tbuckley/cabot-search huggingface dataset:
Phase III Trial of Maintenance Gefitinib or Placebo After Concurrent Chemoradiotherapy and Docetaxel Consolidation in Inoperable Stage III Non–Small-Cell Lung Cancer: SWOG S0023
Authors: Karen Kelly, Kari Chansky, Laurie E. Gaspar, Kathy S. Albain, James Jett, Yee C. Ung, Derick H.M. Lau, John J. Crowley, David R. Gandara
Journal: Journal of Clinical Oncology (2008)

Purpose Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non–small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease. Patients and Methods Untreated patients with stage III NSCLC, a performance score of 0 to 1, and adequate organ function were eligible. All patients received cisplatin 50 mg/m 2 on days 1 and 8 plus etoposide 50 mg/m 2 on days 1 to 5, every 28 days for two cycles with concurrent thoracic radiation (1.8- to 2-Gy fractions per day; total dose, 61 Gy) followed by three cycles of docetaxel 75 mg/m 2 . Patients whose disease did not progress were randomly assigned to gefitinib 250 mg/d or placebo until disease progression, intolerable toxicity, or the end of 5 years. The planned sample size was 672 patients to confer power of 0.89 to detect a 33% increase over the expected median survival time of 21 months (one-sided P = .025, log-rank test). Random assignment was stratified by stage, histology, and measurable versus nonmeasurable disease. Results Enrollment began in July 2001. An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 randomly assigned patients. The study closed, and preliminary results were reported. Now, with a median follow-up time of 27 months, median survival time was 23 months for gefitinib (n = 118) and 35 months for placebo (n = 125; two-sided P = .013). The toxic death rate was 2% with gefitinib compared with 0% for placebo. Conclusion In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.
Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus
Authors: Samuel K Shimp, Cristen B Chafin, Nicole L Regna, Sarah E Hammond, Molly A Read, David L Caudell, MarissaNichole Rylander, Christopher M Reilly
Journal: Cellular and Molecular Immunology (2012)
Do the New Threshold Levels for the Diagnosis of Gestational Diabetes Mellitus Correctly Identify Women at Risk?
Authors: Michael d’Emden
Journal: Diabetes Care (2014)

Pregnant women with gestational diabetes mellitus (GDM) are at risk for certain neonatal complications. The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) blood glucose level (BGL) diagnostic thresholds correspond to an odds ratio of at least 1.75 for selected complications (1). In the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study (2), 16.1% of subjects had GDM, with the majority (11.1%) having one elevated BGL only (1). As the thresholds are statistically validated, subjects with GDM must have a risk of ≥1.75. But is this the case? All three BGL thresholds were defined independently. For example, when the 2-h BGL threshold was defined, the impact of fasting and 1-h BGLs were not considered. Their elevation should increase …
Parent-Reported Social Outcomes After Treatment for Pediatric Embryonal Tumors: A Prospective Longitudinal Study
Authors: Tara M. Brinkman, Shawna L. Palmer, Si Chen, Hui Zhang, Karen Evankovich, Michelle A. Swain, Melanie J. Bonner, Laura Janzen, Sarah Knight, Carol L. Armstrong, Robyn Boyle, Amar Gajjar
Journal: Journal of Clinical Oncology (2012)

To examine longitudinal parent-reported social outcomes for children treated for pediatric embryonal brain tumors.Patients (N=220) were enrolled onto a multisite clinical treatment protocol. Parents completed the Child Behavior Checklist/6-18 at the time of their child's diagnosis and yearly thereafter. A generalized linear mixed effects model regression approach was used to examine longitudinal changes in parent ratings of social competence, social problems, and withdrawn/depressed behaviors with demographic and treatment factors as covariates.During the 5-year period following diagnosis and treatment, few patients were reported to have clinically elevated scores on measures of social functioning. Mean scores differed significantly from population norms, yet remained within the average range. Several factors associated with unfavorable patterns of change in social functioning were identified. Patients with high-risk treatment status had a greater increase in parent-reported social problems (P=.001) and withdrawn/depressed behaviors (P=.01) over time compared with average-risk patients. Patients with posterior fossa syndrome had greater parent-reported social problems over time (P=.03). Female patients showed higher withdrawn/depressed scores over time compared with male patients (P<.001). Patient intelligence, age at diagnosis, and parent education level also contributed to parent report of social functioning.Results of this study largely suggest positive social adjustment several years after diagnosis and treatment of a pediatric embryonal tumor. However, several factors, including treatment risk status and posterior fossa syndrome, may be important precursors of long-term social outcomes. Future research is needed to elucidate the trajectory of social functioning as these patients transition into adulthood.
Differential roles of Smad2 and Smad3 in the regulation of TGF-β1-mediated growth inhibition and cell migration in pancreatic ductal adenocarcinoma cells: control by Rac1
Authors: Hendrik Ungefroren, Stephanie Groth, Susanne Sebens, Hendrik Lehnert, Frank Gieseler, Fred Fändrich
Journal: Molecular Cancer (2011)

