tbuckley/cabot-search huggingface dataset:
Childhood Vaccination and Type 1 Diabetes
Authors: Anders Hviid, Michael Stellfeld, Jan Wohlfahrt, Mads Melbye
Journal: New England Journal of Medicine (2004)

A link between childhood vaccinations and the development of type 1 diabetes has been proposed.We evaluated a cohort comprising all children born in Denmark from January 1, 1990, through December 31, 2000, for whom detailed information on vaccinations and type 1 diabetes was available. Using Poisson regression models, we estimated rate ratios according to vaccination status, including the trend associated with the number of doses, among all children and in a subgroup of children who had siblings with type 1 diabetes. Given recent claims of clustering of cases of diabetes two to four years after vaccination, we also estimated rate ratios during the period after vaccination.Type 1 diabetes was diagnosed in 681 children during 4,720,517 person-years of follow-up. The rate ratio for type 1 diabetes among children who received at least one dose of vaccine, as compared with unvaccinated children, was 0.91 (95 percent confidence interval, 0.74 to 1.12) for Haemophilus influenzae type b vaccine; 1.02 (95 percent confidence interval, 0.75 to 1.37) for diphtheria, tetanus, and inactivated poliovirus vaccine; 0.96 (95 percent confidence interval, 0.71 to 1.30) for diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine; 1.06 (95 percent confidence interval, 0.80 to 1.40) for whole-cell pertussis vaccine; 1.14 (95 percent confidence interval, 0.90 to 1.45) for measles, mumps, and rubella vaccine; and 1.08 (95 percent confidence interval, 0.74 to 1.57) for oral poliovirus vaccine. The development of type 1 diabetes in genetically predisposed children (defined as those who had siblings with type 1 diabetes) was not significantly associated with vaccination. Furthermore, there was no evidence of any clustering of cases two to four years after vaccination with any vaccine.These results do not support a causal relation between childhood vaccination and type 1 diabetes.
Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab
Authors: Alessandra Magnifico, Luisa Albano, Stefano Campaner, Domenico Delia, Fabio Castiglioni, Patrizia Gasparini, Gabriella Sozzi, Enrico Fontanella, Sylvie Menard, Elda Tagliabue
Journal: Clinical Cancer Research (2009)

The existence of tumor-initiating cells in breast cancer has profound implications for cancer therapy. In this study, we investigated the sensitivity of tumor-initiating cells isolated from human epidermal growth factor receptor type 2 (HER2)-overexpressing carcinoma cell lines to trastuzumab, a compound used for the targeted therapy of breast cancer.Spheres were analyzed by indirect immunofluorescence for HER2 cell surface expression and by real-time PCR for HER2 mRNA expression in the presence or absence of the Notch1 signaling inhibitor (GSI) or Notch1 small interfering RNA. Xenografts of HER2-overexpressing breast tumor cells were treated with trastuzumab or doxorubicin. The sphere-forming efficiency (SFE) and serial transplantability of tumors were assessed.In HER2-overexpressing carcinoma cell lines, cells with tumor-initiating cell properties presented increased HER2 levels compared with the bulk cell population without modification in HER2 gene amplification. HER2 levels were controlled by Notch1 signaling, as shown by the reduction of HER2 cell surface expression and lower SFE following gamma-secretase inhibition or Notch1 specific silencing. We also show that trastuzumab was able to effectively target tumor-initiating cells of HER2-positive carcinoma cell lines, as indicated by the significant decrease in SFE and the loss of serial transplantability, following treatment of HER2-overexpressing xenotransplants.Here, we provide evidence for the therapeutic efficacy of trastuzumab in debulking and in targeting tumor-initiating cells of HER2-overexpressing tumors. We also propose that Notch signaling regulates HER2 expression, thereby representing a critical survival pathway of tumor-initiating cells.
Involvement of the peripheral nervous system in primary Sjögren's syndrome
Authors: P J Barendregt, M J van den Bent, V J M van Raaij-van den Aarssen, A H van den Meiracker, Ch J Vecht, G L van der Heijde, H M Markusse
Journal: Annals of the Rheumatic Diseases (2001)

Involvement of the peripheral nervous system in patients with primary Sjögren's syndrome (SS) has been reported, but its prevalence in neurologically asymptomatic patients is not well known.To assess clinical and neurophysiological features of the peripheral nervous system in patients with primary SS.39 (38 female) consecutive patients with primary SS, aged 20-81 years (mean 50), with a disease duration of 1-30 years (mean 8) were studied. The peripheral nervous system was evaluated by a questionnaire, physical examination, quantified sensory neurological examination, and neurophysiological measurements (nerve conduction studies). To assess autonomic cardiovascular function an orthostatic challenge test, a Valsalva manoeuvre, a forced respiration test, and pupillography were done.Abnormalities as indicated in the questionnaire were found in 8/39 (21%) patients, while an abnormal neurological examination was found in 7/39 (18%) patients. Abnormalities in quantified sensory neurological examination were found in 22/38 (58%) patients. In 9/39 (23%) patients, neurophysiological signs compatible with a sensory polyneuropathy were found. No differences were found in the autonomic test results, disease duration, serological parameters, or erythrocyte sedimentation rate between the patients with primary SS with and those without evidence of peripheral nervous involvement.Subclinical abnormalities of the peripheral nervous system may occur in patients with primary SS selected from a department of rheumatology, but clinically relevant involvement of the peripheral nervous system in this patient group is rare.
A Randomized Trial of Direct Mailing of Fecal Occult Blood Tests To Increase Colorectal Cancer Screening
Authors: T. R. Church, M. W. Yeazel, R. M. Jones, L. K. Kochevar, G. D. Watt, S. J. Mongin, J. E. Cordes, D. Engelhard
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Although colorectal cancer screening by using a fecal occult blood test (FOBT), flexible sigmoidoscopy, colonoscopy, or barium enema x-ray reduces the incidence of and death from colorectal cancer, the rate of colorectal cancer screening in the general population is low. We conducted a randomized trial consisting of direct mailing of FOBT kits to increase colorectal cancer screening among residents of Wright County, Minnesota, a community in which colorectal cancer screening was promoted. Methods: At baseline, we mailed a questionnaire about colorectal cancer screening to a random sample of Wright County residents aged 50 years or older who were randomly selected from the Minnesota State Driver’s License and Identification Card database (estimated N = 1451). The sample was randomly allocated into three equal subgroups: one group (control) received only the questionnaire, one group received FOBT kits by direct mail with reminders, and one group received FOBT kits by direct mail without reminders. Study participants were sent a follow-up questionnaire 1 year after baseline. We used the responses to the questionnaires to estimate the 1-year change in self-reported screening rates in each group and the differences in the changes among the groups, along with the associated bootstrap 95% confidence intervals (CIs). Results: At baseline, the estimated response rate was 86.5%, self-reported adherence to FOBT guidelines was 21.5%, and overall adherence to any colorectal cancer screening test guidelines was 55.8%. The 1-year rate changes in absolute percentage for self-reported adherence to FOBT use were 1.5% (95% CI = –2.9% to 5.9%) for the control group, 16.9% (95% CI = 11.5% to 22.3%) for the direct-mail-FOBT-with-no-reminders group, and 23.2% (95% CI = 17.2% to 29.3%) for the direct-mail-FOBT-with-reminders group. The 1-year rate changes for self-reported adherence to any colorectal cancer screening test were 7.8% (95% CI = 3.2% to 12.0%) for the control group, 13.2% (95% CI = 8.4% to 18.2%) for the direct-mail-FOBT-with-no-reminders group, and 14.1% (95% CI = 9.1% to 19.1%) for the direct-mail-FOBT-with-reminders group. Conclusion: Direct mailing of FOBT kits combined with follow-up reminders promotes more rapid increases in the use of FOBT and nearly doubles the increase in overall rate of adherence to colorectal cancer screening guidelines in a general population compared with a community-wide screening promotion and awareness campaign.
Essential Role of PDGFRα-p70S6K Signaling in Mesenchymal Cells During Therapeutic and Tumor Angiogenesis In Vivo
Authors: Norifumi Tsutsumi, Yoshikazu Yonemitsu, Yasunori Shikada, Mitsuho Onimaru, Mitsugu Tanii, Shinji Okano, Kazuhiro Kaneko, Mamoru Hasegawa, Makoto Hashizume, Yoshihiko Maehara, Katsuo Sueishi
Journal: Circulation Research (2004)

Discovery of the common and ubiquitous molecular targets for the disruption of angiogenesis, that are independent of the characteristics of malignant tumors, is desired to develop the more effective antitumor drugs. In this study, we propose that the platelet-derived growth factor receptor-α (PDGFRα)-p70S6K signal transduction pathway in mesenchymal cells, which is required for functional angiogenesis induced by fibroblast growth factor-2, is the potent candidate. Using murine limb ischemia as a tumor-free assay system, we demonstrated that p70S6K inhibitor rapamycin (RAPA) targets mesenchymal cells to shut down the sustained expression of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), via silencing of the PDGFRα-p70S6K pathway. Irrespective of the varied expression profiles of angiogenic factors in each tumor tested, RAPA constantly led the tumors to dormancy and severe ischemia in the time course, even associated with upregulated expression of VEGF from tumors. Because RAPA showed only a minimal effect to hypoxia-related expression of VEGF in culture, these results suggest that RAPA targets the host-vasculature rather than tumor itself in vivo. Thus, our current study indicates that the PDGFRα-p70S6K pathway is an essential regulator for FGF-2–mediated therapeutic neovascularization, as well as for the host-derived vasculature but not tumors during tumor angiogenesis, via controlling continuity of expression of multiple angiogenic growth factors.
Mechanisms of intron gain and loss in Cryptococcus
Authors: Thomas J Sharpton, Daniel E Neafsey, James E Galagan, John W Taylor
Journal: Genome biology (2008)

Genome comparisons across deep phylogenetic divergences have revealed that spliceosomal intron gain and loss are common evolutionary events. However, because of the deep divergences involved in these comparisons, little is understood about how these changes occur, particularly in the case of intron gain. To ascertain mechanisms of intron gain and loss, we compared five relatively closely related genomes from the yeast Cryptococcus. We observe a predominance of intron loss over gain and identify a relatively slow intron loss rate in Cryptococcus. Some genes preferentially lose introns and a large proportion of intron losses occur in the middle of genes (so called internal intron loss). Finally, we identify a gene that displays a differential number of introns in a repetitive DNA region. Based the observed patterns of intron loss and gain, population resequencing and population genetic analysis, it appears that recombination causes the widely observed but poorly understood phenomenon of internal intron loss and that DNA repeat expansion can create new introns in a population.
Reconstructing the Ancestral Germ Line Methylation State of Young Repeats
Authors: L. Feuerbach, R. B. Lyngso, T. Lengauer, J. Hein
Journal: Molecular Biology and Evolution (2011)

One of the key objectives of comparative genomics is the characterization of the forces that shape genomes over the course of evolution. In the last decades, evidence has been accumulated that for vertebrate genomes also epigenetic modifications have to be considered in this context. Especially, the elevated mutation frequency of 5-methylcytosine (5mC) is assumed to facilitate the depletion of CpG dinucleotides in species that exhibit global DNA methylation. For instance, the underrepresentation of CpG dinucleotides in many mammalian genomes is attributed to this effect, which is only neutralized in so-called CpG islands (CGIs) that are preferentially unmethylated and thus partially protected from rapid CpG decay. For primate-specific CpG-rich transposable elements from the ALU family, it is unclear whether their elevated CpG frequency is caused by their small age or by the absence of DNA methylation. In consequence, these elements are often misclassified in CGI annotations. We present a method for the estimation of germ line methylation from pairwise ancestral-descendant alignments. The approach is validated in a simulation study and tested on DNA repeats from the AluSx family. We conclude that a predicted unmethylated state in the germ line is highly correlated with epigenetic activity of the respective genomic region. Thus, CpG-rich repeats can be facilitated as in silico probes for the epigenetic potential of their genomic neighborhood.
In vivo evidence of enhanced guanylyl cyclase activation during the hyperdynamic circulation of acute liver failure
Authors: Francis Schneider, Philippe Lutun, Karim Boudjema, Philippe Wolf, Jean-Daniel Tempé
Journal: Hepatology (1994)

Nitric oxide and atrial natriuretic peptides are the main activators of guanylyl cyclases, which transform GTP into cyclic GMP and thereby contribute to the decrease of vascular tone. To investigate the increase, if any, of plasma cyclic GMP concentrations in human patients with hyperdynamic circulation resulting from acute liver failure and to ascertain whether guanylyl cyclase activation is involved in the decline of systemic vascular resistance that occurs in this pathophysiological condition, we simultaneously recorded hemodynamic data and cyclic GMP levels in patients with fulminant liver failure before and after liver transplantation and in normokinetic patients undergoing abdominal nonseptic surgery. We also compared these data with those recorded in patients with hyperkinetic shock resulting from gram-negative sepsis or nitric oxide-independent vasomotor agent (carbamate) over-dose. In all these patients we simultaneously studied kidney function, platelet counts and atrial natriuretic peptides. Patients with fulminant liver failure had higher cyclic GMP concentrations than did control patients undergoing abdominal surgery (11.02 +/- 1.55 pmol.ml-1 vs. 1.77 +/- 0.18 pmol.ml-1, p < 0.001). At similar heart-loading conditions these concentrations were lower than those in gram-negative septic shock (18.2 +/- 1.35 pmol.ml-1, p < 0.05) but higher than those in carbamate-induced shock (3.6 +/- 0.7 pmol.ml-1, p < 0.01). In addition, cyclic GMP concentrations significantly decreased from the fulminant liver failure period to the posttransplantation period, although atrial natriuretic peptide levels did not change significantly and kidney function worsened.(ABSTRACT TRUNCATED AT 250 WORDS)
Indoleamine 2,3-Dioxygenase Serves as a Marker of Poor Prognosis in Gene Expression Profiles of Serous Ovarian Cancer Cells
Authors: Aikou Okamoto, Takashi Nikaido, Kazunori Ochiai, Satoshi Takakura, Misato Saito, Yuko Aoki, Nobuya Ishii, Nozomu Yanaihara, Kyosuke Yamada, Osamu Takikawa, Rie Kawaguchi, Seiji Isonishi, Tadao Tanaka, Mitsuyoshi Urashima
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We aimed to find key molecules associated with chemoresistance in ovarian cancer using gene expression profiling as a screening tool. Experimental Design: Using two newly established paclitaxel-resistant ovarian cancer cell lines from an original paclitaxel-sensitive cell line and four supersensitive and four refractory surgical ovarian cancer specimens from paclitaxel-based chemotherapy, molecules associated with chemoresistance were screened with gene expression profiling arrays containing 39,000 genes. We further analyzed 44 genes that showed significantly different expressions between paclitaxel-sensitive samples and paclitaxel-resistant samples with permutation tests, which were common in cell lines and patients' tumors. Results: Eight of these genes showed reproducible results with real-time reverse transcription-PCR, of which indoleamine 2,3-dioxygenase gene expression was the most prominent and consistent. Moreover, by immunohistochemical analysis using a total of 24 serous-type ovarian cancer surgical specimens (stage III, n = 21; stage IV, n = 7), excluding samples used for GeneChip analysis, the Kaplan-Meier survival curve showed a clear relationship between indoleamine 2,3-dioxygenase staining patterns and overall survival (log-rank test, P = 0.0001). All patients classified as negative survived without relapse. The 50% survival of patients classified as sporadic, focal, and diffuse was 41, 17, and 11 months, respectively. Conclusion: The indoleamine 2,3-dioxygenase screened with the GeneChip was positively associated with paclitaxel resistance and with impaired survival in patients with serous-type ovarian cancer.
Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance
Authors: Federica Sallusto, Jens Geginat, Antonio Lanzavecchia
Journal: Annual Review of Immunology (2004)

The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (T CM ) and effector memory (T EM ) cells characterized by distinct homing capacity and effector function. This review addresses the heterogeneity of T CM and T EM , their differentiation stages, and the current models for their generation and maintenance in humans and mice.
ADMA Levels Correlate with Proteinuria, Secondary Amyloidosis, and Endothelial Dysfunction
Authors: Mahmut Ilker Yilmaz, Alper Sonmez, Mutlu Saglam, Abdul R. Qureshi, Juan Jesus Carrero, Kayser Caglar, Tayfun Eyileten, Erdinc Cakir, Yusuf Oguz, Abdulgaffar Vural, Mujdat Yenicesu, Bengt Lindholm, Peter Stenvinkel, Jonas Axelsson
Journal: Journal of the American Society of Nephrology (2008)

