tbuckley/cabot-search huggingface dataset:
Differential Impact of Complement Mutations on Clinical Characteristics in Atypical Hemolytic Uremic Syndrome
Authors: Anne-Laure Sellier-Leclerc, Veronique Fremeaux-Bacchi, Marie-Agnès Dragon-Durey, Marie-Alice Macher, Patrick Niaudet, Geneviève Guest, Bernard Boudailliez, Franc[COMBINING CEDILLA]ois Bouissou, Georges Deschenes, Sophie Gie, Michel Tsimaratos, Michel Fischbach, Denis Morin, Hubert Nivet, Corinne Alberti, Chantal Loirat
Journal: Journal of the American Society of Nephrology (2007)

Mutations in factor H (CFH), factor I (IF), and membrane cofactor protein (MCP) genes have been described as risk factors for atypical hemolytic uremic syndrome (aHUS). This study analyzed the impact of complement mutations on the outcome of 46 children with aHUS. A total of 52% of patients had mutations in one or two of known susceptibility factors (22, 13, and 15% of patients with CFH, IF, or MCP mutations, respectively; 2% with CFH+IF mutations). Age <3 mo at onset seems to be characteristic of CFH and IF mutation–associated aHUS. The most severe prognosis was in the CFH mutation group, 60% of whom reached ESRD or died within <1 yr. Only 30% of CFH mutations were localized in SCR20. MCP mutation–associated HUS has a relapsing course, but none of the children reached ESRD at 1 yr. Half of patients with IF mutation had a rapid evolution to ESRD, and half recovered. Plasmatherapy seemed to have a beneficial effect in one third of patients from all groups except for the MCP mutation group. Only eight (33%) of 24 kidney transplantations that were performed in 15 patients were successful. Graft failures were due to early graft thrombosis (50%) or HUS recurrence. In conclusion, outcome of HUS in patients with CFH mutation is catastrophic, and posttransplantation outcome is poor in all groups except for the MCP mutation group. New therapies are urgently needed, and further research should elucidate the unexplained HUS group.
Proteoglycans in Atherosclerosis and Restenosis
Authors: Thomas N. Wight, Mervyn J. Merrilees
Journal: Circulation Research (2004)

The proteoglycan versican is one of several extracellular matrix (ECM) molecules that accumulate in lesions of atherosclerosis and restenosis. Its unique structural features create a highly interactive molecule that binds growth factors, enzymes, lipoproteins, and a variety of other ECM components to influence fundamental events involved in vascular disease. Versican is one of the principal genes that is upregulated after vascular injury and is a prominent component in stented and nonstented restenotic lesions. The synthesis of versican is highly regulated by specific growth factors and cytokines and the principal source of versican is the smooth muscle cell. Versican interacts with hyaluronan, a long chain glycosaminoglycan, to create expanded viscoelastic pericellular matrices that are required for arterial smooth muscle cell (ASMC) proliferation and migration. Versican is also prominent in advanced lesions of atherosclerosis, at the borders of lipid-filled necrotic cores as well as at the plaque-thrombus interface, suggesting roles in lipid accumulation, inflammation, and thrombosis. Versican influences the assembly of ECM and controls elastic fiber fibrillogenesis, which is of fundamental importance in ECM remodeling during vascular disease. Collectively, these studies highlight the critical importance of this specific ECM component in atherosclerosis and restenosis.
EGFRvIII Antibody–Conjugated Iron Oxide Nanoparticles for Magnetic Resonance Imaging–Guided Convection-Enhanced Delivery and Targeted Therapy of Glioblastoma
Authors: Costas G. Hadjipanayis, Revaz Machaidze, Milota Kaluzova, Liya Wang, Albert J. Schuette, Hongwei Chen, Xinying Wu, Hui Mao
Journal: Cancer Research (2010)