Progression of pancreatic ductal adenocarcinoma (PDAC) is largely the result of genetic and/or epigenetic alterations in the transforming growth factor-beta (TGF-β)/Smad signalling pathway, eventually resulting in loss of TGF-β-mediated growth arrest and an increase in cellular migration, invasion, and metastasis. These cellular responses to TGF-β are mediated solely or partially through the canonical Smad signalling pathway which commences with activation of receptor-regulated Smads (R-Smads) Smad2 and Smad3 by the TGF-β type I receptor. However, little is known on the relative contribution of each R-Smad, the possible existence of functional antagonism, or the crosstalk with other signalling pathways in the control of TGF-β1-induced growth inhibition and cell migration. Using genetic and pharmacologic approaches we have inhibited in PDAC cells endogenous Smad2 and Smad3, as well as a potential regulator, the small GTPase Rac1, and have analysed the consequences for TGF-β1-mediated growth inhibition and cell migration (chemokinesis). SiRNA-mediated silencing of Smad3 in the TGF-β responsive PDAC cell line PANC-1 reduced TGF-β1-induced growth inhibition but increased the migratory response, while silencing of Smad2 enhanced growth inhibition but decreased chemokinesis. Interestingly, siRNA-mediated silencing of the small GTPase Rac1, or ectopic expression of a dominant-negative Rac1 mutant largely mimicked the effect of Smad2 silencing on both TGF-β1-induced growth inhibition, via upregulation of the cdk inhibitor p21WAF1, and cell migration. Inhibition of Rac1 activation reduced both TGF-β1-induction of a Smad2-specific transcriptional reporter and Smad2 C-terminal phosphorylation in PDAC cells while Smad3-specific transcriptional activity and Smad3 C-terminal phosphorylation appeared increased. Disruption of autocrine TGF-β signalling in PANC-1 cells rendered cells less susceptible to the growth-suppressive effect of Rac1 inhibition, suggesting that the decrease in "basal" proliferation upon Rac1 inhibition was caused by potentiation of autocrine TGF-β growth inhibition. In malignant cells with a functional TGF-β signalling pathway Rac1 antagonizes the TGF-β1 growth inhibitory response and enhances cell migration by antagonistically regulating Smad2 and Smad3 activation. This study reveals that Rac1 is prooncogenic in that it can alter TGF-β signalling at the R-Smad level from a tumour-suppressive towards a tumour-promoting outcome. Hence, Rac1 might represent a viable target for therapeutic intervention to inhibit PDAC progression.
Detection of anti-cytokeratin 8 antibody in the serum of patients with cryptogenic fibrosing alveolitis and pulmonary fibrosis associated with collagen vascular disorders
Authors: N. Dobashi, J. Fujita, Y. Ohtsuki, I. Yamadori, T. Yoshinouchi, T. Kamei, M. Tokuda, S. Hojo, H. Okada, J. Takahara
Journal: Thorax (1998)

