tbuckley/cabot-search huggingface dataset:
Preferential V beta gene usage and lack of junctional sequence conservation among human T cell receptors specific for a tetanus toxin-derived peptide: evidence for a dominant role of a germline-encoded V region in antigen/major histocompatibility complex recognition.
Authors: B Boitel, M Ermonval, P Panina-Bordignon, R A Mariuzza, A Lanzavecchia, O Acuto
Journal: The Journal of Experimental Medicine (1992)

To investigate the structural and genetic basis of the T cell response to defined peptide/major histocompatibility (MHC) class II complexes in humans, we established a large panel of T cell clones (61) from donors of different HLA-DR haplotypes and reactive with a tetanus toxin-derived peptide (tt830-844) recognized in association with most DR molecules (universal peptide). By using a bacterial enterotoxin-based proliferation assay and cDNA sequencing, we found preferential use of a particular V beta region gene segment, V beta 2.1, in three of the individuals studied (64%, n = 58), irrespective of whether the peptide was presented by the DR6wcI, DR4w4, or DRw11.1 and DRw11.2 alleles, demonstrating that shared MHC class II antigens are not required for shared V beta gene use by T cell receptors (TCRs) specific for this peptide. V alpha gene use was more heterogeneous, with at least seven different V alpha segments derived from five distinct families encoding alpha chains able to pair with V beta 2.1 chains to form a tt830-844/DR-specific binding site. Several cases were found of clones restricted to different DR alleles that expressed identical V beta and (or very closely related) V alpha gene segments and that differed only in their junctional sequences. Thus, changes in the putative complementary determining region 3 (CDR3) of the TCR may, in certain cases, alter MHC specificity and maintain peptide reactivity. Finally, in contrast to what has been observed in other defined peptide/MHC systems, a striking heterogeneity was found in the junctional regions of both alpha and beta chains, even for TCRs with identical V alpha and/or V beta gene segments and the same restriction. Among 14 anti-tt830-844 clones using the V beta 2.1 gene segment, 14 unique V beta-D-J beta junctions were found, with no evident conservation in length and/or amino acid composition. One interpretation for this apparent lack of coselection of specific junctional sequences in the context of a common V element, V beta 2.1, is that this V region plays a dominant role in the recognition of the tt830-844/DR complex.
Does living in urban or rural settings affect aspects of physical fitness in children? An allometric approach
Authors: P D Tsimeas, A L Tsiokanos, Y Koutedakis, N Tsigilis, S Kellis
Journal: British Journal of Sports Medicine (2005)

The aim of this study was to investigate physical fitness in relation to fatness in urban and rural Greek children by means of allometric scaling.The sample consisted of 360 (189 urban and 171 rural; age 12.3+/-0.42 years) boys and 247 (125 urban and 122 rural; age 12.3+/-0.43 years) girls. The sample was highly representative (32-64%) of all 12 year old children registered in the prefecture of Trikala, Greece. All volunteers were assessed for BMI and % body fat, as well as sit and reach, basketball throw (BT), vertical jump (VJ), handgrip strength (HG), 40 m sprint, agility run, and 20 m shuttle run. To correct for possible associations between fatness and fitness, a single cause allometric scaling was employed using the natural logarithms (ln) of fitness parameters that were significantly correlated with the ln body fat.Independent-samples t tests revealed that VJ (p<0.05) was significantly higher in boys living in urban settings compared to their rural counterparts. Similarly, BT was found to be significantly better (p<0.05) in urban girls, whereas HG was significantly higher (p<0.05) in rural girls.Considering that (a) only three out of the 14 possible cases (seven fitness parameters for boys and seven for girls) were significantly different between urban and rural children, and (b) these differences were not uniformly distributed in children living in either urban or rural environments, it is concluded that the place of residence has no clear impact on physical fitness as studied herein.
Underestimation of airflow obstruction among young adults using FEV1/FVC &lt;70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes
Authors: I Cerveri, A G Corsico, S Accordini, R Niniano, E Ansaldo, J M Anto, N Kunzli, C Janson, J Sunyer, D Jarvis, C Svanes, T Gislason, J Heinrich, J P Schouten, M Wjst, P Burney, R de Marco
Journal: Thorax (2008)

