tbuckley/cabot-search huggingface dataset:
Dasatinib (BMS-354825) Pharmacokinetics and Pharmacodynamic Biomarkers in Animal Models Predict Optimal Clinical Exposure
Authors: Feng R. Luo, Zheng Yang, Amy Camuso, Richard Smykla, Kelly McGlinchey, Krista Fager, Christine Flefleh, Stephen Castaneda, Ivan Inigo, David Kan, Mei-Li Wen, Robert Kramer, Anne Blackwood-Chirchir, Francis Y. Lee
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Chronic myeloid leukemia (CML) is caused by reciprocal translocation between chromosomes 9 and 22, forming BCR-ABL, a constitutively activated tyrosine kinase. Imatinib mesylate, a selective inhibitor of BCR-ABL, represents current frontline therapy for CML; however, emerging evidence suggests that drug resistance to imatinib may limit its long-term success. To improve treatment options, dasatinib (BMS-354825) was developed as a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases. To date, dasatinib has shown promising anti-leukemic activity in preclinical models of CML and in phase I/II clinical studies in patients with imatinib-resistant or imatinib-intolerant disease. Experimental Design: The pharmacokinetic and pharmacodynamic biomarkers of dasatinib were investigated in K562 human CML xenografts grown s.c. in severe combined immunodeficient mice. Tumoral levels of phospho-BCR-ABL/phospho-CrkL were determined by Western blot. Results: Following a single oral administration of dasatinib at a preclinical efficacious dose of 1.25 or 2.5 mg/kg, tumoral phospho-BCR-ABL/phospho-CrkL were maximally inhibited at ∼3 hours and recovered to basal levels by 24 hours. The time course and extent of the inhibition correlated with the plasma levels of dasatinib in mice. Pharmacokinetic/biomarker modeling predicted that the plasma concentration of dasatinib required to inhibit 90% of phospho-BCR-ABL in vivo was 10.9 ng/mL in mice and 14.6 ng/mL in humans, which is within the range of concentrations achieved in CML patients who responded to dasatinib treatment in the clinic. Conclusions: Phospho-BCR-ABL/phospho-CrkL are likely to be useful clinical biomarkers for the assessment of BCR-ABL kinase inhibition by dasatinib.
Uptake of ln-111 Antifibrin in Crush Injuries
Authors: F De GEETER, A BOSSUYT
Journal: Clinical Nuclear Medicine (1989)

In-111 labeled antifibrin antibodies have been put forward for the detection of deep venous thrombi in man. They bind specifically to human fibrin, which is present in fresh as well as aged thrombl. However, the presence of this protein, which results from fibrinogenolysis, is not limited to clots. The authors report on a patient suffering from crush syndrome and suspected of having deep venous thrombosis, in whom extravascular uptake of in-111 antifibrin was observed in a thigh hematoma. No deep venous thrombosis could be demonstrated.
Risk Factors for Coronary Heart Disease in Men 18 to 39 Years of Age
Authors: Elena L. Navas-Nacher, Laura Colangelo, Craig Beam, Philip Greenland
Journal: Annals of Internal Medicine (2001)

Background: Few studies have evaluated the long-term predictive capacity of risk factors for death from coronary heart disease in men younger than 40 years of age. Objective: To assess the predictive capacity and discriminatory ability of major coronary risk factors in predicting death from coronary heart disease in young men. Design: Prospective cohort study with 20 years of follow-up. Setting: 84 companies in the Chicago area that participated in the Chicago Heart Association Detection Project in Industry (1967–1973). Participants: 11 016 men 18 to 39 years of age (mean age, 29.7 years) at baseline were the primary focus of this report; 8955 men 40 to 59 years of age at baseline served as a reference group. Measurements: The main end point was death from coronary heart disease. Results: All major risk factors—age, serum cholesterol level, systolic blood pressure, and cigarette smoking—were significantly associated with death from coronary heart disease over 20 years in young men. Relative risks for the major risk factors were of generally similar magnitude in young and middle-aged men. Receiver-operating characteristic curves for the best predictive model yielded an area under the curve of 0.82, indicating that standard risk factors were highly predictive of long-term outcome in young men. Conclusions: Major coronary disease risk factors, many of which are modifiable, are strong contributors to prediction of future risk, even in young men. These data may help in formulating appropriate strategies to identify young men at heightened risk for death from coronary heart disease in later adulthood.
A DIPHTHERIA CARRIER OF UNUSUAL TYPE
Authors: J. Allen, D. R. Wood
Journal: BMJ (1920)

