tbuckley/cabot-search huggingface dataset:
Correlates and Long-Term Outcomes of Angiographically Proven Stent Thrombosis With Sirolimus- and Paclitaxel-Eluting Stents
Authors: Pramod K. Kuchulakanti, William W. Chu, Rebecca Torguson, Patrick Ohlmann, Seung-Woon Rha, Leonardo C. Clavijo, Sang-Wook Kim, Ahn Bui, Natalie Gevorkian, Zhenyi Xue, Kimberly Smith, Jana Fournadjieva, William O. Suddath, Lowell F. Satler, Augusto D. Pichard, Kenneth M. Kent, Ron Waksman
Journal: Circulation (2006)

Stent thrombosis (ST) is a serious complication of drug-eluting stent (DES) implantation regardless of the timing (acute, subacute, or late). The correlates of ST with DES are not yet completely elucidated.From a total cohort of 2974 consecutive patients treated with DES since April 2003, we identified 38 patients who presented with angiographic evidence of ST (1.27%). The ST occurred acutely in 5 patients, subacutely (< or =30 days) in 25 patients, and late (>30 days) in 8 patients. The clinical, angiographic, and procedural variables of these patients were compared with the remaining 2936 consecutive patients who underwent DES implantation and did not experience ST during a follow-up of 12 months. Logistic regression analysis was conducted to determine the correlates of ST. Compared with patients without ST, patients with ST had a higher frequency of diabetes, acute postprocedural renal failure, and chronic renal failure. There were more bifurcation lesions, type C lesions, and a trend for smaller-diameter stents. Discontinuation of clopidogrel was higher in these patients (36.8% versus 10.7%; P<0.0001). The mean duration to ST from the stent implantation was 8.9+/-8.5 days in subacute and 152.7+/-100.4 days in late thrombosis cases. Mortality was significantly higher in patients with ST compared with those without ST at 6 months (31% versus 3%; P<0.001). Multivariate analysis detected cessation of clopidogrel therapy, renal failure, bifurcation lesions, and in-stent restenosis as significant correlates of ST (P<0.05).ST continues to be a serious complication of contemporary DES use. Careful management is warranted in patients with renal failure and in those undergoing treatment for in-stent restenosis and bifurcations. Special focus on clopidogrel compliance may minimize the incidence of ST after DES implantation.
Multicenter Study Using Paraffin-Embedded Tumor Tissue Testing <i>PITX2</i> DNA Methylation As a Marker for Outcome Prediction in Tamoxifen-Treated, Node-Negative Breast Cancer Patients
Authors: Nadia Harbeck, Inko Nimmrich, Arndt Hartmann, Jeffrey S. Ross, Tanja Cufer, Robert Grützmann, Glen Kristiansen, Angelo Paradiso, Oliver Hartmann, Astrid Margossian, John Martens, Ina Schwope, Antje Lukas, Volkmar Müller, Karin Milde-Langosch, Jörg Nährig, John Foekens, Sabine Maier, Manfred Schmitt, Ralf Lesche
Journal: Journal of Clinical Oncology (2008)

We recently reported DNA methylation of the paired-like homeodomain transcription factor 2 (PITX2) gene to be strongly correlated with increased risk of recurrence in node-negative, hormone receptor-positive, tamoxifen-treated breast cancer patients using fresh frozen specimens. Aims of the present study were to establish determination of PITX2 methylation for routine analysis in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue and to test PITX2 DNA methylation as a biomarker for outcome prediction in an independent patient cohort.Real-time polymerase chain reaction (PCR) technology was validated for FFPE tissue by comparing methylation measurements in FFPE specimens with those in fresh frozen specimens from the same tumor. The impact of PITX2 methylation on time to distant metastasis was then evaluated in FFPE specimens from hormone receptor-positive, node-negative breast cancer patients (n = 399, adjuvant tamoxifen monotherapy).Reproducibility of the PCR assay in replicate measurements (r(s) > or = 0.95; n = 150) and concordant measurements between fresh frozen and FFPE tissues (r(s) = 0.81; n = 89) were demonstrated. In a multivariate model, PITX2 methylation added significant information (hazard ratio = 2.35; 95% CI, 1.20 to 4.60) to established prognostic factors (tumor size, grade, and age).PITX2 methylation can be reliably assessed by real-time PCR technology in FFPE tissue. Together with our earlier studies, we have accumulated substantial evidence that PITX2 methylation analysis holds promise as a practical assay for routine clinical use to predict outcome in node-negative, tamoxifen-treated breast cancer, which might allow, based on future validation studies, the identification of low-risk patients who may be treated by tamoxifen alone.
Prevalence of sleep apnoea and snoring in hypertensive men: a population based study
Authors: C Sjostrom
Journal: Thorax (2002)