<h3>Background:</h3> Early detection of airflow obstruction is particularly important among young adults because they are more likely to benefit from intervention. Using the forced expiratory volume in 1 s (FEV<sub>1</sub>) to forced vital capacity (FVC) (FEV<sub>1</sub>/FVC) &lt;70% fixed ratio, airflow obstruction may be underdiagnosed. The lower limit of normal (LLN), which is statistically defined by the lower fifth percentile of a reference population, is physiologically appropriate but it still needs a clinical validation. <h3>Methods:</h3> To evaluate the characteristics and longitudinal outcomes of subjects misidentified as normal by the fixed ratio with respect to the LLN, 6249 participants (aged 20–44 years) in the European Community Respiratory Health Survey were examined and divided into three groups (absence of airflow obstruction by the LLN and the fixed ratio; presence of airflow obstruction only by the LLN; presence of airflow obstruction by the two criteria) for 1991–1993. LLN equations were obtained from normal non-smoking participants. A set of clinical and functional outcomes was evaluated in 1999–2002. <h3>Results:</h3> The misidentified subjects were 318 (5.1%); only 45.6% of the subjects with airflow obstruction by the LLN were also identified by the fixed cut-off. At baseline, FEV<sub>1</sub> (107%, 97%, 85%) progressively decreased and bronchial hyperresponsiveness (slope 7.84, 6.32, 5.57) progressively increased across the three groups. During follow-up, misidentified subjects had a significantly higher risk of developing chronic obstructive pulmonary disease and a significantly higher use of health resources (medicines, emergency department visits/hospital admissions) because of breathing problems than subjects without airflow obstruction (p&lt;0.001). <h3>Conclusions:</h3> Our findings show the importance of using statistically derived spirometric criteria to identify airflow obstruction.
Targeting Src in Mucinous Ovarian Carcinoma
Authors: Koji Matsuo, Masato Nishimura, Justin N. Bottsford-Miller, Jie Huang, Kakajan Komurov, Guillermo N. Armaiz-Pena, Mian M.K. Shahzad, Rebecca L. Stone, Ju Won Roh, Angela M. Sanguino, Chunhua Lu, Dwight D. Im, Neil B. Rosenshien, Atsuko Sakakibara, Tadayoshi Nagano, Masato Yamasaki, Takayuki Enomoto, Tadashi Kimura, Prahlad T. Ram, Kathleen M. Schmeler, Gary E. Gallick, Kwong K. Wong, Michael Frumovitz, Anil K. Sood
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma. Experimental Design: A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2). Results: Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P &amp;lt; 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model. Conclusions: Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib and oxaliplatin may be an attractive approach for this disease. Clin Cancer Res; 17(16); 5367–78. ©2011 AACR.
Providing Cancer Care to a Graying and Diverse Cancer Population in the 21st Century: Are We Prepared?
Authors: June M. McKoy, Athena T. Samaras, Charles L. Bennett
Journal: Journal of Clinical Oncology (2009)

Cancer incidence will increase dramatically among older individuals and racial and ethnic minorities in the 21st century.From 2010 to 2030, the total projected cancer incidence will increase by 45%, from 1.6 million to 2.3 million. 1This increase will be driven largely by cancers diagnosed in older adults and minorities.By 2030, the elderly will bear 70% of all cancer diagnoses, and elder minorities will fall victim to 28% of all cancers. 1 As projected by Smith et al, 1 a greater than 100% increase in cancer incidence will occur among racial and ethnic minorities by 2030 for most of the individual cancer sites assessed.The management of cancer incidence among a diverse and aging population presents daunting challenges.Shifting cancer demographics and age-, race-, or ethnicity-associated genetic, molecular, cellular, and physiologic effects influence treatment effectiveness.Age-related physiologic changes affect the renal and hepatic systems of older cancer patients, resulting in pharmacokinetic and pharmacodynamic changes, putting them at risk for serious adverse reactions from many cancer drugs.Moreover, several barriers to treatment may exist within the elderly and minority populations.These barriers include poverty, lack of transportation, illiteracy, cultural taboos regarding cancer, and poor language communication. 2 Because of the many factors that contribute to cancer incidence within the aging and minority populations and the many barriers to treatment faced by these patients, it is especially important that these populations have access to proper care.Smith et al 1 posit that "unless substantial improvements in cancer therapy and/or prevention strategies emerge, the number of cancer deaths may also grow dramatically over the next 20 years."Although advances in cancer therapeutics and prevention are essential, we also believe that it is imperative to provide more effectively current cancer treatment options and prevention strategies to cancer patients, regardless of age, wealth, or racial or ethnic status.Efforts to reduce age-related disparities in cancer care have been heavily supported.Through the use of validated measures such as the Comprehensive Geriatric Assessment and the use of a comprehensive cancer care team, including social workers, geriatric nurses and nurse practitioners, the oncologist is able to perform in-depth analyses to
Potential impact of global climate change on malaria risk.
Authors: W J Martens, L W Niessen, J Rotmans, T H Jetten, A J McMichael
Journal: Environmental Health Perspectives (1995)