04A OF UNUSUAL TYPE.-.,-$.The initial dose in the enormous majority of cases was half a million.The daily weiglt has been found to be a satisfactory metlhod of conjrolling the dosage..The interval with small doses lhas been tlhree to four days; with larger doses a weel.Patients do not seem to have been quite so sensitive to the secondary organisms when present, but still great caution had to be exercised; streptococci were givenin doses-of half a million to 5 million and B. coli the same, Length of Treatmnent.
Lymphoid Development and Function in X-Linked Severe Combined Immunodeficiency Mice after Stem Cell Gene Therapy
Authors: Makoto Otsu, Stacie M. Anderson, David M. Bodine, Jennifer M. Puck, John J. O'Shea, Fabio Candotti
Journal: Molecular Therapy (2000)

Mutations of the common gamma chain (γc) of cytokine receptors cause X-linked severe combined immunodeficiency (XSCID), a candidate disease for gene therapy. Using an XSCID murine model, we have tested the feasibility of stem cell gene correction. XSCID bone marrow (BM) cells were transduced with a retroviral vector expressing the murine γc (mγc) and engrafted in irradiated XSCID animals. Transplanted mice developed mature B cells, naıve T cells, and mature natural killer (NK) cells, all of which were virtually absent in untreated mice. The mγc transgene was detected in all treated mice, and we could demonstrate mγc expression in newly developed lymphocytes at both the RNA and protein level. In addition, treated mice showed T cell proliferation responses to mitogens and production of antigen-specific antibodies upon immunization. Four of seven treated animals showed a clear increase of the transgene positive cells, suggesting in vivo selective advantage for gene-corrected cells. Altogether, these results show that retroviral-mediated gene transfer can improve murine XSCID and suggest that similar strategies may prove beneficial in human clinical trials.
Gene expression of the GATA-3 transcription factor is increased in atopic asthma
Authors: Yutaka Nakamura, Omar Ghaffar, Ronald Olivenstein, Rame A. Taha, Abdelilah Soussi-Gounni, Dong-Hong Zhang, Anuradha Ray, Qutayba Hamid
Journal: Journal of Allergy and Clinical Immunology (1999)
Impact of Social Support and Stress on Compliance in Women With Gestational Diabetes
Authors: Laurie Ruggiero, Anthony Spirito, Andrea Bond, Donald Coustan, Stephen McGarvey
Journal: Diabetes Care (1990)

Compliance with medical recommendations is especially important for women with gestational diabetes because of the health implications for both mother and fetus. This study examined compliance with two daily selfmanagement tasks, diet and insulin administration, in 98 women with gestational diabetes. Furthermore, the influence of stress and regimen-related social support on compliance was investigated. Results indicate that the level of reported compliance was high for both insulin administration and diet. Fewer minor stressors and greater social support were associated with greater compliance.
Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: A novel consideration in atrial remodeling☆
Authors: B BURSTEIN, X QI, Y YEH, A CALDERONE, S NATTEL
Journal: Cardiovascular Research (2007)

