. First, we showed in patients with liver fibrosis that CCL5 haplotypes and intrahepatic CCL5 mRNA expression were associated with severe liver fibrosis. Consistent with this, we detected Ccl5 mRNA and CCL5 protein in 2 mouse models of liver fibrosis, induced by either injection of carbon tetrachloride (CCl4) or feeding on a methionine and choline–deficient (MCD) diet. In these models, Ccl5–/– mice exhibited decreased hepatic fibrosis, with reduced stellate cell activation and immune cell infiltration. Transplantation of Ccl5-deficient bone marrow into WT recipients attenuated liver fibrosis, identifying infiltrating hematopoietic cells as the main source of Ccl5. We then showed that treatment with the CCL5 receptor antagonist Met-CCL5 inhibited cultured stellate cell migration, proliferation, and chemokine and collagen secretion. Importantly, in vivo administration of Met-CCL5 greatly ameliorated liver fibrosis in mice and was able to accelerate fibrosis regression. Our results define a successful therapeutic approach to reduce experimental liver fibrosis by antagonizing Ccl5 receptors.
Symptoms and Quadriceps Fatigability after Walking and Cycling in Chronic Obstructive Pulmonary Disease
Authors: William D.-C. Man, Mohamed G. G. Soliman, Johanne Gearing, Sheena G. Radford, Gerrard F. Rafferty, Barry J. Gray, Michael I. Polkey, John Moxham
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Patients with chronic obstructive pulmonary disease (COPD) may stop cycling due to leg effort rather than breathlessness. However, cycling is not relevant to many patients, although walking may be more familiar. A total of 84 patients with COPD were asked to name the predominant symptom limiting incremental shuttle walking, endurance shuttle walking, incremental cycle ergometry, and endurance cycle ergometry, performed to exhaustion on four separate days. Furthermore, quadriceps fatigability was evaluated in 12 patients by measuring unpotentiated and potentiated twitch quadriceps tensions before and 30 minutes after incremental walking and cycling. Breathlessness alone was a more commonly cited limiting symptom after incremental walking compared with incremental cycling (81 vs. 34%; p < 0.001) and after endurance walking compared with endurance cycling (75 vs. 29%; p < 0.001). In addition, there was no significant change in mean pre- and postwalking twitch quadriceps tensions. However, cycling produced a significant reduction (unpotentiated 7.42 +/- 2.22 vs. 6.48 +/- 2.09 kg [p < 0.001]; potentiated 10.19 +/- 3.99 vs. 8.45 +/- 3.18 kg [p < 0.001]). Pre- to postexercise changes were significantly greater during cycling compared with walking (unpotentiated p = 0.01; potentiated p = 0.003). Leg effort is an infrequent symptom after walking in COPD, and low frequency fatigue of the quadriceps is an infrequent feature of incremental walking.
Risk-Adapted Androgen Deprivation and Escalated Three-Dimensional Conformal Radiotherapy for Prostate Cancer: Does Radiation Dose Influence Outcome of Patients Treated With Adjuvant Androgen Deprivation? A GICOR Study
Authors: Almudena Zapatero, Francisco Valcárcel, Felipe A. Calvo, Rosa Algás, Amelia Béjar, Javier Maldonado, Salvador Villá
Journal: Journal of Clinical Oncology (2005)