The biological activity and geographic distribution of the malarial parasite and its vector are sensitive to climatic influences, especially temperature and precipitation. We have incorporated General Circulation Model-based scenarios of anthropogenic global climate change in an integrated linked-system model for predicting changes in malaria epidemic potential in the next century. The concept of the disability-adjusted life years is included to arrive at a single measure of the effect of anthropogenic climate change on the health impact of malaria. Assessment of the potential impact of global climate change on the incidence of malaria suggests a widespread increase of risk due to expansion of the areas suitable for malaria transmission. This predicted increase is most pronounced at the borders of endemic malaria areas and at higher altitudes within malarial areas. The incidence of infection is sensitive to climate changes in areas of Southeast Asia, South America, and parts of Africa where the disease is less endemic; in these regions the numbers of years of healthy life lost may increase significantly. However, the simulated changes in malaria risk must be interpreted on the basis of local environmental conditions, the effects of socioeconomic developments, and malaria control programs or capabilities.
Effect of growth hormone-release inhibiting hormone on hormones stimulating exocrine pancreatic secretion.
Authors: S J Konturek, J Tasler, W Obtulowicz, D H Coy, A V Schally
Journal: Journal of Clinical Investigation (1976)

The nature and extent of growth hormone-release inhibiting hormone (GH-RIH, somatostatin)-induced inhibition of pancreatic secretion of bicarbonate and protein, an index of enzyme secretion, were studied by administration of exogenous secretin or cholecystokinin (CCK) and of a number of stimulants for endogenous release of these hormones in fasted pancreatic fistula dogs with and without an infusion of GH-RIH. The results of this study show that GH-RIH inhibits the pancreatic fluid and bicarbonate secretion induced by duodenal acidification and exogenous secretion. The kinetic analysis shows that the interaction between GH-RIH and secretin affecting pancreatic bicarbonate secretion possesses the characteristics of competitive inhibition. GH-RIH does not change the pancreatic protein response to exogenous CCK, but profoundly inhibits pancreatic response to a variety of the endogenous stimulants of CCK release, including duodenal perfusion of sodium oleate, amino acid mixture, or feeding of a peptone meal. We conclude that GH-RIH is a very potent inhibitor of the endogenous release of CCK from the intestinal mucosa and inhibits competitively the action of secretin but not CCK on the exocrine pancreatic secretion.
Structural Determinants of the Rate of Protein Evolution in Yeast
Authors: Jesse D. Bloom, D. Allan Drummond, Frances H. Arnold, Claus O. Wilke
Journal: Molecular Biology and Evolution (2006)

We investigate how a protein's structure influences the rate at which its sequence evolves. Our basic hypothesis is that proteins with highly designable structures (structures that are encoded by many sequences) will evolve more rapidly. Recent theoretical advances argue that structures with a higher density of interresidue contacts are more designable, and we show that high contact density is correlated with an increased rate of sequence evolution in yeast. In addition, we investigate the correlations between the rate of sequence evolution and several other structural descriptors, carefully controlling for the strong effect of expression level on evolutionary rate. Overall, we find that the structural descriptors that we consider appear to explain roughly 10% of the variation in rates of protein evolution in yeast. We also show that despite the well-known trend for buried residues to be more conserved, proteins with a higher fraction of buried residues, nonetheless, tend to evolve their sequences more rapidly. We suggest that this effect is due to the increased designability of structures with more buried residues. Our results provide evidence that protein structure plays an important role in shaping the rate of sequence evolution and provide evidence to support recent theoretical advances linking structural designability to contact density.
Objectively Measured Time Spent Sedentary Is Associated With Insulin Resistance Independent of Overall and Central Body Fat in 9- to 10-Year-Old Portuguese Children
Authors: Luis B. Sardinha, Lars Bo Andersen, Sigmund A. Anderssen, Ana L. Quitério, Rui Ornelas, Karsten Froberg, Chris J. Riddoch, Ulf Ekelund
Journal: Diabetes Care (2008)

