tbuckley/cabot-search huggingface dataset:
C-type Natriuretic Peptide Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats
Authors: Takefumi Itoh, Noritoshi Nagaya, Shinsuke Murakami, Takafumi Fujii, Takashi Iwase, Hatsue Ishibashi-Ueda, Chikao Yutani, Masakazu Yamagishi, Hiroshi Kimura, Kenji Kangawa
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

C-type natriuretic peptide (CNP) has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether CNP ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Rats received a continuous infusion of CNP or placebo. Significant pulmonary hypertension developed 3 weeks after MCT. However, infusion of CNP significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, CNP enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. CNP significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, CNP significantly increased the survival rate in MCT rats. Finally, infusion of CNP after the establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of CNP ameliorated MCT-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.
Breast Cancer Resistance Protein–Mediated Efflux of Androgen in Putative Benign and Malignant Prostate Stem Cells
Authors: Wendy J. Huss, Danny R. Gray, Norman M. Greenberg, James L. Mohler, Gary J. Smith
Journal: Cancer Research (2005)

Abstract Malignantly transformed stem cells represent a potential common nidus for the primary cancer and the recurrent cancer that arises after treatment failure. Putative prostate stem cells and prostate tumor stem cells in benign and malignant human prostate tissue, in primary human prostate xenografts, and in the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model of prostate cancer, are defined by expression of breast cancer resistance protein (BCRP), a marker of pluripotent hematopoietic, muscle, and neural stem cells, and by an absence of androgen receptor (AR) protein. Inhibition of BCRP-mediated efflux of dihydrotestosterone by novobiocin or fumitremorgin C in a rat prostate progenitor cell line that expresses BCRP and AR mRNAs, but minimal AR protein, results in stabilization and nuclear translocation of AR protein, providing a mechanism for lack of AR protein in BCRP-expressing stem cells. In both benign and malignant human prostate tissue, the rare epithelial cells that express BCRP and lack AR protein are localized in the basal cell compartment, survive androgen deprivation, and maintain proliferative potential in the hypoxic, androgen-deprived prostate. Putative prostate tumor stem cells that express BCRP but not AR protein in TRAMP are the source of a BCRP-negative and AR-negative, Foxa2- and SV40Tag-expressing, transit amplifying compartment that progresses to the poorly differentiated carcinomas that arise rapidly after castration. Therefore, BCRP expression isolates prostate stem/tumor stem cells from the prostate tissue microenvironment through constitutive efflux of androgen, protecting the putative tumor stem cells from androgen deprivation, hypoxia, or adjuvant chemotherapy, and providing the nidus for recurrent prostate cancer.
Progression to rheumatoid arthritis in early inflammatory arthritis is associated with low IL-7 serum levels
Authors: Vincent Goëb, Philippe Aegerter, Rekha Parmar, Patrice Fardellone, Oliver Vittecoq, Philip G Conaghan, Paul Emery, Xavier Le Loët, Frédérique Ponchel
Journal: Annals of the Rheumatic Diseases (2012)

Objective Early diagnosis of rheumatoid arthritis (RA) remains a challenge. Interleukin (IL)-7 is a pleiotropic cytokine that plays a central role in the development and maintenance of T-cells and has been associated with T-cell dysfunction in RA. Serum levels of IL-7 are reduced in both early and established disease. The aim of this study was to determine whether serum IL-7 can identify patients with very early inflammatory joint symptoms who will progress to RA, and to examine whether IL-7 levels predict disease persistence and radiographic progression. Methods Patients with inflammatory joint symptoms &lt;6 months followed over 5 years for progression to RA and 80 healthy controls were studied. Baseline IL-7 levels were measured by ELISA. Results Of 250 patients, 108 developed RA (ACR 1987- criteria). IL-7 at inclusion was reduced significantly in RA compared with non-RA patients (p=0.009). IL-7 was categorised using the lower limit of the healthy control distribution (10 pg/ml). In multivariate analysis, independent predictors of RA development were: antibodies against citrullinated peptides (ACPA) positivity (p=0.001), IL-7&lt;10 pg/ml (p=0.003) and swollen joint count (p=0.050). In the ACPA-negative subgroup (n=199), the only predictors were: DAS-44 (p=0.001), IL-7&lt;10 pg/ml (p=0.010) and radiographic erosions (p=0.050). At 1-year follow-up, remission (DAS&lt;1.6) was only predicted by ACPA negativity (p=0.019) and IL-7&gt;17 pg/ml at recruitment (p=0.013). Conclusion These data demonstrate that low IL-7 levels in patients with recent onset of symptoms may have value as a diagnostic biomarker predicting the progression to RA, particularly in ACPA-negative disease, as well as being related to RA progression.
Expression of Erythropoietin and Erythropoietin Receptor in Non–Small Cell Lung Carcinomas
Authors: Koami Dagnon, Emilie Pacary, Frédéric Commo, Martine Antoine, Myriam Bernaudin, Jean-Francois Bernaudin, Patrice Callard
Journal: Clinical Cancer Research (2005)