<b>Background:</b> Several studies have reported an association between sleep disordered breathing (SDB) and hypertension (HT) but there is still a debate as to whether this is an effect of confounders. Some researchers have found an age dependent relationship between SDB and HT with higher risk at lower ages. A case-control study was performed in hypertensive men and non-hypertensive male controls matched for age and body mass index to assess whether there is an independent association between SDB and HT. If so, we further wanted to investigate whether this effect is age dependent. <b>Methods:</b> An overnight sleep study was performed in a population based, age stratified sample of 102 hypertensive men aged 43–82 years and 102 non-hypertensive controls. <b>Results:</b> Hypertensive subjects had a significantly higher prevalence of SDB than non-hypertensive subjects (apnoea-hypopnoea index (AHI): 10.8 <i>v</i> 7.3; desaturation index (DI): 8.5 <i>v</i> 5.2; AHI ≥10: 37% <i>v</i> 24%, p&lt;0.05; DI ≥10: 29% <i>v</i> 12%; lowest desaturation: mean (SD) 81.9 (7.3) <i>v</i> 84.7 (6.1), p&lt;0.01). After adjusting for neck circumference and physical inactivity, DI ≥10 and lowest desaturation were still independent predictors of HT with adjusted odds ratios of 2.3 (95% CI 1.0 to 5.3) and 0.94 (95% CI 0.89 to 0.99), respectively. When the subjects were split into two groups according to age (&lt;60 and ≥60 years), the influence of DI ≥10 on HT was strongest in the younger men (adjusted OR 4.3 (95% CI 1.0 to 19.3 <i>v</i> 2.1 (95% CI 0.7 to 6.5)) and the association between minimum oxygen saturation (Sao<sub>2</sub>) and HT reached statistical significance in the younger men only. <b>Conclusion:</b> SDB is more prevalent in men with HT than in controls. DI ≥10 and lowest desaturation are independent predictors of HT irrespective of confounders. The results indicate that the influence of SDB on HT is more pronounced in younger and middle aged men than in those above 60 years.
CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors
Authors: Sergey V. Shmelkov, Jason M. Butler, Andrea T. Hooper, Adilia Hormigo, Jared Kushner, Till Milde, Ryan St. Clair, Muhamed Baljevic, Ian White, David K. Jin, Amy Chadburn, Andrew J. Murphy, David M. Valenzuela, Nicholas W. Gale, Gavin Thurston, George D. Yancopoulos, Michael D’Angelica, Nancy Kemeny, David Lyden, Shahin Rafii
Journal: Journal of Clinical Investigation (2008)

