tbuckley/cabot-search huggingface dataset:
Reduction of plasma renin activity by inhibition of the fatty acid cyclooxygenase in human subjects: independence of sodium retention.
Authors: J C Frölich, J W Hollifield, A M Michelakis, B S Vesper, J P Wilson, D G Shand, H J Seyberth, W H Frölich, J A Oates
Journal: Circulation Research (1979)

We carried out the present studies to determine whether the suppression of plasma renin activity (PRA) that follows inhibition of prostaglandin (PG) synthesis can be dissociated from the sodium-retaining effects of these drugs. In an initial investigation we studied the effect of indomethacin on PRA in normal subjects in balance on a 10 mM Na+ diet to prevent Na+ retention. Under these experimental conditions indomethacin did not lower PRA even though the fatty acid cyclooxygenase was inhibited, as indicated by a greater than 70% reduction in the major urinary metabolite of prostaglandin E (PGE-M). Sodium depletion leads to enhanced sympathetic activity. We therefore studied the effect of indomethacin on a group of subjects in 10 mM Na+ balance in whom the effect of increased beta-sympathetic activity was blocked by the administration of propranolol. In this group, indomethacin caused 65% suppression of PGE-M and had no effect on Na+ balance, but reversibly reduced PRA in the supine and upright positions by 84% and 70%, respectively. In normal subjects in 10 mM Na+ balance, the isoproterenol-induced increase in PRA also was unaffected by indomethacin. These data establish that inhibition of the cyclooxygenase can result in a reduction of PRA that is independent of changes in Na+ balance or beta-sympathetic tone.
Improved Assay Methods for Renin "Concentration" and "Activity" in Human Plasma
Authors: SANDFORD L. SKINNER
Journal: Circulation Research (1967)

Simplified methods are described for the measurement of human plasma renin "concentration" (PRC) and "activity" (PRA) based on the denaturation of renin substrate in which separation and concentration steps are avoided and recovery of renin is complete. In the PRA method effective inhibition of angiotensinase is achieved by warming plasma at pH 4.5 with EDTA followed by dialysis to pH 7.5. Neither renin nor renin substrate is affected by this treatment. In the PRC method, renin substrate is selectively denatured by warming at pH 3.3. After dialysis to pH 7.5 and addition of a standard substrate prepared from nephrectomized sheep, incubation results in a linear increase of pressor material which is assayed without extraction on rat blood pressure against synthetic angiotensin. Specificity is established by nephrectomy and immunological studies. The linear relationship between plasma renin concentration and reaction rate contrasted with the nonlinearity observed with renal renin. The systems are suitable for routine diagnostic use.
Obstetric Complications and Schizophrenia: Historical and Meta-Analytic Review
Authors: Mary Cannon, Peter B. Jones, Robin M. Murray
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: This paper reviews the literature on obstetric complications as a risk factor for schizophrenia. The authors trace the evolution of this literature through different methods and carry out a quantitative review of the results from prospective, population-based studies. METHOD: Relevant papers were identified by a MEDLINE search, by examination of reference lists of published papers, and through personal contact with researchers in the field. Studies were grouped in chronological order according to common themes or methods. Meta-analytic techniques were used to summarize the findings of prospective population-based studies. RESULTS: The meta-analytic synthesis of the prospective population-based studies revealed that three groups of complications were significantly associated with schizophrenia: 1) complications of pregnancy (bleeding, diabetes, rhesus incompatibility, preeclampsia); 2) abnormal fetal growth and development: (low birthweight, congenital malformations, reduced head circumference), and 3) complications of delivery (uterine atony, asphyxia, emergency Cesarean section). Pooled estimates of effect sizes were generally less than 2. CONCLUSIONS: Current methods of investigating the relationship between obstetric complications and schizophrenia are reaching the limit of their usefulness. Lack of statistical power to measure small and interactive effects and lack of detailed information about the prenatal period are major problems with current approaches. A combination of disciplines and approaches will be needed to elucidate the mechanisms underlying these small but important associations.
Dose-Intensification in Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD14 Trial
Authors: Bastian von Tresckow, Annette Plütschow, Michael Fuchs, Beate Klimm, Jana Markova, Andreas Lohri, Zdenek Kral, Richard Greil, Max S. Topp, Julia Meissner, Josée M. Zijlstra, Martin Soekler, Harald Stein, Hans T. Eich, Rolf P. Mueller, Volker Diehl, Peter Borchmann, Andreas Engert
Journal: Journal of Clinical Oncology (2012)