Expression of erythropoietin (Epo) and its receptor (Epo-R) has been shown in various normal and neoplastic nonhematopoietic tissues. This study, in non-small cell lung carcinoma, was designed to investigate the previously unreported expression of Epo and Epo-R as well as hypoxia-inducible factor-1alpha (HIF-1alpha), which is known to control Epo expression.Samples from lung squamous cell carcinomas (n = 17) and adenocarcinomas (n = 12) were obtained from patients undergoing curative surgery. mRNA transcripts of Epo, Epo-R, soluble Epo-R (sEpo-R), HIF-1alpha, and factor inhibiting HIF-1 (FIH-1) were evaluated by reverse transcription-PCR, whereas localization of Epo, Epo-R, and HIF-1alpha was assessed by immunohistochemistry.Epo, Epo-R, sEpo-R, HIF-1alpha, and FIH-1 transcripts were detected by reverse transcription-PCR in all samples tested, but with heterogeneous levels of expression for Epo, Epo-R, and sEpo-R. Coordinated levels of mRNA were observed for HIF-1alpha and FIH-1.Epo was detected in carcinomatous cells by immunohistochemistry in 50% of samples and Epo-R was detected in 96% of samples. Co-expression of Epo and Epo-R was observed on contiguous sections from 50% of tumors. HIF-1alpha was immunolocalized in 80% of non-small cell lung carcinomas.Epo-R was expressed in almost all samples and Epo was expressed in one half of samples on immunohistochemistry and in 100% of samples by mRNA detection, suggesting a potential paracrine and/or autocrine role of endogenous Epo in non-small cell lung carcinoma. The detection of stabilized HIF-1alpha suggests a possible role in Epo expression. Moreover, in the light of these results, the potential interactions between therapeutic recombinant Epo and the putative neoplastic Epo/Epo-R signaling pathways must be considered.
Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial
Authors: Femke Mol, Norah M van Mello, Annika Strandell, Karin Strandell, Davor Jurkovic, Jackie Ross, Kurt T Barnhart, Tamer M Yalcinkaya, Harold R Verhoeve, Giuseppe C M Graziosi, Carolien A M Koks, Ingmar Klinte, Lars Hogström, Ineke C A H Janssen, Harry Kragt, Annemieke Hoek, Trudy C M Trimbos-Kemper, Frank J M Broekmans, Wim N P Willemsen, Willem M Ankum, Ben W Mol, Madelon van Wely, Fulco van der Veen, Petra J Hajenius
Journal: The Lancet (2014)
Phase I Study of Vorinostat in Patients With Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study
Authors: Suresh S. Ramalingam, Shivaani Kummar, John Sarantopoulos, Stephen Shibata, Patricia LoRusso, Mara Yerk, Julianne Holleran, Yan Lin, Jan H. Beumer, R. Donald Harvey, S. Percy Ivy, Chandra P. Belani, Merrill J. Egorin
Journal: Journal of Clinical Oncology (2010)

Purpose Vorinostat is the first US Food and Drug Administration–approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction. Patients and Methods Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography–tandem mass spectrometry assay and modeled noncompartmentally. Results Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years. Conclusion Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.
Phase I Trial of Intraperitoneal Gemcitabine in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity
Authors: Robert J. Morgan, Timothy W. Synold, Bixin Xi, Dean Lim, Stephen Shibata, Kim Margolin, Roderich E. Schwarz, Lucille Leong, George Somlo, Przemyslaw Twardowski, Yun Yen, Warren Chow, Merry Tetef, Paul Lin, Benjamin Paz, Mariana Koczywas, Lawrence Wagman, David Chu, Paul Frankel, Susan Stalter, James H. Doroshow
Journal: Clinical Cancer Research (2007)