Colon cancer stem cells are believed to originate from a rare population of putative CD133+ intestinal stem cells. Recent publications suggest that a small subset of colon cancer cells expresses CD133, and that only these CD133+ cancer cells are capable of tumor initiation. However, the precise contribution of CD133+ tumor-initiating cells in mediating colon cancer metastasis remains unknown. Therefore, to temporally and spatially track the expression of CD133 in adult mice and during tumorigenesis, we generated a knockin lacZ reporter mouse (CD133lacZ/+), in which the expression of lacZ is driven by the endogenous CD133 promoters. Using this model and immunostaining, we discovered that CD133 expression in colon is not restricted to stem cells; on the contrary, CD133 is ubiquitously expressed on differentiated colonic epithelium in both adult mice and humans. Using Il10-/-CD133lacZ mice, in which chronic inflammation in colon leads to adenocarcinomas, we demonstrated that CD133 is expressed on a full gamut of colonic tumor cells, which express epithelial cell adhesion molecule (EpCAM). Similarly, CD133 is widely expressed by human primary colon cancer epithelial cells, whereas the CD133- population is composed mostly of stromal and inflammatory cells. Conversely, CD133 expression does not identify the entire population of epithelial and tumor-initiating cells in human metastatic colon cancer. Indeed, both CD133+ and CD133- metastatic tumor subpopulations formed colonospheres in in vitro cultures and were capable of long-term tumorigenesis in a NOD/SCID serial xenotransplantation model. Moreover, metastatic CD133- cells form more aggressive tumors and express typical phenotypic markers of cancer-initiating cells, including CD44 (CD44+CD24-), whereas the CD133+ fraction is composed of CD44lowCD24+ cells. Collectively, our data suggest that CD133 expression is not restricted to intestinal stem or cancer-initiating cells, and during the metastatic transition, CD133+ tumor cells might give rise to the more aggressive CD133(- )subset, which is also capable of tumor initiation in NOD/SCID mice.
Is Pubertal Onset a Risk Factor for Blindness and Renal Replacement Therapy in Childhood-Onset Type 1 Diabetes in Japan?
Authors: Aya Morimoto, Rimei Nishimura, Toru Matsudaira, Hironari Sano, Naoko Tajima
Journal: Diabetes Care (2007)

We previously reported that mortality is worse for pubertal-onset type 1 diabetes than for the prepubertal-onset variety (1). Other studies have disparately reported that the risk for incipient microangiopathy in type 1 diabetic patients is higher during puberty than before puberty (2–4) or that the risk is similar (5,6). However, evidence regarding the relationship between puberty and advanced microangiopathy is limited (7). We therefore investigated the incidence of blindness and renal replacement therapy (RRT) by pubertal status at diagnosis.

A total of 1,408 type 1 diabetic patients diagnosed at <18 years of age were placed on insulin therapy within 1 month of diagnosis. They were chosen from two nationwide type 1 diabetes surveys (1,8,9). The patients were either 1 ) diagnosed between 1965 and 1969 and alive as of 1 January 1970 (the 1960s cohort) or 2 ) diagnosed between 1970 and 1979 and alive as of 1 January 1980 (the 1970s cohort). Follow-up for the 1960s and 1970s cohorts was initiated on 1 January in 1970 or 1980, respectively. Diagnosis in males aged ≥12 years and females aged ≥11 years was defined as pubertal onset, as earlier reported (1,2,5,9–11). The cohorts accounted for ∼75% of all type 1 diabetic subjects in Japan (1,8,12).

Status of blindness and …
Faecal elastase 1 Reply
Authors: S. T AMANN, P. P TOSKES, C. LOSER, A MOLLGAARD, U R FOLSCH
Journal: Gut (1997)

Editor,—I read with interest a recent study by Loser et al ( Gut 1996; 39: 580–6). This detailed and well designed study compares a new tubeless test of pancreatic function, faecal pancreatic elastase 1 (FPE1) assay, against the secretin test which is the accepted gold standard pancreatic function test. It had very good sensitivity and specificity for pancreatic insufficiency, confirmed by the secretin test and the presence of steatorrhoea. The FPE1 assay in mild chronic pancreatitis, abnormal function but no steatorrhoea, had a much lower sensitivity of 63%. These results are not entirely different from our pilot study.1 The majority (nine of 14) of our chronic pancreatitis subjects were diagnosed by the secretin test and not anatomical/radiographic criteria only. The other five subjects without a secretin test had chronic pancreatitis …
Enteral supplementation with ornithine alpha ketoglutarate improves the early adaptive response to resection.
Authors: B Czernichow, E Nsi-Emvo, M Galluser, F Gosse, F Raul
Journal: Gut (1997)