It has been suggested that the humoral immune system plays a role in the pathogenesis of cryptogenic fibrosing alveolitis (CFA). Although circulating autoantibodies to lung protein(s) have been suggested, none of the lung proteins have been characterised. The purpose of this study was to determine the antigen to which the serum from patients with pulmonary fibrosis reacted.The anti-A549 cell antibody was characterised in a patient with CFA using Western immunoblotting and immunohistochemical staining of A549 cells. As we identified that one of the antibodies against A549 cells was anti-cytokeratin 8, the expression of mRNA of cytokeratin 8 in A549 cells was evaluated. In addition, we attempted to establish an enzyme linked immunosorbent assay to measure the levels of anti-cytokeratin 8 antibody in the serum of patients with CFA and pulmonary fibrosis associated with collagen vascular disorders (PF-CVD).Initially two anti-A549 cell antibodies were detected in the serum of patients with pulmonary fibrosis, one of which was characterised as anticytokeratin 8 antibody by Western immunoblotting. We were able to establish an ELISA to measure anti-cytokeratin 8 antibody and found significantly higher levels in patients with CFA and PF-CVD than in normal volunteers, patients with sarcoidosis, pneumonia, and pulmonary emphysema.One of the anti-A549 cell antibodies in the serum of patients with CFA was against cytokeratin 8. The serum levels of anti-cytokeratin 8 antibody were increased in patients with CFA and PF-CVD. These results suggest that anticytokeratin 8 antibody may be involved in the process of lung injury in pulmonary fibrosis.
Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma
Authors: Gary Hudes, Michael Carducci, Piotr Tomczak, Janice Dutcher, Robert Figlin, Anil Kapoor, Elzbieta Staroslawska, Jeffrey Sosman, David McDermott, István Bodrogi, Zoran Kovacevic, Vladimir Lesovoy, Ingo G.H. Schmidt-Wolf, Olga Barbarash, Erhan Gokmen, Timothy O'Toole, Stephanie Lustgarten, Laurence Moore, Robert J. Motzer
Journal: New England Journal of Medicine (2007)

Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).
Continuity of airway goblet cells and intraluminal mucus in the airways of patients with bronchial asthma
Authors: S. Shimura, Y. Andoh, M. Haraguchi, K. Shirato
Journal: European Respiratory Journal (1996)

The aim of this study was to elucidate the mechanism of the formation of the widespread mucous-plugging observed in autopsied lungs from patients with bronchial asthma. We performed morphometric analysis of airways of autopsied lungs from eight patients with bronchial asthma (Group BA), and compared it with those of six chronic bronchitics (Group CB) and four control patients (Control). The following parameters were measured in paraffin sections: volume proportion of bronchial glands to bronchial wall (Gland%); goblet cell granules to total epithelial layer (Goblet %); intraluminal mucus expressed as the mucus occupying ratio (MOR); volume ratio of intraluminal mucus continuous with goblet cells to total intraluminal mucus (Vc/Vtol %); and surface ratio of the contact surface of intraluminal mucus continuous with goblet cells to the total luminal surface (Sc/Stot %). Gland%, Goblet %, and MOR or inflammatory cell numbers in the airway walls both from Group BA and CB were larger than those from the Control group. However, no significant differences were observed between Group BA and CB in Gland%, Goblet %, MOR or inflammatory cell numbers, except for the eosinophil number: i.e. 23 +/- 3, 22 +/- 3 and 6 +/- 2% in Gland%; 22 +/- 9, 5 +/- 4 and 2 +/- 2% in Goblet%; 10 +/- 3, 18 +/- 3 and 0.3 +/- 0.5% in MOR; 199 +/- 68, 10 +/- 3 and 2 +/- 2 cells. mm-2 in eosinophil number of the peripheral airways from Groups BA, CB and Control, respectively. In contrast, marked and significant increases were observed both in Vc/Vtot% and Sc/Stot% in Group BA compared to Groups CB and Control both in central and peripheral airways: i.e. Vc/Vtot% in the peripheral airways was 53 +/- 5, 4 +/- 3 and 0.8 +/- 0.8% from Groups BA, CB and Control, respectively (BA vs CB or BA vs Control, p &lt; 0.01 each). These findings suggest that the continuity of goblet cells and intraluminal mucus or lack of full release of mucus, from goblet cells, is peculiar to asthmatic airways, and may contribute to the formation of mucous-plugs.
Differential Usage of Class II Transactivator Promoters PI and PIV during Inflammation and Injury in Kidney
Authors: Oki Takeuchi, Tasha N. Sims, Yutaka Takei, Vido Ramassar, Konrad S. Famulski, Philip F. Halloran
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Expression of class II transactivator (CIITA), the transcriptional regulator that controls all class II expression, is controlled in cell lines in vitro by three promoters: the dendritic cell promoter PI, the B cell promoter PIII, and the interferon-γ (IFN-γ)–inducible promoter, PIV. The authors examined the promoter usage in vivo in mouse kidney in the basal state and in response to IFN-γ, endotoxin, allostimulation, and renal injury. Genetically modified mice were used to examine the dependency of each promoter on IFN-γ and on the transcription factor interferon regulatory factor 1 (IRF-1). Usage of distinct CIITA promoters was monitored by real-time reverse transcriptase polymerase chain reaction (RT-PCR) using the unique sequences in the 5′ end of the transcript from each promoter. Kidneys in both control mice and IFN-γ knockouts expressed chiefly PI- and PIV–related products. Administration of recombinant IFN-γ activated only promoter PIV. Endotoxin or allogeneic stimulation elevated the PIV-related mRNA, dependent on IFN-γ and on IRF-1. Ischemic renal injury, however, increased the PI- and PIV–driven mRNA expression in wild-type but also in IFN-γ–deficient mice. Thus the in vivo control of CIITA promoters in kidney is similar to that observed in vitro ( i.e. , basal-state usage of PI and IFN-γ–dependent usage of PIV during inflammation), but it also shows additional levels of control: IFN-γ–independent basal activity of PIV and IFN-γ–independent induction of PIV during tissue injury. E-mail: phil.halloran@ualberta.ca
Thrombotic Calcific Mitral Stenosis
Authors: CHARLES F. WOOLEY, NOBUHISA BABA, JAMES W. KILMAN, JOSEPH M. RYAN
Journal: Circulation (1974)

