tbuckley/cabot-search huggingface dataset:
CRACing the Cluster
Authors: Kimberly A. Smith, Jason X.-J. Yuan
Journal: Circulation Research (2012)

P latelet-derived growth factor (PDGF) signaling is impli- cated in a wide range of diseases, and PDGF drives the pathological responses in many vascular disorders and fibrotic diseases such as atherosclerosis, restenosis, pulmonary arterial hypertension, and pulmonary fibrosis.In vascular smooth muscle cells (VSMC), PDGF is a potent mitogen which promotes proliferation and migration and contributes to pathological vascular remodeling.Recent studies have demonstrated a role for PDGF in stromal interaction molecule 1 (STIM1)/Orai1-mediated Ca 2ϩ influx in VSMC. 1 Regulation of cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] cyt ) is critical for many cellular processes.A rise in [Ca 2ϩ ] cyt is a major trigger for VSMC proliferation and contraction.One of the major routes of Ca 2ϩ entry into cells is through store-operated Ca 2ϩ (SOC) channels.On depletion of Ca 2ϩ from the stores (sarcoplasmic or endoplasmic reticulum, SR/ER), a Ca 2ϩ deficiency signal is transmitted to the SOC channels in the plasma membrane via STIM1.This causes the SOC to open, allowing Ca 2ϩ to flow into the cytosol, a process referred to as store-operated Ca 2ϩ entry (SOCE).The cytosolic Ca 2ϩ is then sequestered into the stores by the sarco(endo)plasmic reticulum Ca 2ϩ ATPase (SERCA), thus replenishing the stores.Studies have demonstrated a role for Ca 2ϩ release-activated Ca 2ϩ (CRAC) channels in SOCE, with STIM1 and Orai1 as the major components.
An Ancient Evolutionary Origin of Genes Associated with Human Genetic Diseases
Authors: T. Domazet-Loso, D. Tautz
Journal: Molecular Biology and Evolution (2008)

Several thousand genes in the human genome have been linked to a heritable genetic disease. The majority of these appear to be nonessential genes (i.e., are not embryonically lethal when inactivated), and one could therefore speculate that they are late additions in the evolutionary lineage toward humans. Contrary to this expectation, we find that they are in fact significantly overrepresented among the genes that have emerged during the early evolution of the metazoa. Using a phylostratigraphic approach, we have studied the evolutionary emergence of such genes at 19 phylogenetic levels. The majority of disease genes was already present in the eukaryotic ancestor, and the second largest number has arisen around the time of evolution of multicellularity. Conversely, genes specific to the mammalian lineage are highly underrepresented. Hence, genes involved in genetic diseases are not simply a random subset of all genes in the genome but are biased toward ancient genes.
The EPICure study: maximal exercise and physical activity in school children born extremely preterm
Authors: L. Welsh, J. Kirkby, S. Lum, D. Odendaal, N. Marlow, G. Derrick, J. Stocks
Journal: Thorax (2009)

<h3>Rationale</h3> Evidence regarding exercise capacity and physical activity in children born extremely preterm (EP) is limited. Since survivors remain at high risk for developing bronchopulmonary dysplasia (BPD) and long-term pulmonary sequelae, reductions in exercise capacity and activity levels may be present. <h3>Objectives</h3> To compare maximal exercise ventilation characteristics and physical activity levels at 11 years of age in children born EP (&lt;25 completed weeks gestation) with those of full-term controls. <h3>Methods</h3> Participants performed spirometry, body plethysmography and gas transfer testing. A peak exercise test was performed on a cycle ergometer. Physical activity was monitored by accelerometry for 7 days. <h3>Results</h3> Lung function and exercise results were obtained in 38 EP children (71% prior BPD) and 38 controls. Those born EP had significantly lower Z-scores (mean (95% CI) of difference) for forced expiratory volume in 1 s (FEV<sub>1</sub>; −1.74 (−2.25 to −1.23) and gas transfer (−0.73 (−1.31 to −0.17), and significantly greater Z-scores for residual volume (RV; 0.58 (0.10 to 1.10)) and RV/total lung capacity (TLC; 0.74 (0.29 to 1.19)). EP birth was associated with a significant reduction in peak oxygen consumption. EP children employed greater breathing frequencies and lower tidal volumes during peak exercise. No differences were observed in physical activity between groups. <h3>Conclusions</h3> The reduction in peak oxygen consumption in children born EP, and alterations in ventilatory adaptations during peak exercise were not explained by differences in physical activity, but probably reflects the long-term pathophysiological impact of EP birth.
Antiangiogenic Concentrations of Paclitaxel Induce an Increase in Microtubule Dynamics in Endothelial Cells but Not in Cancer Cells
Authors: Eddy Pasquier, Stéphane Honore, Bertrand Pourroy, Mary Ann Jordan, Maxime Lehmann, Claudette Briand, Diane Braguer
Journal: Cancer Research (2005)

Abstract Microtubule-targeted drugs such as paclitaxel exhibit potent antiangiogenic activity at very low concentrations, but the mechanism underlying such an effect remains unknown. To understand the involvement of microtubules in angiogenesis, we analyzed the dynamic instability behavior of microtubules in living endothelial cells [human microvascular endothelial cells (HMEC-1) and human umbilical vascular endothelial cells (HUVEC)] following 4 hours of paclitaxel treatment. Unexpectedly, antiangiogenic concentrations of paclitaxel (0.1-5 nmol/L) strongly increased microtubule overall dynamicity in both HMEC-1 (86-193%) and HUVEC (54-83%). This increase was associated with increased microtubule growth and shortening rates and extents and decreased mean duration of pauses. The enhancement of microtubule dynamics by paclitaxel seemed to be specific to antiangiogenic concentrations and to endothelial cells. Indeed, cytotoxic concentration (100 nmol/L) of paclitaxel suppressed microtubule dynamics by 40% and 54% in HMEC-1 and HUVECs, respectively, as observed for all tested concentrations in A549 tumor cells. After 4 hours of drug incubation, antiangiogenic concentrations of paclitaxel that inhibited endothelial cell proliferation without apoptosis (1-5 nmol/L) induced a slight decrease in anaphase/metaphase ratio, which was more pronounced and associated with increased mitotic index after 24 hours of incubation. Interestingly, the in vitro antiangiogenic effect also occurred at 0.1 nmol/L paclitaxel, a concentration that did not alter mitotic progression and endothelial cell proliferation but was sufficient to increase interphase microtubule dynamics. Altogether, our results show that paclitaxel mediates antiangiogenesis by an increase in microtubule dynamics in living endothelial cells and suggest that the impairment of interphase microtubule functions is responsible for the inhibition of angiogenesis.
Use of anti-citrullinated peptide and anti-RA33 antibodies in distinguishing erosive arthritis in patients with systemic lupus erythematosus and rheumatoid arthritis
Authors: R Mediwake
Journal: Annals of the Rheumatic Diseases (2001)

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) can both present with an erosive arthritis with the small joints of the hands affected. Therefore a serological marker would be useful to distinguish between these two diseases at onset. In this study anti-RA33 antibodies, which are found in patients with SLE and RA, and anti-citrullinated peptide antibodies (anti-CCP), which have recently been described as highly specific for RA, were assessed.Two hundred and thirty one patients receiving long term follow up for SLE were evaluated for arthritis and classified as erosive and non-erosive disease. Sixty six patients were tested for anti-RA33 and anti-CCP antibodies. All the patients were tested for rheumatoid factor (RF) and HLA-DR4 status.Ten patients had erosive disease, six of whom were RF positive (60%), and six anti-RA33 positive (60%), whereas only two were anti-CCP positive (20%). Two hundred and twenty one patients had non-erosive disease, 40 of whom were RF positive (18%), 14 were anti-RA33 positive (6%), whereas only one patient was found to be anti-CCP positive (0.5%).The presence of anti-CCP antibodies may be useful in distinguishing RA from erosive SLE. Anti-RA33 antibodies and RF are unhelpful.
Controlling the obesity epidemic is important for maintaining musculoskeletal health
Authors: A D Woolf, F Breedveld, T K Kvien
Journal: Annals of the Rheumatic Diseases (2006)