To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine.Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m(2)) was administered into the peritoneal cavity in 2 L of warmed saline on days 1, 4, 8, and 12 of a 28-day cycle.Thirty patients received 63 (median, 2; range, 0-6) courses. Tumors included ovary (14), uterus (2), colon (6), pancreas (3), and others (5). Dose-limiting toxicity included nausea, vomiting, diarrhea, dyspnea, fatal respiratory failure, and grade 3 elevation of alanine aminotransferase in three patients. Hematologic toxicity and pain were </=grade 2. Three patients had decreased or resolved ascites. Of 19 patients evaluable for response, 10 had stable disease (median, 3.5 courses) and 9 had progressive disease. The median peak peritoneal concentration was 1,116-fold (range, 456-1,886) higher than the peak plasma level. Plasma and peritoneal levels were undetectable within 8 to 12 h. At 120 mg/m(2), the median peritoneal area under the concentration versus time curve (AUC) was 82,612 ng/mL x h (range, 53,296-199,830) and the plasma AUC was 231 ng/mL x h (range, 47.6-259.5). The mean peritoneal advantage (AUC(peritoneal)/AUC(plasma)) was 847 (range, 356-1,385).I.p. administration of gemcitabine is tolerated within the tested dosage range. Technical problems with the Porta-Cath device and i.p. therapy per se may have been exacerbated by the enrollment of many patients with a variety of advanced i.p. diseases. Given the significant increase in local dose intensity and the documented activity of this drug, this agent may be an excellent candidate for i.p. therapy in optimally debulked ovarian cancer, either alone or in combination.
High-Density Livestock Operations, Crop Field Application of Manure, and Risk of Community-Associated Methicillin-Resistant<i>Staphylococcus aureus</i>Infection in Pennsylvania
Authors: Joan A. Casey, Frank C. Curriero, Sara E. Cosgrove, Keeve E. Nachman, Brian S. Schwartz
Journal: JAMA Internal Medicine (2013)

Nearly 80% of antibiotics in the United States are sold for use in livestock feeds. The manure produced by these animals contains antibiotic-resistant bacteria, resistance genes, and antibiotics and is subsequently applied to crop fields, where it may put community members at risk for antibiotic-resistant infections.To assess the association between individual exposure to swine and dairy/veal industrial agriculture and risk of methicillin-resistant Staphylococcus aureus (MRSA) infection.A population-based, nested case-control study of primary care patients from a single health care system in Pennsylvania from 2005 to 2010. Incident MRSA cases were identified using electronic health records, classified as community-associated MRSA or health care-associated MRSA, and frequency matched to randomly selected controls and patients with skin and soft-tissue infection. Nutrient management plans were used to create 2 exposure variables: seasonal crop field manure application and number of livestock animals at the operation. In a substudy, we collected 200 isolates from patients stratified by location of diagnosis and proximity to livestock operations.Community-associated MRSA, health care-associated MRSA, and skin and soft-tissue infection status (with no history of MRSA) compared with controls.From a total population of 446,480 patients, 1539 community-associated MRSA, 1335 health care-associated MRSA, 2895 skin and soft-tissue infection cases, and 2914 controls were included. After adjustment for MRSA risk factors, the highest quartile of swine crop field exposure was significantly associated with community-associated MRSA, health care-associated MRSA, and skin and soft-tissue infection case status (adjusted odds ratios, 1.38 [95% CI, 1.13-1.69], 1.30 [95% CI, 1.05-1.61], and 1.37 [95% CI, 1.18-1.60], respectively); and there was a trend of increasing odds across quartiles for each outcome (P ≤ .01 for trend in all comparisons). There were similar but weaker associations of swine operations with community-associated MRSA and skin and soft-tissue infection. Molecular testing of 200 isolates identified 31 unique spa types, none of which corresponded to CC398 (clonal complex 398), but some have been previously found in swine.Proximity to swine manure application to crop fields and livestock operations each was associated with MRSA and skin and soft-tissue infection. These findings contribute to the growing concern about the potential public health impacts of high-density livestock production.
Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr–/– mice
Authors: Bin Zhao, Jingmei Song, Woon N. Chow, Richard W. St. Clair, Lawrence L. Rudel, Shobha Ghosh
Journal: Journal of Clinical Investigation (2007)

Accumulation of cholesteryl esters (CEs) in macrophage foam cells, central to atherosclerotic plaque formation, occurs as a result of imbalance between the cholesterol influx and efflux pathways. While the uptake, or influx, of modified lipoproteins is largely unregulated, extracellular acceptor-mediated free cholesterol (FC) efflux is rate limited by the intracellular hydrolysis of CE. We previously identified and cloned a neutral CE hydrolase (CEH) from human macrophages and demonstrated its role in cellular CE mobilization. In the present study, we examined the hypothesis that macrophage-specific overexpression of CEH in atherosclerosis-susceptible Ldlr(-/-) mice will result in reduction of diet-induced atherosclerosis. Transgenic mice overexpressing this CEH specifically in the macrophages (driven by scavenger receptor promoter/enhancer) were developed and crossed into the Ldlr(-/-) background (Ldlr(-/-)CEHTg mice). Macrophage-specific overexpression of CEH led to a significant reduction in the lesion area and cholesterol content of high-fat, high-cholesterol diet-induced atherosclerotic lesions. The lesions from Ldlr(-/-)CEHTg mice did not have increased FC, were less necrotic, and contained significantly higher numbers of viable macrophage foam cells. Higher CEH-mediated FC efflux resulted in enhanced flux of FC from macrophages to gall bladder bile and feces in vivo. These studies demonstrate that by enhancing cholesterol efflux and reverse cholesterol transport, macrophage-specific overexpression of CEH is antiatherogenic.
Peritonitis in Children Who Receive Long-Term Peritoneal Dialysis
Authors: Bradley A Warady, Reinhard Feneberg, Enrico Verrina, Joseph T Flynn, Dirk E Müller-Wiefel, Nesrin Besbas, Aleksandra Zurowska, Nejat Aksu, Michel Fischbach, Ernesto Sojo, Osman Donmez, Lale Sever, Aydan Sirin, Steven R Alexander, Franz Schaefer
Journal: Journal of the American Society of Nephrology (2007)