We examined the independent relationships between objectively measured physical activity and insulin resistance in Portuguese children.This is a school-based, cross-sectional study in 147 randomly selected girls (aged 9.8 +/- 0.3 years; 27.8 +/- 9.3% body fat) and 161 boys (aged 9.8 +/- 0.3 years; 22.0 +/- 9.2% body fat). Physical activity was assessed by the Actigraph accelerometer for 4 days and summarized as time spent sedentary (accelerometer counts <500/min), in light-intensity (accelerometer counts 500-2,000/min), and in moderate- and vigorous-intensity activity (accelerometer counts >2,001/min). We measured total and central fat mass by dual-energy X-ray absorptiometry. Insulin resistance was expressed as the homeostasis model assessment score.Time (min/day) spent sedentary was significantly and positively associated with insulin resistance (beta-coefficient = 0.001 [95% CI 0.0002-0.002]; P = 0.013). Time spent in moderate- and vigorous-intensity physical activity (-0.002 [-0.003 to -0.001]; P = 0.0009) and overall physical activity (-0.001 [-0.008 to 0.003]; P < 0.0001) were significantly and inversely associated with insulin resistance. All associations remained statistically significant, although they were attenuated after further adjustments for sex, birth weight, sexual maturity, and total or central fat mass (P < 0.03).Physical activity is associated with insulin resistance independent of total and central fat mass in children. Our results emphasize the importance of decreasing sedentary behavior and increasing time spent in moderate- and vigorous-intensity activity in children, which may have beneficial effects on metabolic risk factors regardless of the degree of adiposity.
Distinction between Asymptomatic Monoclonal B-cell Lymphocytosis with Cyclin D1 Overexpression and Mantle Cell Lymphoma: From Molecular Profiling to Flow Cytometry
Authors: Blanca Espinet, Ana Ferrer, Beatriz Bellosillo, Lara Nonell, Antonio Salar, Concepción Fernández-Rodríguez, Eulàlia Puigdecanet, Javier Gimeno, Mar Garcia-Garcia, Maria Carmen Vela, Elisa Luño, Rosa Collado, José Tomás Navarro, Esmeralda de la Banda, Pau Abrisqueta, Leonor Arenillas, Cristina Serrano, Josep Lloreta, Belén Miñana, Andrea Cerutti, Lourdes Florensa, Alberto Orfao, Ferran Sanz, Francesc Solé, David Dominguez-Sola, Sergio Serrano
Journal: Clinical Cancer Research (2013)

According to current diagnostic criteria, mantle cell lymphoma (MCL) encompasses the usual, aggressive variants and rare, nonnodal cases with monoclonal asymptomatic lymphocytosis, cyclin D1-positive (MALD1). We aimed to understand the biology behind this clinical heterogeneity and to identify markers for adequate identification of MALD1 cases.We compared 17 typical MCL cases with a homogeneous group of 13 untreated MALD1 cases (median follow-up, 71 months). We conducted gene expression profiling with functional analysis in five MCL and five MALD1. Results were validated in 12 MCL and 8 MALD1 additional cases by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in 24 MCL and 13 MALD1 cases by flow cytometry. Classification and regression trees strategy was used to generate an algorithm based on CD38 and CD200 expression by flow cytometry.We found 171 differentially expressed genes with enrichment of neoplastic behavior and cell proliferation signatures in MCL. Conversely, MALD1 was enriched in gene sets related to immune activation and inflammatory responses. CD38 and CD200 were differentially expressed between MCL and MALD1 and confirmed by flow cytometry (median CD38, 89% vs. 14%; median CD200, 0% vs. 24%, respectively). Assessment of both proteins allowed classifying 85% (11 of 13) of MALD1 cases whereas 15% remained unclassified. SOX11 expression by qRT-PCR was significantly different between MCL and MALD1 groups but did not improve the classification.We show for the first time that MALD1, in contrast to MCL, is characterized by immune activation and driven by inflammatory cues. Assessment of CD38/CD200 by flow cytometry is useful to distinguish most cases of MALD1 from MCL in the clinical setting. MALD1 should be identified and segregated from the current MCL category to avoid overdiagnosis and unnecessary treatment.
A case of imported Middle East Respiratory Syndrome coronavirus infection and public health response, Greece, April 2014
Authors: S Tsiodras, A Baka, A Mentis, D Iliopoulos, X Dedoukou, G Papamavrou, S Karadima, M Emmanouil, A Kossyvakis, N Spanakis, A Pavli, H Maltezou, A Karageorgou, G Spala, V Pitiriga, E Kosmas, S Tsiagklis, S Gkatzias, N G Koulouris, A Koutsoukou, P Bakakos, E Markozanhs, G Dionellis, K Pontikis, N Rovina, M Kyriakopoulou, P Efstathiou, T Papadimitriou, J Kremastinou, A Tsakris, G Saroglou
Journal: Eurosurveillance (2014)

On 18 April 2014, a case of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infection was laboratory confirmed in Athens, Greece in a patient returning from Jeddah, Saudi Arabia. Main symptoms upon initial presentation were protracted fever and diarrhoea, during hospitalisation he developed bilateral pneumonia and his condition worsened. During 14 days prior to onset of illness, he had extensive contact with the healthcare environment in Jeddah. Contact tracing revealed 73 contacts, no secondary cases had occurred by 22 April.
A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies
Authors: M Dastmalchi, C Grundtman, H Alexanderson, C P Mavragani, H Einarsdottir, S B. Helmers, K Elvin, M K Crow, I Nennesmo, I E Lundberg
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. <h3>Methods:</h3> A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1α, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon γ (IFNγ), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. <h3>Results:</h3> Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by ⩾20% in three or more variables of the disease activity core set, four were unchanged and two worsened ⩾30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. <h3>Conclusions:</h3> Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.