BACKGROUND: Polyamine synthesis or uptake, or both, might be an important event that initiates the adaptive hyperplasia seen in the intestinal remnant after partial small bowel resection. AIM: The ability of an enteral diet supplemented with the ornithine salt: ornithine alpha ketoglutarate (OKG), a precursor for polyamine synthesis, to modulate the adaptive response of the remnant ileum after jejunectomy was evaluated. METHODS: Adult Wistar rats underwent a resection of the proximal 50% of the small intestine. Controls underwent a single transection. The rats were fed intragastrically with a nutritive mixture supplemented either with casein hydrolysate or with OKG (1 g/kg). The isoenergetic and isonitrogeneous diets was given continuously for seven days. RESULTS: Villus and crypt hyperplasia was observed in the remnant ileum compared with transfected controls. OKG supplementation started after resection a further increase in villus height. After resection, OKG supplementation increased significantly the putrescine content and the amount of ornithine decarboxylase mRNA. A twofold to threefold increase of sucrase activity was measured in the resected animals compared with the transected rats. In contrast, the amount of sucrase mRNA was significantly lower in the ileum of the resected rats and OKG supplementation initiated a further drop in the amount of sucrase mRNA without pronounced changes in enzyme activity. CONCLUSIONS: The adaptive hypertrophy seen after resection can be accelerated by supplementing the diet with ornithine (OKG) a precursor of polyamine synthesis. In the remnant ileum, the reduced amount of sucrase mRNA, despite the increased level of sucrase activity, suggests a post-translational control of sucrase expression.
Models of complexity: The example of emotions
Authors: Catherine Belzung, Catherine Chevalley
Journal: Behavioral and Brain Sciences (2001)

Using the example of the difficulties which emerge when trying to model complex behaviors – such as emotional expression – that result from stochastic interactions between different components, we argue that biorobotics may well describe one possible evolution of certain features of a biological system, but cannot pretend to be a simulation of the whole behavior of the system.
Quantitative Analysis of Cell-Free Epstein-Barr Virus DNA in Plasma of Patients with Nonnasopharyngeal Head and Neck Carcinomas
Authors: Kwok Hung Yu, Y. M. Dennis Lo, Gary M. Tse, K. C. Allen Chan, Amy B. W. Chan, Katherine C. K. Chow, Tony K. F. Ma, Alexander C. Vlantis, Sing Fai Leung, C. Andrew van Hasselt, Philip J. Johnson, Anthony T. C. Chan
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We investigated the detectability of EBV DNA in the plasma of patients with non-nasopharyngeal head and neck carcinomas (NNHNC). Previous studies have shown that EBV is present in the tumor tissue of some NNHNC. Experimental Design: We recruited 101 patients with NNHNC and 48 healthy controls. Blood samples were taken from controls and patients before treatment. Tumor tissue samples were tested for the presence of EBV in the first 69 patients by in situ hybridization for small EBV-encoded RNA (EBER). Plasma EBV DNA was measured by real-time quantitative PCR in patients and controls. Results: Squamous cell carcinoma (SCC) was the commonest histology (78 patients) followed by lymphoepithelial carcinoma (8 patients). EBER was detected in tumor cells in 7 of 69 patients tested. All of the EBER-positive tumors were lymphoepithelial carcinoma. Two controls (2 of 48; 4.2%) had detectable plasma EBV DNA. Plasma EBV DNA was detected in all of the patients with EBER-positive tumors, and in 23 of 94 (24.5%) patients with tumors of EBER-negative or unknown status. The proportion of plasma EBV DNA-positive cases in either group was significantly higher than that in the control group (P &amp;lt; 0.0027). Plasma EBV DNA concentrations in patients with EBER-positive tumors (median, 3827 copies/ml) were significantly higher than those in the controls (median, 0 copy/ml; P = 0.0001). Of patients with SCC, 21 (26.9%) had detectable plasma EBV DNA (median concentration, 34 copies/ml). Plasma EBV DNA concentrations in the whole group of patients with SCC (median, 0 copy/ml; interquartile range, 0–4 copies/ml) were also significantly higher than those in the controls (P = 0.001). Conclusions: Our data indicate that plasma EBV DNA reflects tumoral EBER status, and it may be of use as a tumor marker for EBER-positive NNHNC. The biological and clinical significance of low levels of circulating EBV DNA in the minority of patients with EBER-negative tumors remain to be elucidated.
Importance of integrin LFA-1 deactivation for the generation of immune responses
Authors: Monika Semmrich, Andrew Smith, Carolin Feterowski, Sandra Beer, Britta Engelhardt, Dirk H. Busch, Bernadett Bartsch, Melanie Laschinger, Nancy Hogg, Klaus Pfeffer, Bernhard Holzmann
Journal: The Journal of Experimental Medicine (2005)