The magnetic nanoparticle has emerged as a potential multifunctional clinical tool that can provide cancer cell detection by magnetic resonance imaging (MRI) contrast enhancement as well as targeted cancer cell therapy. A major barrier in the use of nanotechnology for brain tumor applications is the difficulty in delivering nanoparticles to intracranial tumors. Iron oxide nanoparticles (IONP; 10 nm in core size) conjugated to a purified antibody that selectively binds to the epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIII) present on human glioblastoma multiforme (GBM) cells were used for therapeutic targeting and MRI contrast enhancement of experimental glioblastoma, both in vitro and in vivo, after convection-enhanced delivery (CED). A significant decrease in glioblastoma cell survival was observed after nanoparticle treatment and no toxicity was observed with treatment of human astrocytes (P < 0.001). Lower EGFR phosphorylation was found in glioblastoma cells after EGFRvIIIAb-IONP treatment. Apoptosis was determined to be the mode of cell death after treatment of GBM cells and glioblastoma stem cell-containing neurospheres with EGFRvIIIAb-IONPs. MRI-guided CED of EGFRvIIIAb-IONPs allowed for the initial distribution of magnetic nanoparticles within or adjacent to intracranial human xenograft tumors and continued dispersion days later. A significant increase in animal survival was found after CED of magnetic nanoparticles (P < 0.01) in mice implanted with highly tumorigenic glioblastoma xenografts (U87DeltaEGFRvIII). IONPs conjugated to an antibody specific to the EGFRvIII deletion mutant constitutively expressed by human glioblastoma tumors can provide selective MRI contrast enhancement of tumor cells and targeted therapy of infiltrative glioblastoma cells after CED.
Appeal court rules against compulsory caesarean sections
Authors: C. Dyer
Journal: BMJ (1997)

<h3>Background</h3> The risks associated with using an angiotensin-converting-enzyme (ACE) inhibitor and an angiotensin-receptor blocker together are unclear. This study was designed to determine the safety of combination therapy with these two drugs in clinical practice. <h3>Methods</h3> We conducted a population-based longitudinal analysis using linked administrative and laboratory data for elderly patients who were new users of an ACE inhibitor, an angiotensin-receptor blocker or a combination of both medications between May 1, 2002, and Dec. 31, 2006. We compared outcomes in patients given combination therapy versus patients given monotherapy using Cox proportional hazards analyses with adjustment for baseline characteristics. <h3>Results</h3> Of the 32 312 new users of either medication (mean age 76.1 years, median creatinine level 92 μmol/L), 1750 (5.4%) received combination therapy. However, 1512 (86.4%) of the patients who were given combination therapy did not have trial-established indications such as heart failure or proteinuria. Renal dysfunction was more common among patients given combination therapy (5.2 [95% confidence interval (CI) 3.4 to 7.9] events per 1000 patients per month) than among patients given monotherapy (2.4 [95% CI 2.2 to 2.7] events per 1000 patients per month) (adjusted hazard ratio [HR] 2.36, 95% CI 1.51 to 3.71). Hyperkalemia was also more common among patients given combination therapy (2.5 [95% CI 1.4 to 4.3] events per 1000 patients per month) than among patients given monotherapy (0.9 [95% CI 0.8 to 1.0] events per 1000 patients per month) (adjusted HR 2.42, 95% CI 1.36 to 4.32). Most patients took combination therapy for only a short time (median three months before at least one agent was stopped). <h3>Interpretation</h3> Combination therapy was frequently prescribed for patients without established indications and was associated with an increased risk of adverse renal outcomes when compared with monotherapy. These results mirrored data from randomized controlled trials.
Toll-like receptor 3 signaling attenuates liver regeneration
Authors: Elina Zorde-Khvalevsky, Rinat Abramovitch, Hila Barash, Irit Spivak-Pohis, Ludmila Rivkin, Jacob Rachmilewitz, Eithan Galun, Hilla Giladi
Journal: Hepatology (2009)

The current model for liver regeneration suggests that cell damage triggers Toll-like receptor (TLR) signaling via MyD88, leading to the induction of nuclear factor kappaB (NF-kappaB) and secretion of inflammatory cytokines that in turn prime liver regeneration. TLR3 is unique among TLRs in that it signals through TRIF (TIR domain-containing adaptor-inducing interferon-beta), not through MyD88, and may lead to activation of either the inflammatory or apoptotic pathway. The inflammatory pathway leads to NF-kappaB activation, whereas the apoptotic pathway, believed to be mediated by Rip3, leads to caspase-8 activation. In this study, we explored the role of TLR3 in liver regeneration by comparing the response to 70% partial hepatectomy of TLR3(wt) and TLR3(-/-) mice. We found that following partial hepatectomy, TLR3(-/-) mice demonstrated earlier hepatocyte proliferation. Furthermore, within the first hours, we observed a dramatic TLR3-dependent NF-kappaB activation and an increase in Rip3 levels in hepatocytes, accompanied by caspase-8 activation but without an apoptotic outcome.TLR3 plays an inhibitory role in the priming of liver regeneration, thus reinforcing the role of the innate immune system in balancing tissue regeneration.
ITF-2, a downstream target of the Wnt/TCF pathway, is activated in human cancers with β-catenin defects and promotes neoplastic transformation
Authors: Frank T. Kolligs, Marvin T. Nieman, Ira Winer, Gang Hu, David Van Mater, Ying Feng, Ian M. Smith, Rong Wu, Yali Zhai, Kathleen R. Cho, Eric R. Fearon
Journal: Cancer Cell (2002)
Nedd4-1 is an exceptional prognostic biomarker for gastric cardia adenocarcinoma and functionally associated with metastasis
Authors: Aiqin Sun, Guanzhen Yu, Xiaoyan Dou, Xiaowei Yan, Wannian Yang, Qiong Lin
Journal: Molecular Cancer (2014)

Gastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric carcinoma. New molecular markers and therapeutic targets are needed for diagnosis, prognosis and treatment of GCA. This study is to establish the E3 ubiquitin ligase Nedd4-1 as a prognostic biomarker to predict the survival and guide the treatment of GCA patients. Expression of Nedd4-1 in 214 GCA tumor samples was detected by immunohistochemistry staining (IHC) using tissue microarray assay (TMA). Association of Nedd4-1 with cumulative survival of the TNM stages I-III patients and clinicopathological characteristics was statistically analyzed. The role of Nedd4-1 in gastric cancer cell migration and invasion were determined by transwell and wound healing assays. Nedd4-1 is overexpressed in 83% of the GCA tumors. The 5-year survival rate in Nedd4-1 negative GCA patients is as high as 96%. Log-rank analysis indicated that overexpression of Nedd4-1 is inversely correlated with cumulative survival (χ2 = 21.885, p <0.001). Multivariate logistic regression analysis showed that overexpression of Nedd4-1 is associated with an extremely low GCA survival rate with a hazard ratio (HR) = 0.068 (p = 0.008) in TNM stages I-III patients. Statistical analysis of association of Nedd4-1 overexpression with clinicopathological characteristics revealed that overexpression of Nedd4-1 is tightly associated with TNM stage (p < 0.001). Knockdown of Nedd4-1 in gastric cancer cell lines AGS and N87 dramatically inhibited the gastric cancer cell migration and invasion. Our results indicate that Nedd4-1 is an exceptional prognostic biomarker for GCA and suggest that Nedd4-1 may play an essential role in GCA metastasis.
Cigarette smoke and platelet-activating factor receptor dependent adhesion of<i>Streptococcus pneumoniae</i>to lower airway cells
Authors: Jonathan Grigg, Haydn Walters, Sukhwinder Singh Sohal, Richard Wood-Baker, David W Reid, Cang-Bao Xu, Lars Edvinsson, Mathieu C Morissette, Martin R Stämpfli, Michael Kirwan, Lee Koh, Reetika Suri, Naseem Mushtaq
Journal: Thorax (2012)

<h3>Background</h3> Exposure to cigarette smoke (CS) is associated with increased risk of pneumococcal infection. The mechanism for this association is unknown. We recently reported that the particulate matter from urban air simulates platelet-activating factor receptor (PAFR)-dependent adhesion of pneumococci to airway cells. We therefore sought to determine whether CS stimulates pneumococcal adhesion to airway cells. <h3>Methods</h3> Human alveolar (A549), bronchial (BEAS2-B), and primary bronchial epithelial cells (HBEpC) were exposed to CS extract (CSE), and adhesion of <i>Streptococcus pneumoniae</i> determined. The role of PAFR in mediating adhesion was determined using a blocker (CV-3988). PAFR transcript level was assessed by quantitative real-time PCR, and PAFR expression by flow cytometry. Lung PAFR transcript level was assessed in mice exposed to CS, and bronchial epithelial PAFR expression assessed in active-smokers by immunostaining. <h3>Results</h3> In A549 cells, CSE 1% increased pneumococcal adhesion (p&lt;0.05 vs control), PAFR transcript level (p&lt;0.01), and PAFR expression (p&lt;0.01). Pneumococcal adhesion to A549 cells was attenuated by CV-3988 (p&lt;0.001). CSE 1% stimulated pneumococcal adhesion to BEAS2-B cells and HBEpC (p&lt;0.01 vs control). CSE 1% increased PAFR expression in BEAS2-B (p&lt;0.01), and in HBEpC (p&lt;0.05). Lung PAFR transcript level was increased in mice exposed to CS in vivo (p&lt;0.05 vs room air). Active smokers (n=16) had an increased percentage of bronchial epithelium with PAFR-positive cells (p&lt;0.05 vs never smokers, n=11). <h3>Conclusion</h3> CSE stimulates PAFR-dependent pneumococcal adhesion to lower airway epithelial cells. We found evidence that CS increases bronchial PAFR in vivo.
Modulation of Cytokine Production and Protection Against Lethal Endotoxemia by the Cardiac Glycoside Ouabain
Authors: Akira Matsumori, Koh Ono, Ryosuke Nishio, Hideki Igata, B Pharm, Tetsuo Shioi, Shigeo Matsui, Yutaka Furukawa, Atsushi Iwasaki, Yoshisuke Nose, Shigetake Sasayama
Journal: Circulation (1997)