We compared the morphology of the calcific stenotic mitral valve (CSMV) with noncalcific stenotic mitral valves (NCSMV) removed at surgery; control valves were obtained at autopsy. X-rays of the excised valves permitted localization and quantitation of calcification. A classification of CSMV applicable to noninvasive techniques based on this methodology is presented. Moderate to heavily CSMV had greater weight, volume, specific gravity, weight per area, with smaller orifice size when compared with NCSMV and controls. Leaflet mobility was obliterated in moderate to heavily CSMV, while most NCSMV had some degree of leaflet mobility. Surface morphology was strikingly different in CSMV with 1) surface ulceration , due to eruption of the underlying calcific focus through valvular endothelium, 2) thrombosis in the areas of ulceration ( associated with symptomatic arterial embolization in four patients), 3) whisker formation , filamentous stalks along the line of valve closure. Calcification in the CSMV is viewed as an active, progressive process resulting in altered physical characteristics of the valve, progressive leaflet immobility and orifice narrowing, and eruptive surface changes with thrombus formation and arterial embolization arising from the CSMV itself. Clinical implications and a rationale for more precise classification of mitral stenosis on the basis of valvular calcification are presented.
Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs
Authors: Haiyan Jiang, David Lillicrap, Susannah Patarroyo-White, Tongyao Liu, Xiaobing Qian, Ciaran D. Scallan, Sandra Powell, Tracey Keller, Morag McMurray, Andrea Labelle, Dea Nagy, Joseph A. Vargas, Shangzhen Zhou, Linda B. Couto, Glenn F. Pierce
Journal: Blood (2006)
Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin
Authors: John G. McHutchison, Thierry Poynard, Rafael Esteban-Mur, Gary L. Davis, Zachary D. Goodman, Joann Harvey, Mei-Hsiu Ling, Jean Jacques Garaud, Janice K. Albrecht, Keyur Patel, Jules L. Dienstag
Journal: Hepatology (2002)