In patients with early unfavorable Hodgkin's lymphoma (HL), combined modality treatment with four cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) and 30 Gy involved-field radiotherapy (IFRT) results in long-term tumor control of approximately 80%. We aimed to improve these results using more intensive chemotherapy.Patients with newly diagnosed early unfavorable HL were randomly assigned to either four cycles of ABVD or an intensified treatment consisting of two cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (2 + 2). Chemotherapy was followed by 30 Gy IFRT in both arms. The primary end point was freedom from treatment failure (FFTF); secondary end points included progression-free survival (PFS) and treatment-related toxicity.With a total of 1,528 qualified patients included, the 2 + 2 regimen demonstrated superior FFTF compared with four cycles of ABVD (P < .001; hazard ratio, 0.44; 95% CI, 0.30 to 0.66), with a difference of 7.2% at 5 years (95% CI, 3.8 to 10.5). The difference in 5-year PFS was 6.2% (95% CI, 3.0% to 9.5%). There was more acute toxicity associated with 2 + 2 than with ABVD, but there were no overall differences in treatment-related mortality or secondary malignancies.Intensified chemotherapy with two cycles of BEACOPP escalated followed by two cycles of ABVD followed by IFRT significantly improves tumor control in patients with early unfavorable HL.
Body Iron Stores and Dietary Iron Intake in Relation to Diabetes in Adults in North China
Authors: De Chun Luan, Hui Li, Sui Jing Li, Zhuo Zhao, Xin Li, Zhong Mei Liu
Journal: Diabetes Care (2008)

To evaluate the association between body iron stores, dietary iron intake, and risk of diabetes in northern China.The data of a cross-sectional household survey in 2002 in Liaoning Province in northern China was used. The final sample in our study contained 2,997 subjects aged >or=18 years. Fasting plasma glucose and serum ferritin were measured. Dietary information was collected by 3-day food records.Serum ferritin was associated with elevated risk of diabetes even adjusted for age, sex, nondietary factors, and dietary factors. No association among total iron intake, nonheme iron intake, and diabetes risk was found. However, higher heme iron intake was significantly associated with elevated risk of diabetes after adjusting for known factors.In Chinese, associations among higher serum ferritin level, higher heme iron intake, and elevated risk of diabetes were found.
Trypanosoma cruzi amastigote adhesion to macrophages is facilitated by the mannose receptor.
Authors: S Kahn, M Wleklinski, A Aruffo, A Farr, D Coder, M Kahn
Journal: The Journal of Experimental Medicine (1995)

Trypanosoma cruzi is an obligate intracellular protozoan parasite. The mammalian stage of the parasite life cycle describes amastigotes as an intracellular form that replicates, and trypomastigotes as an extracellular form that disseminates and invades cells. Recent studies, however, have demonstrated that amastigotes circulate in the blood of infected mammals and can invade mammalian cells. In this report, a T. cruzi surface glycoprotein gene, SA85-1.1, was expressed as an immunoglobulin chimera, and this recombinant globulin was used to screen normal mouse tissues for adhesive interactions. This approach identified a subset of macrophages in the skin and peripheral lymph node that bind the T. cruzi surface glycoproteins through the mannose receptor. To further examine the T. cruzi mannose receptor carbohydrate ligands, the interaction between T. cruzi and the mannose-binding protein, a mammalian lectin with similar carbohydrate binding specificities as the mannose receptor, was examined. These studies demonstrated that the mannose-binding protein recognized amastigotes, but not trypomastigotes or epimastigotes, and suggested that amastigotes would also be recognized by the mannose receptor. Therefore, amastigote adhesion to macrophages was investigated, and these experiments demonstrated that the mannose receptor contributes to amastigote adhesion. The data identify the first mammalian lectins that bind to T. cruzi, and are involved in T. cruzi invasion of mammalian cells. The data suggest that amastigotes and trypomastigotes may have developed different mechanisms to adhere to and invade host cells. In addition, it has been established that IFN-gamma-activated macrophages express low levels of the mannose receptor and are trypanocidal; this suggests that the interaction between amastigotes and the mannose receptor enables amastigotes to increase their adherence with a population of macrophages that are nontrypanocidal and permissive for their intracellular replication.
Reply to F.V. Raimundo et al
Authors: Kimmie Ng, Bruce W. Hollis, Charles S. Fuchs
Journal: Journal of Clinical Oncology (2011)