Atrial fibrillation (AF) causes tachycardia-induced atrial electrical remodeling, contributing to the progressive nature of the arrhythmia. Ventricular dysfunction due to a rapid response to AF can cause structural remodeling, but whether AF itself directly promotes atrial fibrosis is controversial. This study investigated the hypothesis that rapid atrial cardiomyocyte activation produces factors that influence atrial fibroblast proliferation and secretory functions.Cultured canine atrial fibroblasts were treated with medium from rapidly-paced atrial cardiomyocytes, non-paced cardiomyocytes and cardiomyocyte-pacing medium only, and analyzed by [(3)H]thymidine incorporation, Western blot and real-time RT-PCR.Rapidly-paced cardiomyocyte-conditioned medium reduced [(3)H]thymidine uptake compared to non-paced cardiomyocyte-conditioned medium and medium alone (approximately 85%, P<0.01). Rapidly-paced cardiomyocyte medium increased alpha SMA protein (approximately 55%, p<0.001), collagen-1 (approximately 85%, P<0.05) and fibronectin-1 (approximately 205%, P<0.05) mRNA expression vs. controls. The angiotensin-1 receptor blocker valsartan attenuated pacing-induced alpha SMA changes but did not affect fibroblast proliferation. Suppression of contraction with blebbistatin did not prevent tachypacing-induced changes in [(3)H]thymidine uptake or alpha SMA upregulation, pointing to a primary role of electrical over mechanical cardiomyocyte activity. Atrial tissue from 1-week atrial-tachypaced dogs with ventricular rate control similarly showed upregulation of alpha SMA protein (approximately 40%, P<0.05), collagen-1 (approximately 380%, P<0.01) and fibronectin-1 (approximately 430%, P<0.001) mRNA versus shams.Rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function, inducing an activated myofibroblast phenotype that is reflected by increased ECM-gene expression in vivo. These findings are consistent with recent observations that AF per se may cause ECM remodeling, and have potentially important consequences for understanding and preventing the mechanisms underlying AF progression.
Differential transcriptional response to cisplatinum in BRCA1-defective <i>versus</i> BRCA1-reconstituted breast cancer cells by microarrays.
Authors: MT Di Martino, M Ventura, PH Guzzi, A Pietragalla, P Neri, A Bulotta, T Calimeri, V Barbieri, M Caraglia, P Veltri, M Cannataro, P Tassone, P Tagliaferri
Journal: Cancer Research (2009)

Abstract Abstract #5062 BRCA1-related breast cancer represents a distinct clinical entity characterized by basal-like molecular phenotype. HCC1937 is a BRCA1-defective breast cancer cell line which discloses higher sensitivity to cisplatinum (CDDP) as compared to the BRCA1 full-length cDNA transfected clone HCC1937/wtBRCA1. To study the molecular bases of BRCA1-related differential sensitivity to the drug, we have analyzed the whole gene expression profile of HCC1937 and HCC1937/wtBRCA1 cells following in vivo and in vitro exposure of tumour cells to CDDP.&amp;#x2028; Differential in vivo sensitivity was evaluated in xenografted tumors in SCID mice after 4 weeks of treatment with CDDP (5 mg/kg) or vehicle. Tumors were retrieved from animals 4 hours after the last dose of drug or vehicle. In vitro data were obtained exposing HCC1937 and HCC1937/wtBRCA1 cell lines to CDDP at IC50 doses of 30 and 70µM, or at 60 or 140µM respectively, for 3, 12 and 24 hours. Gene expression profiling was performed by Affymetrix® technology using GeneArray 1.0ST. Array data were analyzed using Gene Expression Console, GeneSpring software and Ingenuity Pathway Analysis (IPA)®.&amp;#x2028; We found up-regulation of G2/M DNA damage checkpoint pathway, in a dose- and time-dependent manner, as well as down-regulation of Notch signaling pathway in HCC1937 cells, after treatment with CDDP in vitro. Both pathways were not affected in BRCA1-reconstituted cells. Notch signaling pathway plays a key role in normal development of several tissues and its aberrant activation is linked with breast cancer tumourigenesis. Our findings suggest that sensitivity of the BRCA1-defective cells to CDDP exposure is related to the DNA-damage repair machinery due to BRCA1-deficiency but also to the modulation of survival pathways triggered by BRCA1. In vivo data analysis of HCC1937/wtBRCA1 tumours exposed to CDDP identified modulation of pathways involving AKT3 and PRKAR2B, also known as RII-BETA, a cAMP-dependent protein kinase, whereas no Notch signaling pathway modulation was detected.&amp;#x2028; In conclusion, reconstituted expression of BRCA1 induces resistance to CDDP in vitro and in vivo but produces a different transcriptional response to drug exposure. This effect could be related to the different growth and environmental milieu as well as to the different exposure conditions. Signaling pathways involving Notch, AKT and RII-BETA are involved in these events. Our data reinforce the concept that BRCA1 offers a molecular marker for individualized therapeutical options in breast cancer patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5062.
Escherichia coli strains colonising the gastrointestinal tract protect germfree mice against Salmonella typhimurium infection
Authors: S Hudault
Journal: Gut (2001)