Asymmetric dimethyl-arginine (ADMA), a residue of the proteolysis of arginine-methylated proteins, is a potent inhibitor of nitric oxide synthesis. The increased protein turnover that accompanies proteinuric secondary amyloidosis may increase circulating levels of ADMA, and this may contribute to endothelial dysfunction. We performed a cross-sectional study of 121 nondiabetic proteinuric patients with normal GFR (including 39 patients with nephrotic-range proteinuria and secondary amyloidosis) and 50 age-, sex-, and BMI-matched healthy controls. The proteinuric patients had higher levels of serum ADMA, symmetric dimethyl-arginine (SDMA), high-sensitivity C-reactive protein (hsCRP), and insulin resistance (homeostasis model assessment index) than controls. Compared with controls, brachial artery flow-mediated dilatation (FMD), serum L-Arginine, and the L-Arginine/ADMA ratio were significantly lower among proteinuric patients, suggesting greater endothelial dysfunction. When patients with secondary amyloidosis were compared with patients with glomerulonephritis who had similar levels of proteinuria, those with amyloidosis had higher ADMA and SDMA levels and lower L-Arginine/ADMA ratios and FMD measurements (P < 0.001 for all). Finally, even after adjusting for confounders, ADMA level correlated with both proteinuria and the presence of secondary amyloidosis, and was an independent predictor of FMD. We propose that ADMA synthesis may be increased in chronic kidney disease, especially in secondary amyloidosis, and this may explain part of the mechanism by which proteinuria increases cardiovascular morbidity and mortality.
Waldenström macroglobulinemia with extramedullary involvement at initial diagnosis portends a poorer prognosis
Authors: Xin Cao, Qing Ye, Robert Z. Orlowski, Xiaoxiao Wang, Sanam Loghavi, Meifeng Tu, Sheeba K. Thomas, Jatin Shan, Shaoying Li, Muzaffar Qazilbash, C. Cameron Yin, Donna Weber, Roberto N. Miranda, Zijun Y. Xu-Monette, L. Jeffrey Medeiros, Ken H. Young
Journal: Journal of Hematology & Oncology (2015)

The prognostic importance of extramedullary involvement in patients with Waldenström macroglobulinemia (WM) at diagnosis and treatment options for these patients has not been well evaluated. In this study, we investigated the clinical manifestations, biological features, and effect of first-line therapy on the outcome of WM patients diagnosed with extramedullary involvement (EMWM) vs those with only bone marrow involvement (BMWM). We analyzed the clinical data of 312 WM patients diagnosed with EMWM (n = 106) and BMWM (n = 206) at The University of Texas MD Anderson Cancer Center from 1994 to 2014. EMWM was confirmed by biopsy, positron emission tomography–computed tomography, or magnetic resonance imaging, and clinical laboratory analyses. Characteristics associated with EMWM were male sex (P = 0.027), age younger than 65 years (P = 0.048), presence of B symptoms (P < 0.001), high serum beta-2 macroglobulin (P < 0.001) level, low serum albumin level (P = 0.036), and cytogenetic abnormalities (P = 0.010). Kaplan-Meier survival analysis results showed that EMWM patients had a significantly shorter median overall survival (P < 0.001) and progression-free survival (PFS) (P < 0.001) than did BMWM patients. Chemotherapy combined with targeted therapy improved PFS for BMWM patients (P = 0.004) but not for EMWM patients. Additionally, initial treatment with rituximab significantly improved the PFS of BMWM patients (P = 0.012) but had no effect on EMWM patients. However, EMWM patients treated with nucleoside analogs attained a better PFS than those who did not (P = 0.021). We show that extramedullary involvement at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy with nucleoside analogs improved PFS for patients with EMWM. The study provides unique clinical and treatment observations in subtypes of WM patients.
Estimation of random errors in respiratory resistance and reactance measured by the forced oscillation technique
Authors: R Farre, M Rotger, D Navajas
Journal: European Respiratory Journal (1997)

The forced oscillation technique (FOT) allows the measurement of respiratory resistance (Rrs) and reactance (Xrs) and their associated coherence (gamma2). To avoid unreliable data, it is usual to reject Rrs and Xrs measurements with a gamma2 <0.95. This procedure makes it difficult to obtain acceptable data at the lowest frequencies of interest. The aim of this study was to derive expressions to compute the random error of Rrs and Xrs from gamma2 and the number (N) of data blocks involved in a FOT measurement. To this end, we developed theoretical equations for the variances and covariances of the pressure and flow auto- and cross-spectra used to compute Rrs and Xrs. Random errors of Rrs and Xrs were found to depend on the values of Rrs and Xrs, and to be proportional to ((1-gamma2)/(2 x N x gamma2))1/2. Reliable Rrs and Xrs data can be obtained in measurements with low gamma2 by enlarging the data recording (i.e. N). Therefore, the error equations derived may be useful to extend the frequency band of the forced oscillation technique to frequencies lower than usual, characterized by low coherence.
Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction
Authors: Iwan C.C van der Horst, Felix Zijlstra, Arnoud W.J van't Hof, Carine J.M Doggen, Menko-Jan de Boer, Harry Suryapranata, Jan C.A Hoorntje, Jan-Henk E Dambrink, Rijk O.B Gans, Henk J.G Bilo
Journal: Journal of the American College of Cardiology (2003)