previously for another steroid hormone, cortisol. 5,6In the studies by Hamrahian et al 5 and Raff et al, 6 serum total cortisol levels resulted in an underestimation of serum free cortisol levels in patients with hypoalbuminemia because of changes in the binding proteins of cortisol.Moreover, low serum albumin levels have been associated with unfavorable prognosis in patients with cancer 7 and could indeed be associated with the study findings.
Airways obstruction and two year survival in patients with severe alpha 1-antitrypsin deficiency
Authors: N Seersholm, A Dirksen, A Kok-Jensen
Journal: European Respiratory Journal (1994)

Because of the limited number of donor organs available, the selection of patients for lung transplantation is crucial. One important issue in setting priorities is the life expectancy without transplantation. The purpose of this study was to estimate survival based on lung function, in alpha 1-antitrypsin deficient patients. Data from the Danish alpha 1-antitrypsin deficiency registry were analysed. The basic element of the analysis was two year intervals, characterized by date of spirometry and known mortality status 2 yrs later. We found a simple exponential relationship between lung function (forced expiratory volume one second (FEV1)) and two year survival on conservative treatment. The formula implies an almost 100% two year survival until FEV1 falls below one third of predicted normal; at this level two year mortality increases and will reach 50% at a FEV1 of 15% predicted. In conclusion, the two year mortality of emphysema patients due to alpha 1-antitrypsin deficiency increases exponentially with decreasing FEV1 and the results imply that only a few patients who underwent lung transplantation would have had a better two year prognosis without this procedure.
Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models
Authors: K. A. Walters, U. Simanainen, D. J. Handelsman
Journal: Human Reproduction Update (2010)

Androgens and the androgen receptor (AR) have well known roles in male reproduction, and recent genetic mouse models inactivating the Ar gene have conclusively defined a role for androgens in female reproduction. In males, AR gene inactivation severely disrupts spermatogenesis by interrupting completion of meiosis, thereby eliminating production of mature sperm leading to male sterility. These effects have overshadowed the study of additional post-meiotic androgen effects required for the production of fully functional spermatozoa, as well as the production of females with complete androgen insensitivity which cannot be produced by natural breeding. However, these limitations have been overcome by the creation of global and cell-specific AR knockout (ARKO) mouse models using Cre–LoxP genetic engineering. Pubmed searches were carried out using the following search terms: androgen receptor, knockout mouse and fertility. Articles published before the end of November 2009 were included. These experimental models have identified cell-specific AR-mediated androgen actions in testis and androgen actions in sex accessory glands independent of testicular effects which are crucial for sperm maturation, motion and fertilizing ability. The ability to produce homozygous ARKO females has revealed that AR-mediated androgen actions are important for normal female fertility. AR function is required for full functionality in follicle health, development and ovulation through both intra-ovarian and neuroendocrine mechanisms. ARKO mouse models provide valuable tools to unravel novel roles of AR-mediated actions in male and female reproductive function, and new insights into the role of androgens in human reproductive function.
Gene-Expression Profile Changes Correlated with Tumor Progression and Lymph Node Metastasis in Esophageal Cancer
Authors: Eiji Tamoto, Mitsuhiro Tada, Katsuhiko Murakawa, Minoru Takada, Gaku Shindo, Ken-ichi Teramoto, Akihiro Matsunaga, Kazuteru Komuro, Motoshi Kanai, Akiko Kawakami, Yoshie Fujiwara, Nozomi Kobayashi, Katsutoshi Shirata, Norihiro Nishimura, Shun-ichi Okushiba, Satoshi Kondo, Jun-ichi Hamada, Takashi Yoshiki, Tetsuya Moriuchi, Hiroyuki Katoh
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this research was to identify molecular clues to tumor progression and lymph node metastasis in esophageal cancer and to test their value as predictive markers. Experimental Design: We explored the gene expression profiles in cDNA array data of a 36-tissue training set of esophageal squamous cell carcinoma (ESCC) by using generalized linear model-based regression analysis and a feature subset selection algorithm. By applying the identified optimal feature sets (predictive gene sets), we trained and developed ensemble classifiers consisting of multiple probabilistic neural networks combined with AdaBoosting to predict tumor stages and lymph node metastasis. We validated the classifier abilities with 18 independent cases of ESCC. Results: We identified 71 genes of 1289 cancer-related genes of which the expression correlated with tumor stages. Of the 71 genes, 47 significantly differed between the Tumor-Node-Metastasis pT1/2 and pT3/4 stages. Cell cycle regulators and transcriptional factors possibly promoting the growth of tumor cells were highly expressed in the early stages of ESCC, whereas adhesion molecules and extracellular matrix-related molecules possibly promoting invasiveness increased in the later stages. For lymph node metastasis, we identified 44 genes with predictive values, which included cell adhesion molecules and cell membrane receptors showing higher expression in node-positive cases and cell cycle regulators and intracellular signaling molecules showing higher expression in node-negative cases. The ensemble classifiers trained with the selected features predicted tumor stage and lymph node metastasis in the 18 validation cases with respective accuracies of 94.4% and 88.9%. This demonstrated the reproducibility and predictive value of the identified features. Conclusion: We suggest that these characteristic genes will provide useful information for understanding the malignant nature of ESCC as well as information useful for personalizing the treatments.
Role of Rho kinase isoforms in murine allergic airway responses
Authors: M. Zhu, P-Y. Liu, D.I. Kasahara, A.S. Williams, N.G. Verbout, A.J. Halayko, A. Fedulov, T. Shoji, E.S. Williams, K. Noma, S.A. Shore, J.K. Liao
Journal: European Respiratory Journal (2011)

Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1 +/- and ROCK2 +/- , respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1 +/- and ROCK2 +/- mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1 +/- and ROCK2 +/- lungs. Airway responsiveness was comparable in WT, ROCK1 +/- , and ROCK2 +/- mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1 +/- or ROCK2 +/- mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1 +/- and ROCK2 +/- versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1 +/- mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses.
Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer
Authors: Maggie C. U. Cheang, Stephen K. Chia, David Voduc, Dongxia Gao, Samuel Leung, Jacqueline Snider, Mark Watson, Sherri Davies, Philip S. Bernard, Joel S. Parker, Charles M. Perou, Matthew J. Ellis, Torsten O. Nielsen
Journal: JNCI Journal of the National Cancer Institute (2009)

Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival. Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan–Meier curves and multivariable Cox regression. Gene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor–positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer–specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal–HER2 subtypes. Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.
Circulating Tumor Cells and EpCAM Expression in Neuroendocrine Tumors
Authors: Mohid S. Khan, Theodora Tsigani, Mohammed Rashid, Jeremy S. Rabouhans, Dominic Yu, Tu Vinh Luong, Martyn Caplin, Tim Meyer
Journal: Clinical Cancer Research (2011)

Neuroendocrine tumors (NET) are heterogeneous tumors with widely variable survival. It is unknown whether they express EpCAM (epithelial cell adhesion molecule) and thus whether NET circulating tumor cells (CTC) are detectable. We systematically investigated EpCAM expression and CTC detection in patients with metastatic NETs and evaluated the potential of CTCs to predict radiological progression.EpCAM protein expression was evaluated in 74 samples of formalin-fixed, paraffin-embedded NET tissue by immunohistochemistry. Seventy-nine patients with metastatic NETs (42 midgut, 5 unknown primary, 19 pancreatic, 13 bronchopulmonary) had blood samples drawn for CTC isolation and enumeration utilizing the CellSearch platform. Patients were classified as having progressive or nonprogressive disease on the basis of serial imaging.Strong homogeneous, membranous EpCAM expression was observed in all ileal (n = 26) and pancreatic NETs (n = 16), whereas variable EpCAM expression was observed in bronchopulmonary NETs (n = 13). Forty-three percent of midgut and 21% of pancreatic NETs had CTCs detected with a range of 0-62 and 0-11, respectively. The absence of CTCs was strongly associated with stable disease (P < 0.001). There was a moderate correlation between CTC levels and urinary 5-hydroxyindole acetic acid (r = 0.5, P = 0.007) and between CTC levels and burden of liver metastases (B = 8.91, P < 0.001). There was no or low correlation between CTC levels and Ki-67 (r = 0.08, P = 0.59) and serum chromogranin A (r = 0.246, P = 0.03).This is the first systematic analysis showing EpCAM expression and CTC detection in NETs. CTCs seem to be associated with progressive disease and may provide useful prognostic information given the variable survival rates in these tumors.