Multicenter study conducted to determine the impact on biochemical control and survival of risk-adapted androgen deprivation (AD) combined with high-dose three-dimensional conformal radiotherapy (3DCRT) for prostate cancer. Results of biochemical control are reported.Between October 1999 and October 2001, 416 eligible patients with prostate cancer were assigned to one of three treatment groups according to their risk factors: 181 low-risk patients were treated with 3DCRT alone; 75 intermediate-risk patients were allocated to receive neoadjuvant AD (NAD) 4-6 months before and during 3DCRT; and 160 high-risk patients received NAD and adjuvant AD (AAD) 2 years after 3DCRT. Stratification was performed for treatment/risk group and total radiation dose.After a median follow-up of 36 months (range, 18 to 63 months), the actuarial biochemical disease-free survival (bDFS) at 5 years for all patients was 74%. The corresponding figures for low-risk, intermediate-risk, and high-risk disease were 80%, 73%, and 79%, respectively (P = .847). Univariate analysis showed that higher radiation dose was the only significant factor associated with bDFS for all patients (P = .0004). When stratified for treatment group, this benefit was evident for low-risk patients (P = .009) and, more interestingly, for high-risk patients treated with AAD. The 5-year bDFS for high-risk patients treated with AAD was 63% for radiation doses less than 72 Gy and 84% for those > or = 72 Gy (P = .003).The results of combined AAD plus high-dose 3DCRT are encouraging. To our knowledge, this is the first study showing an additional benefit of high-dose 3DCRT when combined with long-term AD for unfavorable disease.
Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. I. Significant variation in repertoire expression between individual mice
Authors: LM Staudt, W Gerhard
Journal: The Journal of Experimental Medicine (1983)

The paratypic and idiotypic diversity of the BALB/c antibody response to the hemagglutinin (HA) of the influenza A/PR/8/34 virus (PR8) was investigated using a panel of 125 anti-HA hybridoma antibodies derived from 14 BALB/c mice. The paratypic diversity, as assessed by a fine specificity analysis using 51 related influenza viruses, was extensive: 104 distinct paratopes were observed. In three instances, antibodies with indistinguishable paratopes were isolated from two individual mice. A minimum estimate of the size of the adult BALB/c anti-HA paratypic repertoire, calculated from these data, is 1,500. The generation of this diverse repertoire was studied by screening the anti-HA hybridoma panel for the presence of idiotypes (Id) that are markers for variable (V) region sequences derived from related germ line V genes. Three cross-reactive Id (IdX) that are markers for the V(k)21C, V(k)21B, and V(k)21A, D, E, or F L chain subgroups were found, respectively on 16, 1, and 10 anti-HA hybridoma antibodies derived from seven individual BALB/c mice. Thus, the V(k)21 IdX(+) hybridomas constitute 22 percent of the anti-HA hybridoma panel. The V(k)21 IdX are also present on 8.6 percent of K-bearing immunoglobulin in normal BALB/c serum. This suggests that the V(k)21 group is used preferentially in the BALB/c anti-HA immune response. The generation of the anti-HA repertoire was further studied using large panels of anti-HA hybridomas derived from two individual adult BALB/c mice. Anti-idiotypic antisera were raised in rabbits against individual hybridomas from each mouse. One anti-Id serum defined a family of four idiotypically and paratypically related, but not identical, antibodies from mouse 36, which represented 31 percent of the hybridoma antibodies isolated from this mouse. None of the 112 anti-HA hybridoma antibodies derived from 13 other individual mice showed idiotypic cross-reactivity. Furthermore, this Id could not be detected in anti-PR8 antisera from 75 individual BALB/c mice. Another anti-Id serum defined a family of 27 idiotypically related antibodies from mouse 37, which represented 50 percent of the hybridoma antibodies isolated from this mouse. Only 1 of the 71 hybridoma antibodies isolated from 13 other individuals was idiotypically cross-reactive. These results demonstrate that individual adult BALB/c mice express paratypically and idiotypically distinct antibody repertoires to the HA of influenza virus PR8. Based on these observations, we suggest that somatic mutation plays an important role in the generation of the adult anti-HA repertoire. Mechanisms that could account for differences in repertoire expression among individual mice are discussed.
Preconditional Activation of Hypoxia-Inducible Factors Ameliorates Ischemic Acute Renal Failure
Authors: Wanja M. Bernhardt, Valentina Ca[Combining Circumflex Accent]mpean, Sarah Kany, Jan-Steffen Ju[Combining Diaeresis]rgensen, Alexander Weidemann, Christina Warnecke, Michael Arend, Stephen Klaus, Volkmar Gu[Combining Diaeresis]nzler, Kerstin Amann, Carsten Willam, Michael S. Wiesener, Kai-Uwe Eckardt
Journal: Journal of the American Society of Nephrology (2006)

Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Normoxic degradation of HIF is mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative alpha-subunits by HIF prolyl hydroxylases (PHD). It was hypothesized that inhibition of HIF degradation by either hypoxia or pharmacologic inhibition of PHD would confer protection against subsequent ischemic injury. For testing this hypothesis ischemic acute renal failure was induced in rats by 40 min of clamping of the left renal artery after right-sided nephrectomy. Before surgery, pretreatment with either carbon monoxide, leading to tissue hypoxia, or the novel PHD inhibitor FG-4487 was applied. No toxic effects of FG-4487 were observed. Both pretreatments strongly induced the accumulation of HIF-1alpha and HIF-2alpha in tubular and peritubular cells, respectively, as well as HIF target gene expression. The course of subsequent ischemic injury was significantly ameliorated by both strategies of preconditioning, as evident from a significant improvement of serum creatinine and serum urea after 24 and 72 h. Furthermore, tissue injury and apoptosis were less severe, which were quantified by application of a standardized histologic scoring system in a blinded manner. In conclusion, the data provide proof of principle that preconditional activation of the HIF system protects against ischemic injury. Inhibiting the activity of HIF hydroxylases therefore seems to have considerable clinical perspectives.
Objectively Measured Light-Intensity Physical Activity Is Independently Associated With 2-h Plasma Glucose
Authors: Genevieve N. Healy, David W. Dunstan, Jo Salmon, Ester Cerin, Jonathan E. Shaw, Paul Z. Zimmet, Neville Owen
Journal: Diabetes Care (2007)

We examined the associations of objectively measured sedentary time, light-intensity physical activity, and moderate- to vigorous-intensity activity with fasting and 2-h postchallenge plasma glucose in Australian adults.A total of 67 men and 106 women (mean age +/- SD 53.3 +/- 11.9 years) without diagnosed diabetes were recruited from the 2004-2005 Australian Diabetes, Obesity, and Lifestyle (AusDiab) study. Physical activity was measured by Actigraph accelerometers worn during waking hours for 7 consecutive days and summarized as sedentary time (accelerometer counts/min <100; average hours/day), light-intensity (counts/min 100-1951), and moderate- to vigorous-intensity (counts/min > or =1,952). An oral glucose tolerance test was used to ascertain 2-h plasma glucose and fasting plasma glucose.After adjustment for confounders (including waist circumference), sedentary time was positively associated with 2-h plasma glucose (b = 0.29, 95% CI 0.11-0.48, P = 0.002); light-intensity activity time (b = -0.25, -0.45 to -0.06, P = 0.012) and moderate- to vigorous-intensity activity time (b = -1.07, -1.77 to -0.37, P = 0.003) were negatively associated. Light-intensity activity remained significantly associated with 2-h plasma glucose following further adjustment for moderate- to vigorous-intensity activity (b = -0.22, -0.42 to -0.03, P = 0.023). Associations of all activity measures with fasting plasma glucose were nonsignificant (P > 0.05).These data provide the first objective evidence that light-intensity physical activity is beneficially associated with blood glucose and that sedentary time is unfavorably associated with blood glucose. These objective data support previous findings from studies using self-report measures, and suggest that substituting light-intensity activity for television viewing or other sedentary time may be a practical and achievable preventive strategy to reduce the risk of type 2 diabetes and cardiovascular disease.
Exon identity crisis: disease-causing mutations that disrupt the splicing code
Authors: Timothy Sterne-Weiler, Jeremy R Sanford
Journal: Genome biology (2014)

Cis-acting RNA elements control the accurate expression of human multi-exon protein coding genes. Single nucleotide variants altering the fidelity of this regulatory code and, consequently, pre-mRNA splicing are expected to contribute to the etiology of numerous human diseases.
Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma
Authors: Rachel G. Liao, Joonil Jung, Jeremy Tchaicha, Matthew D. Wilkerson, Andrey Sivachenko, Ellen M. Beauchamp, Qingsong Liu, Trevor J. Pugh, Chandra Sekhar Pedamallu, D. Neil Hayes, Nathanael S. Gray, Gad Getz, Kwok-Kin Wong, Robert I. Haddad, Matthew Meyerson, Peter S. Hammerman
Journal: Cancer Research (2013)

A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC.