tbuckley/cabot-search huggingface dataset:
Tenascin Is Increased in Airway Basement Membrane of Asthmatics and Decreased by an Inhaled Steroid
Authors: ANNIKA LAITINEN, ALAN ALTRAJA, MARY KÄMPE, MARGARETHA LINDEN, ISMO VIRTANEN, LAURI A. LAITINEN
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Tenascin and fibronectin are extracellular matrix glycoproteins expressed during morphogenesis and tissue repair. In the present study bronchial biopsies were studied by the morphometric method of immunocytochemistry to reveal the distribution of different tenascin and fibronectin isoforms as well as the presence of inflammatory cells in the airway mucosa of patients with chronic asthma (n = 32) and those with seasonal birch-pollen-sensitive asthma out of season (n = 17), both in comparison with healthy control subjects (n = 12). The results showed an increase in tenascin immunoreactivity in the bronchial subepithelial reticular basement membrane layer in patients with chronic asthma (p < 0.0001) and in those with seasonal asthma (p < 0.01) compared with control subjects. The tenascin immunoreactivity, appearing as an intense wide subepithelial band in asthma, was seen only occasionally in the basement membrane of control specimens. Instead, a diffuse immunoreaction against both total fibronectin and locally produced extradomain A fibronectin was similarly visible in the airway mucosa of both patients and control subjects. Despite the significant increase in the airway mucosa of eosinophils and lymphocytes in patients with chronic asthma (p < 0.0001 and p < 0.0001, respectively) and of eosinophils in patients with seasonal asthma (p < 0.001), there was no correlation between the number of these cell types and level of tenascin expression. In patients with birch-pollen–sensitive asthma during the birch-pollen season, inhaled corticosteroid treatment, budesonide 400 μ g twice daily, decreased tenascin immunoreactivity, in comparison with effects of placebo (p = 0.01). Our results suggest that the higher amount of tenascin reflects disease activity in asthma and may be an indicator of a remodeling process rather than of injury itself.
Rotavirus Antigenemia in Children Is Associated with Viremia
Authors: Sarah E Blutt, David O Matson, Sue E Crawford, Mary Allen Staat, Parvin Azimi, Berkeley L Bennett, Pedro A Piedra, Margaret E Conner
Journal: PLoS Medicine (2007)

Background Antigenemia is commonly detected in rotavirus-infected children. Although rotavirus RNA has been detected in serum, definitive proof of rotavirus viremia has not been shown. We aimed to analyze a defined patient population to determine if infectious virus could be detected in sera from children with rotavirus antigenemia. Methods and Findings Serum samples obtained upon hospitalization from children with gastroenteritis (57 stool rotavirus-positive and 41 rotavirus-negative), children with diagnosed bronchiolitis of known (n = 58) or unknown (n = 17) viral etiology, children with noninfectious, nonchronic conditions (n = 17), and healthy adults (n = 28) were tested for rotavirus antigen by enzyme immunoassay (EIA). Results of serum antigen testing were assessed for association with clinical and immunological attributes of the children. Rotavirus antigenemia was detected in 90% (51/57) of children with rotavirus-positive stools, in 89% (8/9) of children without diarrhea but with rotavirus-positive stools, in 12% (2/17) of children with bronchiolitis of unknown etiology without gastroenteritis, and in 12% (5/41) of children with gastroenteritis but with rotavirus-negative stools. Antigenemia was not detected in sera from children with noninfectious nonchronic conditions, children with bronchiolitis of known etiology and no gastroenteritis, or healthy adults. Neither age nor timing of serum collection within eight days after onset of gastroenteritis significantly affected levels of antigenemia, and there was no correlation between antigenemia and viral genotype. However, there was a negative correlation between serum rotavirus antigen and acute rotavirus-specific serum IgA (r = −0.44, p = 0.025) and IgG (r = −0.40, p = 0.01) titers. We examined 11 antigen-positive and nine antigen-negative sera for infectious virus after three blind serial passages in HT-29 cells using immunofluorescence staining for rotavirus structural and nonstructural proteins. Infectious virus was detected in 11/11 (100%) sera from serum antigen-positive children and in two out of nine (22%) sera samples from antigen-negative children (p = 0.002). Conclusions Most children infected with rotavirus are viremic. The presence of viremia is directly related to the detection of antigenemia and is independent of the presence of diarrhea. Antigenemia load is inversely related to the titer of antirotavirus antibody in the serum. The finding of infectious rotavirus in the blood suggests extraintestinal involvement in rotavirus pathogenesis; however, the impact of rotavirus viremia on clinical manifestations of infection is unknown.
The Regulation of Granulocyte Production
Authors: Gerald Rothstein
Journal: New England Journal of Medicine (1972)

The neutrophilic granulocyte system is both flexible and responsive. It releases enormous numbers of neutrophils into the blood in response to pyogenic infection and replaces them by increasing cell production; when the infection is under control, the production and blood concentration of neutrophils return to normal. Also, after neutropenia and bone-marrow hypoplasia from drug toxicity or irradiation the system can return to normal. Equally noteworthy is the fact that in the absence of such stresses, granulocyte production and delivery to the blood are such that the marrow granulocyte cellularity and blood neutrophil concentration remain within narrow "normal" limits. Both the . . .
Previous tumour as a prognostic factor in stage I non-small cell lung cancer
Authors: A. Lopez-Encuentra, A. Gomez de la Camara, R. Rami-Porta, J. L. Duque-Medina, J. L. M. de Nicolas, J. Sayas
Journal: Thorax (2006)

<b>Objective:</b> To evaluate the effect of comorbidity as an independent prognostic factor in lung cancer. <b>Method:</b> Data on 2991 consecutive cases of lung cancer were collected prospectively from 19 Spanish hospitals between 1993 and 1997 by the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S). To evaluate the effect of comorbidity on survival, 1121 patients with non-small cell lung cancer (NSCLC) in pathological stage I who underwent complete resection were selected, excluding operative mortality. The presence of specific comorbidities at the time of thoracotomy was registered prospectively. <b>Results:</b> Cox regression analysis showed that tumour size (0–2, 2–4, 4–7, &gt;7 cm) (HR 1.45 95% CI 1.08 to 1.95), 1.86 (95% CI 1.38 to 2.51), 2.84 (95% CI 1.98 to 4.08)), the presence of a previous tumour (HR 1.45 (95% CI 1.17 to 1.79)) and age (HR 1.02 (95% CI 1.01 to 1.03)) had a significant prognostic association with survival. This study excluded the presence of visceral pleural involvement or other comorbidities as independent variables. <b>Conclusion:</b> The presence of a previous tumour is an independent prognostic factor in pathological stage I NSCLC with complete resection, increasing the probability of death by 1.5 times at 5 years. It is independent of other comorbidities, TNM classification and age.
Improved frontline clinician performance is the secret to NHS efficiency
Authors: A. O'Dowd
Journal: BMJ (2010)

The NHS should focus on improving clinical practice at the front line rather than restructuring the health service to make crucial savings, says a leading health policy think tank.

In a report by the King’s Fund, experts have calculated that the NHS will need to tackle an estimated £14bn (€16.6bn; $21bn) gap a year in productivity—the ratio of outputs to inputs, adjusted for quality—by 2014.

To achieve this, the health service would do best to focus on changing clinical practice among frontline staff as doing so would allow the most important opportunities for improving productivity.

The advice is in contrast to the government’s plans set …
Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott-Aldrich syndrome
Authors: A CIANFERONI, M MASSAAD, S FESKE, M DELAFUENTE, L GALLEGO, N RAMESH, R GEHA
Journal: Journal of Allergy and Clinical Immunology (2005)
Hyperhomocysteinemia accelerates atherosclerosis in cystathionine β-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation
Authors: Hong Wang, XiaoHua Jiang, Fan Yang, John W. Gaubatz, Lang Ma, Mark J. Magera, XiaoFeng Yang, Peter B. Berger, William Durante, Henry J. Pownall, Andrew I. Schafer
Journal: Blood (2003)
Microparticles in Hemostasis and Thrombosis
Authors: A. Phillip Owens, Nigel Mackman
Journal: Circulation Research (2011)

Blood contains microparticles (MPs) derived from a variety of cell types, including platelets, monocytes, and endothelial cells. In addition, tumors release MPs into the circulation. MPs are formed from membrane blebs that are released from the cell surface by proteolytic cleavage of the cytoskeleton. All MPs are procoagulant because they provide a membrane surface for the assembly of components of the coagulation protease cascade. Importantly, procoagulant activity is increased by the presence of anionic phospholipids, particularly phosphatidylserine (PS), and the procoagulant protein tissue factor (TF), which is the major cellular activator of the clotting cascade. High levels of platelet-derived PS(+) MPs are present in healthy individuals, whereas the number of TF(+), PS(+) MPs is undetectable or very low. However, levels of PS(+), TF(+) MPs are readily detected in a variety of diseases, and monocytes appear to be the primary cellular source. In cancer, PS(+), TF(+) MPs are derived from tumors and may serve as a useful biomarker to identify patients at risk for venous thrombosis. This review will summarize our current knowledge of the role of procoagulant MPs in hemostasis and thrombosis.
Local Administration of Interleukin-11 Ameliorates Intestinal Radiation Injury in Rats
Authors: Marjan Boerma, Junru Wang, Alexander F. Burnett, Alessandro D. Santin, Juan J. Roman, Martin Hauer-Jensen
Journal: Cancer Research (2007)

Intestinal radiation injury is dose limiting during abdominal and pelvic radiotherapy and critical for the outcome after accidental whole-body radiation exposure. The multifunctional cytokine, interleukin-11 (IL-11), ameliorates the intestinal radiation response, but its clinical use is hampered by severe toxicity after systemic administration. This study addressed whether protection against intestinal radiation injury can be achieved by intraluminal administration of IL-11. Male rats underwent surgical transposition of a 4-cm small bowel loop to the scrotum. For repeated intraluminal drug administration, an ileostomy, proximal to the bowel loop in the scrotum, was created. The transposed intestinal loop was exposed to 5 Gy fractions on 9 consecutive days. Recombinant human IL-11 (rhIL-11; 2 mg/kg/d) or vehicle was given through the ileostomy from 2 days before until 2 weeks after irradiation. At 2 weeks, structural, cellular, and molecular aspects of intestinal radiation injury were assessed. rhIL-11 ameliorated structural manifestations of radiation enteropathy, including radiation injury score (6.5 +/- 0.6 in the vehicle group versus 4.0 +/- 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 +/- 0.1 versus 0.5 +/- 0.03; P < 0.0001), and intestinal wall thickening (842 +/- 66 microm versus 643 +/- 54 microm; P = 0.02), reduced postradiation transforming growth factor-beta overexpression, and reduced numbers of ED2-positive cells. Postirradiation mucosal mast cell numbers were partially restored by rhIL-11. These data show that local administration of rhIL-11 ameliorates early intestinal radiation injury and support further development of rhIL-11 to reduce manifestations of intestinal radiation injury in the clinic.
Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and "specific" granule deficiency.
Authors: T Ganz, J A Metcalf, J I Gallin, L A Boxer, R I Lehrer
Journal: Journal of Clinical Investigation (1988)

Although several genetic defects are known to impair oxidative microbicidal/cytotoxic mechanisms in human PMN, no deficiencies of PMN granule components that mediate oxygen-independent microbicidal activity have yet been reported. We analyzed PMN from patients with various granulocyte disorders for their content of two azurophil granule constituents, defensins and cathepsin G, that exert microbicidal/cytotoxic activity in vitro, and one component, elastase, that has ancillary microbicidal/cytotoxic activity. PMN from two (of two) patients with specific granule deficiency (SGD) displayed an almost complete deficiency of defensins, which in normal cells constitute greater than 30% of the protein content of azurophil granules. The SGD PMN contained normal or mildly decreased amounts of cathepsin G and elastase. Conversely, the PMN of three (of three) patients with Chediak-Higashi syndrome (CHS) substantially lacked cathepsin G and elastase, but their defensin content was normal or mildly decreased. Both CHS and SGD patients suffer from frequent and severe bacterial infections, and CHS patients frequently develop an atypical lymphoproliferative syndrome. The profound deficiency of PMN components with microbicidal/cytotoxic activity in SGD and CHS may contribute to the clinical manifestations of these disorders.
Connective tissue nevi: An entity revisited
Authors: Anne Saussine, Karine Marrou, Phillippe Delanoé, Nathalie Bodak, Dominique Hamel, Arnaud Picard, Bruno Sassolas, Yves de Prost, Martine Lemerrer, Sylvie Fraitag, Christine Bodemer
Journal: Journal of the American Academy of Dermatology (2011)
Tankyrase and the Canonical Wnt Pathway Protect Lung Cancer Cells from EGFR Inhibition
Authors: Matias Casás-Selves, Jihye Kim, Zhiyong Zhang, Barbara A. Helfrich, Dexiang Gao, Christopher C. Porter, Hannah A. Scarborough, Paul A. Bunn, Daniel C. Chan, Aik Choon Tan, James DeGregori
Journal: Cancer Research (2012)

Abstract Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, relapse inevitably occurs, suggesting the development of escape mechanisms that promote cell survival. Using a loss-of-function, whole genome short hairpin RNA (shRNA) screen, we identified that the canonical Wnt pathway contributes to the maintenance of NSCLC cells during EGFR inhibition, particularly the poly-ADP-ribosylating enzymes tankyrase 1 and 2 that positively regulate canonical Wnt signaling. Inhibition of tankyrase and various other components of the Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo. Our findings therefore reveal a critical role for tankyrase and the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt-tankyrase-β-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC. Cancer Res; 72(16); 4154–64. ©2012 AACR.
A Single-Dose, Crossover, Placebo- and Moxifloxacin-Controlled Study to Assess the Effects of Neratinib (HKI-272) on Cardiac Repolarization in Healthy Adult Subjects
Authors: Bruce Hug, Richat Abbas, Cathie Leister, Jaime Burns, Daryl Sonnichsen
Journal: Clinical Cancer Research (2010)

Neratinib is an orally administered, small-molecule, irreversible pan-ErbB inhibitor in development for the treatment of ErbB2-positive breast cancer. This study assessed the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization, in accordance with current regulatory guidance.This was a two-part study in healthy subjects. In part 1, subjects were randomized to receive placebo, 400 mg moxifloxacin, or 240 mg neratinib (therapeutic dose) following a high-fat meal. In part 2, after a washout period, subjects received placebo plus 400 mg ketoconazole or 240 mg neratinib plus ketoconazole (supratherapeutic dose). ANOVA was used to compare the baseline-adjusted QTc interval for neratinib with that of placebo (reference), and for neratinib plus ketoconazole with that of placebo plus ketoconazole (reference). Pharmacokinetic/pharmacodynamic analyses and categorical summaries of interval data were done. Assay sensitivity was evaluated by the effect of moxifloxacin on QTc compared with placebo.Sixty healthy subjects were enrolled in this study. The upper bounds of the 90% confidence interval for baseline-adjusted QTcN (population-specific corrected QT) were </=10 milliseconds greater than the corresponding reference at all postdose time points under conditions of both therapeutic and supratherapeutic plasma concentrations of neratinib. Pharmacokinetic/pharmacodynamic analysis revealed no relationship between neratinib concentrations and QTc interval. No subjects had QTcI, QTcF, or QTcN intervals >450 milliseconds or change from baseline >30 milliseconds. Moxifloxacin produced a significant increase in QTcN compared with placebo (P < 0.05).Therapeutic and supratherapeutic plasma concentrations of neratinib do not prolong the QTc interval in healthy subjects.
Promoter Methylation status of HIN-1 associated with outcomes of ovarian clear cell adenocarcinoma
Authors: Chih-Ming Ho, Chi-Jung Huang, Chia-Yen Huang, Yih-Yiing Wu, Shwu-Fen Chang, Wen-Fang Cheng
Journal: Molecular Cancer (2012)

Abstract Background This study is to analyze promoter methylation of various tumor suppressor genes in different types of ovarian carcinoma and to identify potential therapeutic targets of ovarian clear cell adenocarcinoma (OCCA). Materials and methods The promoter methylation statuses of 40 genes in primary ovarian carcinomas including 47 clear- and 63 non-clear-cell type tissues, 6 OCCA cell lines, 29 benign ovarian endometriotic cysts, and 31 normal controls were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The MS-MLPA results were correlated with clinicopathological features and outcomes of 47 OCCA patients. Functions of the target genes were further explored by Western Blot Analysis, apoptosis assay, and caspase-3/7 activity analysis. Results Frequencies of methylated RASSF1A, CDH13, CACNA1A, HIN-1, and sFRP5 genes in OCCA tissues were significantly higher than those in non-OCCA cancerous tissues and benign endometriotic cysts . The expected OS for patients with methylated promoters of HIN-1 was significantly worse than those for patients without methylated HIN-1 (30% vs. 62%, p = 0.002). The HIN-1 gene was over-expressed in ES2 cells, a significant reduction in cell growth and induction of apoptosis, and increasing paclitaxel sensitivity by reducing phosphorylation of Akt were observed. Conclusions Methylation of HIN-1 promoter is a novel epigenetic biomarker associated with poor outcomes in OCCA patients. Ectopic expression of the HIN-1 gene increased paclitaxel sensitivity which is partly through Akt pathway.
Functional Neuroanatomy of Visuospatial Working Memory in Fragile X Syndrome: Relation to Behavioral and Molecular Measures
Authors: Hower Kwon, Vinod Menon, Stephan Eliez, Ilana S. Warsofsky, Christopher D. White, Jennifer Dyer-Friedman, Annette K. Taylor, Gary H. Glover, Allan L. Reiss
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Fragile X syndrome is a neurogenetic disorder that is the most common known heritable cause of neurodevelopmental disability. This study examined the neural substrates of working memory in female subjects with fragile X syndrome. Possible correlations among behavioral measures, brain activation, and the FMR1 gene product (FMRP expression), as well as between IQ and behavioral measures, were investigated. METHOD: Functional magnetic resonance imaging was used to examine visuospatial working memory in 10 female subjects with fragile X syndrome and 15 typically developing female subjects (ages 10–23 years). Subjects performed standard 1-back and 2-back visuospatial working memory tasks. Brain activation was examined in four regions of the cortex known to play a critical role in visuospatial working memory. Correlations between behavioral, neuroimaging, and molecular measures were examined. RESULTS: Relative to the comparison group, subjects with fragile X syndrome performed significantly worse on the 2-back task but not on the 1-back task. In a region-of-interest analysis focused on the inferior frontal gyrus, middle frontal gyrus, superior parietal lobule, and supramarginal gyrus, comparison subjects showed significantly increased brain activation between the 1-back and 2-back tasks, but subjects with fragile X syndrome showed no change in activation between the two tasks. Significant correlations were found in comparison subjects between activation in the frontal and parietal regions and the rate of correct responses on the 2-back task, but not on the 1-back task. In subjects with fragile X syndrome, significant correlations were found during the 2-back task between FMRP expression and activation in the right inferior and bilateral middle frontal gyri and the bilateral supramarginal gyri. CONCLUSIONS: Subjects with fragile X syndrome are unable to modulate activation in the prefrontal and parietal cortex in response to an increasing working memory load, and these deficits are related to a lower level of FMRP expression in fragile X syndrome subjects than in normal comparison subjects. The observed correlations between biological markers and brain activation provide new evidence for links between gene expression and cognition.
Alopecia areata and relapsing polychondritis or mosaic autoimmunity? The first experience of co-trimoxazole treatment
Authors: A P Rozin
Journal: Annals of the Rheumatic Diseases (2003)

A 13 year old girl presented with auricular chondritis and recurrent episodes of unexplained chest pain, arthritis, bronchitis, conjunctivitis, prolonged steroid resistant alopecia areata, and a history of recurrent tonsillitis. Both the mosaic of autoimmunity and relapsing polychondritis were considered in the differential diagnosis. The patient was successfully treated with co-trimoxazole. The significance of co-trimoxazole, which is an antibiotic and an immunomodulatory drug, in the treatment of autoimmune disease is discussed.