Escherichia coli is part of the normal gastrointestinal microflora which exerts a barrier effect against enteropathogens. Several E coli strains develop a protective effect against other Enterobacteriaceae.Two E coli strains, EM0, a human faecal strain, and JM105 K-12 were tested for their ability to prevent in vivo and in vitro infection by Salmonella typhimurium C5.Inhibition of C5 cell invasion by E coli was investigated in vitro using Caco-2/TC7 cells. The protective effect of E coli was examined in vivo in germfree or conventional C3H/He/Oujco mice orally infected by the lethal strain C5.EMO expresses haemolysin and cytotoxic necrotising factor in vitro. In vitro, the two strains did not prevent the growth of C5 by secreted microcins or modified cell invasion of C5. In vivo, establishment of EM0 or JM105 in the gut of germfree mice resulted in a significant increase in the number of surviving mice: 11/12 and 9/12, respectively, at 58 days after infection (2x10(6)/mouse) versus 0/12 in control germfree group at 13 days after infection. Colonisation level and translocation rate of C5 were significantly reduced during the three days after infection. In contrast, no reduction in faecal C5 excretion was observed in C5 infected conventional mice (1x10(8)/mouse) receiving the EM0 or JM105 cultures daily.Establishment of E coli strains, which do not display antimicrobial activity, protects germfree mice against infection and delays the establishment of C5 in the gut. Possible mechanisms of defence are discussed.
Elderly need better coordinated services to keep them independent
Authors: L. Eaton
Journal: BMJ (2002)

Older people want better coordinated public services that will help them stay independent as long as possible. But this can be achieved only if different agencies work together and involve older people, says a report from the government's spending watchdog, the Audit Commission.

The commission cites research from the Local Government Centre at Warwick University ( Making a Difference—Better Government for Older People ), published in 2000, which showed the type of help that people wanted as they got older. But older people are too often getting …
960-84 Ramdomized Prospective Comparison of Four Burst Pacing Algorithms for Spontaneous Ventricular Tachycardia
Authors: Rafael Peinado, Jesús Almendral, Teresa Rius, Angel Moya, Angel Arenal, Julián Villacastín, José L. Merino, Olga Medina, Jesús Ma Alday, Agustín Pastor, José Ormaetxe
Journal: Journal of the American College of Cardiology (1995)
Effect of cimetidine treatment in the prevention of gastric ulcer relapse: a one year double blind multicentre study.
Authors: E Hentschel, K Schutze, W Weiss, E Rudiger, G Judmair, W Reichel, E Kerstan, J Horton
Journal: Gut (1983)

One hundred and forty six gastric ulcer patients were given open treatment using 1 g cimetidine daily to heal their ulcers. Of 130 who completed the acute treatment period of eight weeks, 112 (86%) had healed ulcers. Of these 112 patients with healed ulcers, 108 entered a one year double blind study to compare the effect of cimetidine maintenance therapy (400 mg at night) with placebo. Of the 84 patients available for assessment at the end of one year, 86% in the cimetidine treated group were in remission compared with 45% in the placebo treated group (chi 2 = 15.03; p less than 0.001). There were similar losses from non-compliance and drop out in both groups. The incidence of untoward effects and significant drug related laboratory abnormalities was low. The results indicate that cimetidine heals nearly 90% of acute gastric ulcers within eight weeks and that subsequent low dose maintenance treatment at night offers a considerable benefit over placebo therapy.
Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.
Authors: M Roth, M Nauck, S Yousefi, M Tamm, K Blaser, A P Perruchoud, H U Simon
Journal: The Journal of Experimental Medicine (1996)