The clinical use of measuring hepatic hepatitis C virus (HCV) RNA before and after therapy in patients with chronic hepatitis C has been assessed in a number of small clinical trials. Viral clearance from the liver may be a better marker of long-term response than eradication of serum HCV RNA. The aim of this study was to evaluate quantitative hepatic HCV-RNA measurements before and after antiviral therapy. Two thousand eighty-nine chronic hepatitis C patients were enrolled in 3 published clinical trials evaluating interferon alfa-2b alone or with ribavirin either as initial therapy or for interferon relapse. Hepatic HCV-RNA quantitation was performed with a modified reverse-transcription polymerase chain reaction (RT-PCR) before and 24 weeks after therapy in 951 and 1,316 patients, respectively. Pretherapy hepatic HCV-RNA concentrations correlated best with serum HCV-RNA concentrations ( R = .236, P = .0001) and negatively correlated with alanine transaminase (ALT) values (−0.178, P = .0001), duration of infection (−0.09, P = .02), parenchymal injury (−0.135, P = .0001), histologic activity index (HAI) inflammatory score (−0.085, P = .01), Knodell fibrosis score (−0.072, P = .03), and body weight (−0.078, P = .02). In paired liver biopsy specimens (n = 534), change in hepatic HCV RNA correlated with the change in the HAI ( R = .346, P = .0001). Of 400 sustained virologic responders (SVR), 393 (98%) had undetectable hepatic HCV RNA, whereas 7 (2%) had detectable hepatic HCV RNA; 5 have been followed and 2 have had reappearance of serum HCV RNA 12 months after therapy. In conclusion, measurement of hepatic HCV RNA before or after therapy reflects changes observed in serum HCV RNA, and correlates inversely with hepatic inflammation and fibrosis, but otherwise has minimal clinical use.
The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells
Authors: Takeshi Egawa, Robert E. Tillman, Yoshinori Naoe, Ichiro Taniuchi, Dan R. Littman
Journal: The Journal of Experimental Medicine (2008)

Members of the Runx family of transcriptional regulators are required for the appropriate expression of CD4 and CD8 at discrete stages of T cell development. The roles of these factors in other aspects of T cell development are unknown. We used a strategy to conditionally inactivate the genes encoding Runx1 or Runx3 at different stages of thymocyte development, demonstrating that Runx1 regulates the transitions of developing thymocytes from the CD4(-)CD8(-) double-negative stage to the CD4(+)CD8(+) double-positive (DP) stage and from the DP stage to the mature single-positive stage. Runx1 and Runx3 deficiencies caused marked reductions in mature thymocytes and T cells of the CD4(+) helper and CD8(+) cytotoxic T cell lineages, respectively. Runx1-deficient CD4(+) T cells had markedly reduced expression of the interleukin 7 receptor and exhibited shorter survival. In addition, inactivation of both Runx1 and Runx3 at the DP stages resulted in a severe block in development of CD8(+) mature thymocytes. These results indicate that Runx proteins have important roles at multiple stages of T cell development and in the homeostasis of mature T cells.
Unusual case of childhood dermatomyositis.
Authors: A Martini, A Ravelli
Journal: Annals of the Rheumatic Diseases (1985)

Piroxicam-induced acute renal failure (anuria) SIR, We report a case of piroxicam-induced acute renal failure (anuria) (ARFA) of a patient with pre-existing moderate renal failure.Although acute renal failure accompanies the use of other non-steroidal anti- inflammatory drugs (NSAID), to our knowledge ARFA has not been reported with piroxicam.A 75-year-old man with pre-existing moderate renal failure discovered in 1980 had intermittently been on methyldopa and frusemide for hypertension since 1975.He discontinued both drugs three weeks before his admission to the hospital.He had a cerebrovascular episode without residua in 1981.He also had congenital subluxation of his hips.Osteoarthrosis secondary to this presented in 1979, for which he had intermittently been treated with paracetamol and sulindac.Initial laboratory data included: blood urea nitrogen: 80-95 mg/dl (57-68 mmol/l), serum creati- nine: 457 mmol/l, creatinine clearance: 27-8 ml/min, urine specific gravity: 1003, serum calcium: 7-5 mg/dl (1.9 mmol/l), serum phosphorus: 4 mg/dl (13 mmol1l), serum sodium: 125 mEq/l (125 mmol/l), serum potassium: 3-9 mEq/l (3-9 mmol/l), plasma renin activity: 3-26 ng/ml/h.