Background Recent studies have shown that cytokines are capable of modulating cardiovascular function and that some drugs used in the treatment of heart failure variably modulate the production of cytokines. To examine whether cardiac glycosides also modulate cytokine production, we evaluated the effects of ouabain on the production of cytokines in vitro and in vivo. Methods and Results Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured with or without ouabain in the presence or absence of lipopolysaccharide (LPS). Ouabain induced the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in PBMC and induced mRNA of these cytokines, an induction apparently at the transcriptional level. Amiloride, staurosporin, and genistein inhibited cytokine production, and protein kinase C and tyrosine kinase appeared to be involved in the modulation of cytokine production induced by ouabain. However, when PBMC were stimulated with LPS, ouabain suppressed the production of IL-6 and TNF-α. To investigate whether ouabain modulates cytokine production in vivo, we evaluated the effects of ouabain in LPS-treated mice. Ouabain was found to protect against LPS-induced lethal toxicity in mice and decreased circulating IL-6 and TNF-α levels in vivo. Conclusions These previously unrecognized immunomodulating effects of a cardiac glycoside may explain either the beneficial or the detrimental effects of these drugs in heart failure patients.
Duration of Chemotherapy for Advanced Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Trials
Authors: Yu Yang Soon, Martin R. Stockler, Lisa M. Askie, Michael J. Boyer
Journal: Journal of Clinical Oncology (2009)

To determine if it is preferable to extend chemotherapy beyond a standard number of cycles in patients receiving first-line chemotherapy for advanced non-small-cell lung cancer.We searched biomedical literature databases and conference proceedings for randomized controlled trials (RCTs) comparing a defined number of cycles with continuation of the same chemotherapy until disease progression, a larger defined number of cycles of identical chemotherapy, and a defined number of cycles of identical initial chemotherapy followed by additional cycles of an alternative chemotherapy. Meta-analysis was performed using the fixed effect model. The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), adverse events (AE), and health-related quality of life (HRQL).We found 13 RCTs including 3,027 patients. Extending chemotherapy improved PFS substantially (hazard ratio [HR], 0.75; 95% CI, 0.69 to 0.81; P < .00001) and OS modestly (HR, 0.92; 95% CI, 0.86 to 0.99; P = .03). Subgroup analysis revealed that effects on PFS were greater for trials extending chemotherapy with third-generation regimens rather than older regimens (HR, 0.70 interaction v 0.92 interaction; P = .003). Extending chemotherapy was associated with more frequent AE in all trials where it was reported and impaired HRQL in two of seven trials.Extending chemotherapy, particularly with a third-generation regimen, improved PFS substantially, but OS less so. Future trials should test extending treatment with more effective and/or better-tolerated agents.
Lung cancer * 2: Screening and early diagnosis of lung cancer
Authors: J L Mulshine
Journal: Thorax (2002)

Technical developments in spiral CT scanning mean that considerably smaller lung cancers can now be identified than with previous methods of detection. Only time will tell whether this enhanced capability will result in a reduction in the number of deaths from lung cancer. The implications and problems of screening for lung cancer are discussed. Screening implies a careful refinement of a range of clinical activities that must be routinely delivered in a carefully coordinated fashion to allow for the possibility of improved outcome. Critical analyses of the nuances of this process are essential if the field is to move forward.
An International Collaboration to Harmonize the Quantitative Plasma Epstein-Barr Virus DNA Assay for Future Biomarker-Guided Trials in Nasopharyngeal Carcinoma
Authors: Quynh-Thu Le, Qiang Zhang, Hongbin Cao, Ann-Joy Cheng, Benjamin A. Pinsky, Ruey-Long Hong, Joseph T. Chang, Chun-Wei Wang, Kuo-Chien Tsao, YM Dennis Lo, Nancy Lee, K. Kian Ang, Anthony T.C. Chan, K.C. Allen Chan
Journal: Clinical Cancer Research (2013)