Platelet-activating factor (PAF) is a potent proinflammatory phospholipid mediator of the lung. In this study, we demonstrate that PAF receptor mRNA and protein is expressed by human lung fibroblasts. Interaction of PAF with its specific receptor resulted in increases of tyrosine phosphorylation of several intracellular proteins, indicating that the PAF-receptor might be functionally active. PAF-induced transcription of protooncogenes c-fos and c-jun as well as of interleukin (IL)-6 and IL-8 genes in human fibroblasts. Transcription of the interleukins was followed by secretion of the respective proteins. Moreover, PAF enhanced proliferation of fibroblasts in a concentration-dependent manner. Using signaling inhibitors, we demonstrate that PAF-induced transcription of the c-fos, IL-6, and IL-8 genes, as well as proliferation, require activation of pertussis toxin-sensitive G proteins, tyrosine kinases, and protein kinase C (PKC). In contrast, transcription of c-jun was blocked by pertussis toxin, but not by inhibitors for tyrosine kinases or PKC. These data suggest that PAF stimulates distinct signaling pathways in human lung fibroblasts. In addition, the activation of human fibroblasts by PAF leads to enhanced proliferation and to the expression of proinflammatory cytokines, which may contribute to the pathophysiological changes in pulmonary inflammation.
Re: Gianluca Giannarini, Thomas M. Kessler, Frédéric D. Birkhäuser, George N. Thalmann, Urs E. Studer. Antegrade Perfusion With Bacillus Calmette-Guérin in Patients With Non–Muscle-Invasive Urothelial Carcinoma of the Upper Urinary Tract: Who May Benefit? Eur Urol 2011;60:955–60
Authors: Apul Goel, Swarnendu Mandal, Sachin B. Patil
Journal: European Urology (2012)
Psychiatric aspects of urinary incontinence in women attending an outpatient urodynamic clinic.
Authors: K R Norton, A V Bhat, S L Stanton
Journal: BMJ (1990)

<h3>Background</h3> Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade–based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country. <h3>Methods</h3> To evaluate this strategy’s effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (<i>n</i>=397) between 2007 and 2016. <h3>Results</h3> The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients. <h3>Conclusions</h3> Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.
A COMPARATIVE STUDY OF SERUM AND LYMPH FERMENTS AFTER FEEDING
Authors: Benjamin F. Davis, William F. Petersen
Journal: The Journal of Experimental Medicine (1917)

In these experiments in which the lymph and serum ferments and antiferment have been studied separately, the changes that are found to occur are uniform and consistent. Possibly as a result of increased blood flow through the ferment-producing organs a moderate amount of protease is directly absorbed into the blood stream, but when intestinal digestion is actively under way this rapidly diminishes in extent. If any protease is absorbed during digestion from the gastrointestinal tract it is probably removed when it reaches the liver. The ereptase, or peptidase, is evidently absorbed directly from the intestinal tract and enters the circulation through the lymphatic channels. The influence of the diet on the antiferment of the lymph is striking and accounts for the fluctuations observed in previous experiments. Following the milk meal the increase occurs gradually in the lymph in an amount that, when diluted in the blood stream, would be only nominal. When the fats of the milk were replaced by olive oil in large amounts it is surprising to find a decrease in the antiferment instead of an increase in titer, as might be expected in view of the nature of the antiferment. This result, however, is probably due to the fact that the antiferment lipoids of the serum and lymph may exist in both water and fat dispersion phases, but are active as antiferments only when in the former. If the amount of the fats of the serum is increased, as it is after the olive oil feeding, more of the antiferment will enter the fat phase and will as a result be rendered inactive. When the feeding included the sodium oleate, the anti-ferment was in consequence increased in both the serum and the lymph, some of the soap being apparently absorbed directly into the blood stream. It is possible that the titer of the antiferment may be altered, therefore, by means of selective feeding.
Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS)
Authors: Marc Bourlière, Jean-Pierre Bronowicki, Victor de Ledinghen, Christophe Hézode, Fabien Zoulim, Philippe Mathurin, Albert Tran, Dominique G Larrey, Vlad Ratziu, Laurent Alric, Robert H Hyland, Deyuan Jiang, Brian Doehle, Phillip S Pang, William T Symonds, G Mani Subramanian, John G McHutchison, Patrick Marcellin, François Habersetzer, Dominique Guyader, Jean-Didier Grangé, Véronique Loustaud-Ratti, Lawrence Serfaty, Sophie Metivier, Vincent Leroy, Armand Abergel, Stanislas Pol
Journal: The Lancet Infectious Diseases (2015)
Dnmt3b is a haploinsufficient tumor suppressor gene in Myc-induced lymphomagenesis
Authors: Aparna Vasanthakumar, Janet B. Lepore, Matthew H. Zegarek, Masha Kocherginsky, Mahi Singh, Elizabeth M. Davis, Petra A. Link, John Anastasi, Michelle M. Le Beau, Adam R. Karpf, Lucy A. Godley
Journal: Blood (2013)