Obesity: the risks on musculoskeletal health

Awareness of the importance of obesity and an urgency for action in view of the increasing numbers of people of excess weight at all ages is increasing. The focus is on the effect of obesity on conditions with high morbidity and mortality—for example, coronary heart disease, ischaemic stroke, type 2 diabetes and cancers,1 whereas the effect on osteoarthritis, back pain and other musculoskeletal problems2 is underappreciated. Although obesity is recognised as contributing to the burden of osteoarthritis,1 the potential benefits for musculoskeletal health of maintaining an ideal body weight are not recognised.3 There is strong evidence that obesity is a major determinant of osteoarthritis. Consequently, maintaining an ideal body weight at all ages is a major recommendation of the European Action Towards Better Musculoskeletal Health Report4 and of the American College of Rheumatology and European League Against Rheumatism guidelines for osteoarthritis.5–7

Obesity is a major concern in Europe as Europe has one of the highest body mass indices (BMIs (weight (kg)/(height2 (m)2))) of all regions under the World Health Organization, with 400 million adults estimated to be overweight and 130 million to be obese.6,8 The prevalence of obesity has risen threefold or more in many European countries since the 1980s. The main contributors to this increase are unhealthy diets and physical inactivity. In view of the actions being taken to combat this epidemic of obesity, there is a need for better recognition of the effect of obesity on the musculoskeletal problems. The forthcoming World Health Organization European Region Ministerial Conference on Counteracting Obesity is a forum to ensure the development of an integrated strategy that considers all the effects of obesity and the problems of controlling and reducing obesity in a physically inactive …
Thymopentin in Sezary Syndrome
Authors: M. G. Bernengo, A. Appino, M. Bertero, M. Novelli, M. T. Fierro, G. C. Doveil, F. Lisa
Journal: JNCI Journal of the National Cancer Institute (1992)

Background : Response to the treatment of Sézary syndrome (a cutaneous T-cell lymphoma) is poor. Since patients with this syndrome are elderly, aggressive chemotherapy is poorly tolerated and deep immunodepression may result in fatal opportunistic infections. Immunomodulating therapy seems important in the management of Sézary syndrome. Purpose : In a pilot study, we assessed the efficacy of thy-mopentin (TP-5), a synthetic penta-peptide, correlating clinical responses to the histologic and immunologic effects of the drug. Methods: Twenty Sézary syndrome. patients received 50 mg TP-5 intravenously three times a week for a mean time of 16.3 months. Skin and lymph node histology and immunohistochemistry, circulating lymphoid cell subpopulations, and soluble interleukin-2 receptors were evaluated before treatment and during follow-up. Results : Eight complete remissions and seven partial remissions were obtained (75%). No change was observed in three patients, and disease progression was observed in two patients. The median duration of response was 22 months (complete remission, 25.5 months; partial remission, 14 months). Four-year survival probability was 53.9%. The responses were obtained when circulating Sézary cells were less than 2600/mm 3 . A significant reduction of CD4 + cells paralleled a CD8 + cell increase. An increase in NK cells (CD16 + and CD56 + ) was accompanied by significantly longer survival. Serum soluble interleukin-2 receptor values were a useful monitor of the clinical course and treatment. Loss of epidermotropism, reduction of Langherhans' cells, and HLA-DR + keratinocytes were found. Conclusions : TP-5 is a potentially useful agent in the treatment of a subgroup of patients with Sézary syndrome; its activity seems to be mediated by an effect on a normal NK cell-like subpopulation. Implications : The biological and clinical role of this therapy in combination with conventional treatments will be the subject of future investigations. [J Natl Cancer Inst 84: 1341–1346, 1992]
Identification of distinct miRNA target regulation between breast cancer molecular subtypes using AGO2-PAR-CLIP and patient datasets
Authors: Thalia A Farazi, Jelle J ten Hoeve, Miguel Brown, Aleksandra Mihailovic, Hugo M Horlings, Marc J van de Vijver, Thomas Tuschl, Lodewyk FA Wessels
Journal: Genome biology (2014)