In children who are on chronic peritoneal dialysis, peritonitis is the primary complication compromising technique survival, and the optimal therapy of peritonitis remains uncertain. An Internet-based International Pediatric Peritonitis Registry was established in 47 pediatric centers from 14 countries to evaluate the efficacy and safety of largely opinion-based peritonitis treatment guidelines in which empiric antibiotic therapy was stratified by disease severity. Among a total of 491 episodes of nonfungal peritonitis entered into the registry, Gram-positive organisms were cultured in 44%, Gram-negative organisms were cultured in 25%, and cultures remained negative in 31% of the episodes. In vitro evaluation revealed 69% sensitivity of Gram-positive organisms to a first-generation cephalosporin and 80% sensitivity of Gram-negative organisms to a third-generation cephalosporin. Neither the risk factors assumed by the guidelines nor the choice of empiric therapy was predictive of either the early treatment response or the final functional outcome of the peritonitis episodes. Overall, 89% of cases achieved full functional recovery, a portion after relapsing peritonitis (9%). These data serve as the basis for new evidence-based guidelines. Modification of empiric therapy to include aminoglycosides should be considered.
Efficacy and tolerability of lasmiditan, an oral 5-HT1F receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study
Authors: Markus Färkkilä, Hans-Christoph Diener, Gilles Géraud, Miguel Láinez, Jean Schoenen, Nadja Harner, Alison Pilgrim, Uwe Reuter
Journal: The Lancet Neurology (2012)
Phase II Trial of Tipifarnib as Maintenance Therapy in First Complete Remission in Adults with Acute Myelogenous Leukemia and Poor-Risk Features
Authors: Judith E. Karp, B. Douglas Smith, Ivana Gojo, Jeffrey E. Lancet, Jacqueline Greer, Maureen Klein, Larry Morris, Mark J. Levis, Steven D. Gore, John J. Wright, Elizabeth Garrett-Mayer
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Acute myelogenous leukemia (AML) does not have a high cure rate, particularly in patients with poor-risk features. Such patients might benefit from additional therapy in complete remission (CR). Tipifarnib is an oral farnesyltransferase inhibitor with activity in AML. We conducted a phase II trial of maintenance tipifarnib monotherapy for 48 adults with poor-risk AML in first CR. Experimental Design: Tipifarnib 400 mg twice daily for 14 of 21 days was initiated after recovery from consolidation chemotherapy, for a maximum of 16 cycles (48 weeks). Results: Twenty (42%) patients completed 16 cycles, 24 (50%) were removed from study for relapse, and 4 (8%) discontinued drug prematurely for intolerance. Nonhematologic toxicities were rare, but tipifarnib dose was reduced in 58% for myelosuppression. Median disease-free survival (DFS) was 13.5 months (range, 3.5-59+ months), with 30% having DFS &amp;gt;2 years. Comparison of CR durations for 25 patients who received two-cycle timed sequential therapy followed by tipifarnib maintenance with 23 historically similar patients who did not receive tipifarnib showed that tipifarnib was associated with DFS prolongation for patients with secondary AML and adverse cytogenetics. Conclusions: This study suggests that some patients with poor-risk AML, including patients with secondary AML and adverse cytogenetics, may benefit from tipifarnib maintenance therapy. Future studies are warranted to examine alternative tipifarnib dosing and continuation beyond 16 cycles.
Bias-corrected paralinear and LogDet distances and tests of molecular clocks and phylogenies under nonstationary nucleotide frequencies
Authors: X Gu, W H Li
Journal: Molecular Biology and Evolution (1996)

The statistical properties of the paralinear and LogDet distances under nonstationary nucleotide frequencies were studied. First, we developed formulas for correcting the estimation biases of the paralinear and LogDet distances, i.e., the bias-corrected distance is estimated by dc = d - 2var(d), where d and var(d) are the estimated distance and sampling variance, respectively. The performances of these formulas and the formulas for sampling variances were examined by computer simulation. Second, we developed a method for estimating the variance-covariance matrix of paralinear distances, so that statistical tests of DNA phylogenies can be conducted in the nonstationary case. Third, a new LogDet-based method for testing the molecular clock hypothesis was developed under nonstationary nucleotide frequencies.