Persistently elevated posttreatment plasma EBV DNA is a robust predictor of relapse in nasopharyngeal carcinoma (NPC). However, assay standardization is necessary for use in biomarker-driven trials. We conducted a study to harmonize the method between four centers with expertise in EBV DNA quantitation.Plasma samples of 40 patients with NPC were distributed to four centers. DNA was extracted and EBV DNA copy number was determined by real-time quantitative PCR (BamHI-W primer/probe). Centers used the same protocol but generated their own calibrators. A harmonization study was then conducted using the same calibrators and PCR master mix and validated with ten pooled samples.The initial intraclass correlations (ICC) for the first 40 samples between each center and the index center were 0.62 [95% confidence interval (CI): 0.39-0.78], 0.70 (0.50-0.83), and 0.59 (0.35-0.76). The largest variability was the use of different PCR master mixes and calibrators. Standardization improved ICC to 0.83 (0.5-0.95), 0.95 (0.83-0.99) and 0.96 (0.86-0.99), respectively, for ten archival frozen samples. For fresh plasma with spiked-in EBV DNA, correlations were more than 0.99 between the centers. At 5 EBV DNA copies per reaction or above, the coefficient of variance (CV) was less than 10% for the cycle threshold (Ct) among all centers, suggesting this concentration can be reliably used as a cutoff for defining the presence of detectable EBV DNA.Quantitative PCR assays, even when conducted in experienced clinical labs, can yield large variability in plasma EBV DNA copy numbers without harmonization. The use of common calibrators and PCR master mix can help to reduce variability.
LQT1 mutations in KCNQ1 C-terminus assembly domain suppress IKs using different mechanisms
Authors: Ademuyiwa S Aromolaran, Prakash Subramanyam, Donald D Chang, William R Kobertz, Henry M Colecraft
Journal: Cardiovascular Research (2014)

Long QT syndrome 1 (LQT1) mutations in KCNQ1 that decrease cardiac IKs (slowly activating delayed rectifier K+ current) underlie ventricular arrhythmias and sudden death. LQT1 mutations may suppress IKs by preventing KCNQ1 assembly, disrupting surface trafficking, or inhibiting gating. We investigated mechanisms underlying how three LQT1 mutations in KCNQ1 C-terminus assembly domain (R555H/G589D/L619M) decrease IKs in heterologous cells and cardiomyocytes. In Chinese hamster ovary (CHO) cells, mutant KCNQ1 + KCNE1 channels either produced no currents (G589D/L619M) or displayed markedly reduced IKs with a right-shifted voltage-dependence of activation (R555H). When co-expressed with wild-type (wt) KCNQ1, the mutant KCNQ1s displayed varying intrinsic dominant-negative capacities that were affected by auxiliary KCNE1. All three mutant KCNQ1s assembled with wt KCNQ1 as determined by fluorescence resonance energy transfer (FRET). We developed an optical quantum dot labelling assay to measure channel surface density. G589D/R555H displayed substantial reductions in surface density, which were either partially (G589D) or fully (R555H) rescued by wt KCNQ1. Unexpectedly, L619M showed no trafficking defect. In adult rat cardiomyocytes, adenovirus-expressed homotetrameric G589D/L619M + KCNE1 channels yielded no currents, whereas R555H + KCNE1 produced diminished IKs with a right-shifted voltage-dependence of activation, mimicking observations in CHO cells. In contrast to heterologous cells, homotetrameric R555H channels showed no trafficking defect in cardiomyocytes. Distinct LQT1 mutations in KCNQ1 assembly domain decrease IKs using unique combinations of biophysical and trafficking mechanisms. Functional deficits in IKs observed in heterologous cells are mostly, but not completely, recapitulated in adult rat cardiomyocytes. A 'methodological chain' combining approaches in heterologous cells and cardiomyocytes provides mechanistic insights that may help advance personalized therapy for LQT1 mutations.
Two in five practices have expressed an interest in commissioning
Authors: Adrian O'Dowd
Journal: BMJ (2006)

Official figures show that GPs in England are still far from committed to the system of practice based commissioning that lets them decide which health services to buy for their patients.

Less than half (41%) of general practices in England have signed up to practice based commissioning more than a year after it began, show figures released last week by the Department of Health.

The government hailed the figures as promising, but the BMA has questioned them and said that signing up to the system was not the same as actually using it.

Since April last year practices have …