Abstract Background Various microRNAs (miRNAs) are up- or downregulated in tumors. However, the repression of cognate miRNA targets responsible for the phenotypic effects of this dysregulation in patients remains largely unexplored. To define miRNA targets and associated pathways, together with their relationship to outcome in breast cancer, we integrated patient-paired miRNA-mRNA expression data with a set of validated miRNA targets and pathway inference. Results To generate a biochemically-validated set of miRNA-binding sites, we performed argonaute-2 photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (AGO2-PAR-CLIP) in MCF7 cells. We then defined putative miRNA-target interactions using a computational model, which ranked and selected additional TargetScan-predicted interactions based on features of our AGO2-PAR-CLIP binding-site data. We subselected modeled interactions according to the abundance of their constituent miRNA and mRNA transcripts in tumors, and we took advantage of the variability of miRNA expression within molecular subtypes to detect miRNA repression. Interestingly, our data suggest that miRNA families control subtype-specific pathways; for example, miR-17, miR-19a, miR-25, and miR-200b show high miRNA regulatory activity in the triple-negative, basal-like subtype, whereas miR-22 and miR-24 do so in the HER2 subtype. An independent dataset validated our findings for miR-17 and miR-25, and showed a correlation between the expression levels of miR-182 targets and overall patient survival. Pathway analysis associated miR-17, miR-19a, and miR-200b with leukocyte transendothelial migration. Conclusions We combined PAR-CLIP data with patient expression data to predict regulatory miRNAs, revealing potential therapeutic targets and prognostic markers in breast cancer.
PASSIVE IMMUNIZATION BY MEANS OF SCARLET FEVER ANTITOXIN
Authors: J. M. Cowie
Journal: BMJ (1930)

Cl!inical SiI,ns.-Trace of albumin.Left verntricle enlaiged; aoltic systolic murmur.Electro-cardiogram, apart firom left xen- tr icular preponideranice, niormal.CASE 7.-R.C
Assessment of quality of life in lung transplantation using a simple generic tool
Authors: A C Anyanwu
Journal: Thorax (2001)

<h3>BACKGROUND</h3> The EuroQol is a generic questionnaire developed to provide a simple method for assigning utility values to health. This study examines the applicability of the EuroQol to the measurement of quality of life in single, bilateral, and heart-lung transplantation. <h3>METHODS</h3> A cross sectional study was performed in 87 patients awaiting lung transplantation and in 255 transplant recipients attending follow up clinics in four transplant units. <h3>RESULTS</h3> In the waiting list group 61% reported extreme problems in at least one of the five EuroQol quality of life domains compared with 20% single lung recipients, 4% bilateral lung recipients, and 2% heart-lung recipients at 3 or more years after transplantation. The mean utility value of patients on the waiting list was 0.31. In comparison, utility values for recipients 3 years after transplantation were 0.61 for single, 0.82 for bilateral, and 0.87 for heart-lung transplants. The utility scores and health profiles of bilateral and heart-lung recipients were consistently superior to those of single lung recipients. Problems in all five domains were more frequent in single lung recipients. Subjective assessment with a visual analogue scale showed a similar trend. <h3>CONCLUSIONS</h3> The EuroQol is a simple method of deriving a single utility value for quality of life and is responsive to changes after lung transplantation. It is worth considering as a means of monitoring quality of life after transplantation and as an index of quality of survival in research studies in solid organ transplantation. These data suggest that quality of life after transplantation of one lung is inferior to that after transplantation of two lungs.
NK/T cell lymphoma of the lung: a case report and review of literature
Authors: P Laohaburanakit
Journal: Thorax (2006)

Primary lymphoma of the lung is rare and is usually of B cell type. Tissue samplings taken by transbronchial biopsy and computed tomographic (CT) guided needle biopsy of the right perihilar area of an elderly woman who presented with refractory pneumonia showed T cell lymphocytosis with no evidence of active infection. The patient's respiratory status rapidly deteriorated and she eventually died. Post mortem examination revealed primary pulmonary T cell lymphoma with natural killer (NK) cell features. We present what may be the first case of primary NK/T cell pulmonary lymphoma and review the literature on the subject.
Behavioral Treatment of Obesity: Its application to type II diabetes
Authors: Rena R Wing
Journal: Diabetes Care (1993)

This review describes the improvements made in the behavioral treatment of obesity from the 1970s to the present, and then provides a comparable overview of progress that has been made in the behavioral treatment of obese patients with type II diabetes by Wing et al. (13–19) at the University of Pittsburgh. Evidence is presented to show that structured exercise, VLCDs, and intensification of treatment programs may be useful in improving the long-term outcome of behavioral weight-loss interventions.
Stochastic recruitment in parallel fiber activity patterns
Authors: Patrick D. Roberts
Journal: Behavioral and Brain Sciences (1997)