The dynamic regulation of ligand binding is considered crucial for integrin function. However, the importance of activity regulation for integrin function in vivo is largely unknown. Here, we have applied gene targeting to delete the GFFKR sequence of the lymphocyte function-associated antigen–1 (LFA-1) αL subunit cytoplasmic domain in mouse germline. Lymphocytes from Lfa-1d/d mutant mice showed constitutive activation of LFA-1–mediated cell adhesion and impaired de-adhesion from intercellular adhesion molecule-1 that resulted in defective cell migration. In contrast, signaling through LFA-1 was not affected in Lfa-1d/d cells. T cell activation by superantigen-loaded and allogeneic APCs, cytotoxic T cell activity, T-dependent humoral immune responses, and neutrophil recruitment during aseptic peritonitis were impaired in Lfa-1d/d mice. Thus, deactivation of LFA-1 and disassembly of LFA-1–mediated cell contacts seem to be vital for the generation of normal immune responses.
Obesity and the lung: 3 {middle dot} Obesity, respiration and intensive care
Authors: A Malhotra, D Hillman
Journal: Thorax (2008)

Obesity is a major problem from a public health perspective and a difficult practical matter for intensivists. The obesity pandemic has required treating clinicians to develop an appreciation of the substantial pathophysiological effects of obesity on the various organ systems. The important physiological concepts are illustrated by focusing on obstructive sleep apnoea, obesity hypoventilation syndrome, abdominal compartment syndrome and ventilatory management of the obese patient with acute respiratory distress syndrome.
Defective A20 signalling in CF: Anti-inflammatory action of gibberellins
Authors: Catriona Kelly, James Reihill, Beth Malconsom, Agnieszka Czerwiec, Burkhard Hirsch, Stuart Elborn, Madeleine Ennis, Bettina Schock
Journal: European Respiratory Journal (2013)

Introduction: A20 negatively regulates NF-κB signalling and is induced in response to bacteria or viruses. Recently, we reported significant reductions in the expression/function of A20 in the CF airway epithelium (Kelly et al. ERJ 2012). The plant diterpene Gibberellin (GA) induces A20-like zinc fingers in plants and has anti-inflammatory properties in mammals. However the anti-inflammatory mechanism has not been described. We hypothesized that GA works via an A20-dependent mechanism and examined the effects on airways inflammation in CF.  Methods: Human bronchial epithelial cell lines (16HBE14o- and CFBE41o-) and Primary Nasal Epithelial cells (NECs) from healthy volunteers were used. Cells were pre-incubated with GA, (30µM, 1h) and stimulated with P. aeruginosa LPS (10µg/ml). Effects of GA on cytotoxicity (MTT) and proliferation (CellTiter 96 Proliferation Assay) were examined. IL-8 was measured by ELISA. A20 and p65 mRNA and protein expression was measured by qPCR and Western Blot. A20 was silenced in 16HBE14o- cells using siRNA.  Results: 30µM GA did not increase cytotoxicity or cellular proliferation in any cell type. Pre-incubation with GA significantly induced A20 mRNA and protein expression in LPS-stimulated cells (16HBE14o-, CFBE41o- and NECs). A20 induction was accompanied by a reduction in IL-8 release and p65 expression. The anti-inflammatory effect (IL-8 release) of GA was lost in 16HBE14o- cells treated with A20 siRNA.  Conclusions: GA exerts anti-inflammatory effects in airway epithelial cells. Work is on-going in CF NECs. Initial investigations suggest that the anti-inflammatory effect of GA is A20-dependent. GA may therefore overcome defective A20 signalling in CF airways disease.
Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin
Authors: Samantha L. Bowker, Sumit R. Majumdar, Paul Veugelers, Jeffrey A. Johnson
Journal: Diabetes Care (2006)

OBJECTIVE—Numerous studies have identified an increased risk of cancer in type 2 diabetes. We explored the association between antidiabetic therapies and cancer-related mortality in patients with type 2 diabetes, postulating that agents that increase insulin levels might promote cancer. RESEARCH DESIGN AND METHODS—This was a population-based cohort study using administrative databases from Saskatchewan Health. Cancer-related mortality was compared among inception cohorts of metformin users and sulfonylurea monotherapy users. Multivariate Cox regression was used to estimate the hazard ratio (HR) of cancer-related mortality, after adjusting for age, sex, insulin use, and chronic disease score. All statistical tests were two-sided. RESULTS—We identified 10,309 new users of metformin or sulfonylureas with an average follow-up of 5.4 ± 1.9 years (means ± SD). The mean age for the cohort was 63.4 ± 13.3 years, and 55% were men. Cancer mortality over follow-up was 4.9% (162 of 3,340) for sulfonylurea monotherapy users, 3.5% (245 of 6,969) for metformin users, and 5.8% (84 of 1,443) for subjects who used insulin. After multivariate adjustment, the sulfonylurea cohort had greater cancer-related mortality compared with the metformin cohort (adjusted HR 1.3 [95% CI 1.1–1.6]; P = 0.012). Insulin use was associated with an adjusted HR of cancer-related mortality of 1.9 (95% CI 1.5–2.4; P &amp;lt; 0.0001). CONCLUSIONS—Patients with type 2 diabetes exposed to sulfonylureas and exogenous insulin had a significantly increased risk of cancer-related mortality compared with patients exposed to metformin. It is uncertain whether this increased risk is related to a deleterious effect of sulfonylurea and insulin or a protective effect of metformin or due to some unmeasured effect related to both choice of therapy and cancer risk.
Role of Protein Methylation in Regulation of Transcription
Authors: David Y. Lee, Catherine Teyssier, Brian D. Strahl, Michael R. Stallcup
Journal: Endocrine Reviews (2005)

In the last few years, the discovery of lysine and arginine methylation in histones and other proteins and the enzymes that carry out these posttranslational modifications has added a new dimension to the signal transduction field. In particular, there has been a huge surge in our understanding of how methylation of nucleosomal histones at specific lysine or arginine residues affects chromatin conformations and either facilitates or inhibits transcription from neighboring genes. It appears that the responsible methyltransferases can be targeted in some cases to specific genes and in other cases to broader regions of euchromatin or heterochromatin. Methylation of histones is mechanistically linked to other types of histone modifications, such as acetylation, phosphorylation, and monoubiquitylation; combinations of these modifications cooperate to regulate chromatin structure and transcription by stimulating or inhibiting binding of specific proteins. Although lysine methylation has thus far been observed almost exclusively on histones, arginine methylation has been observed on a variety of other proteins associated with gene regulation, including DNA-binding transcriptional activators, transcriptional coactivators, and many RNA binding proteins involved in RNA processing, transport, and stability. Thus, lysine and arginine methylation of proteins, like many other types of posttranslational modifications, are regulated steps of many specific signaling pathways.