Random-excitation granule cells are likely to overwhelm spatiotemporal sequences described as “tidal waves” in Braitenberg et al.'s target article. A mechanism is proposed involving the Golgi cells to reinforce tidal waves against noise. The recurrent inhibition by the Golgi calls can recruit random excitations of granule cells in phase with sequences of mossy fiber input.
Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study
Authors: T. P. Ahern, L. Pedersen, M. Tarp, D. P. Cronin-Fenton, J. P. Garne, R. A. Silliman, H. T. Sorensen, T. L. Lash
Journal: JNCI Journal of the National Cancer Institute (2011)

BackgroundAccumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied.
1119-93 Any measurable coronary artery disease identified in women presenting with ischemic chest pain is associated with an adverse outcome: Findings from the National Institutes of Health-National Heart, Lung, and Blood Institute-sponsored Womens Ischemia Syndrome Evaluation (WISE) study angiographic core laboratory
Authors: Barry L Sharaf, Leslee Shaw, B.Della Johnson, Sheryl F Kelsey, Marian B Olson, Sunil Mankad, William J Rogers, Steven E Reis, Carl J Pepine, C.Noel Bairey Merz
Journal: Journal of the American College of Cardiology (2004)
Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy
Authors: Gadi Borkow, Qibin Leng, Ziva Weisman, Miguel Stein, Noya Galai, Alexander Kalinkovich, Zvi Bentwich
Journal: Journal of Clinical Investigation (2000)

Helminthic parasites cause widespread, persistent infections in humans. The immigration of Ethiopians to Israel (a group denoted here by “Eth.”), many of them infested with helminths and in a chronic immune-activation state, enabled us to investigate the effects of such immune activation on immune responses. We studied the immune profile and immune functions of 190 Eth. and Israeli non-Eth. (Isr.) highly, partially, or non–immune-activated individuals. Immune cells from highly immune-activated individuals were defective in several signaling responses, all of which were restored gradually following anti-helminthic treatment. These cells showed poor transmembrane signaling, as seen by the phosphorylation of various tyrosine kinases and of the MAPK kinases, ERK1/2 and p38; deficient degradation of phosphorylated IκBα; increased expression of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), which appears to block proliferative responses in these cells; decreased β-chemokine secretion by CD8+ cells after stimulation; and reduced proliferation to recall antigen stimulation. Highly immune-activated individuals also showed decreased delayed-type skin hypersensitivity responses to recall antigen before deworming. These findings support the notion that chronic helminthic infections cause persistent immune activation that results in hyporesponsiveness and anergy. Such impaired immune functions may diminish the capacity of these individuals to cope with infections and to generate cellular protective immunity after vaccination.
HS1-Associated Protein X-1 Regulates Carcinoma Cell Migration and Invasion via Clathrin-Mediated Endocytosis of Integrin αvβ6
Authors: Alan G. Ramsay, Melanie D. Keppler, Mona Jazayeri, Gareth J. Thomas, Maddy Parsons, Shelia Violette, Paul Weinreb, Ian R. Hart, John F. Marshall
Journal: Cancer Research (2007)

Abstract Enhanced expression levels of integrin αvβ6 have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how αvβ6 determines invasion and the dynamics of integrin αvβ6 regulation in tumor cells are poorly understood. We have identified the 35-kDa HS1-associated protein X-1 (HAX-1) protein as a novel binding partner of the β6 cytoplasmic tail using a yeast two-hybrid screen. We show that αvβ6-dependent migration is blocked following small interfering RNA (siRNA)–mediated depletion of HAX-1 in oral squamous cell carcinoma cell lines. Using both siRNA and membrane-permeable peptides, we show that αvβ6-dependent migration and invasion require HAX-1 to bind directly to β6 and thereby regulate clathrin-mediated endocytosis of αvβ6 integrins. Progression of oral cancer is associated with enhanced expression of αvβ6 and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for αvβ6-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression. [Cancer Res 2007;67(11):5275–84]