tbuckley/cabot-search huggingface dataset:
Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis
Authors: Hiroshi Uchinami, Ekihiro Seki, David A. Brenner, Jeanine D'Armiento
Journal: Hepatology (2006)

Cholestasis occurs in a variety of clinical settings and often results in liver injury and secondary biliary fibrosis. Several matrix metalloproteinases (MMPs) are upregulated in the liver during cholestasis. The function of the major interstitial collagenase, MMP-13, in the initial phase of liver fibrosis is unknown. The aim of this study was to evaluate the role of MMP-13 during the development of cholestasis-induced liver fibrosis by comparing wild-type and MMP-13-deficient mice. Cholestasis was induced by bile duct ligation (BDL) for 5 days or 3 weeks. Activation and proliferation of hepatic stellate cells (HSCs) were detected by immunohistochemistry. Expression of MMP-13 mRNA increased significantly in BDL livers of WT mice. After BDL for 3 weeks liver fibrosis was suppressed in MMP-13-deficient mice versus WT animals. Activation and proliferation of HSCs were also suppressed in livers of MMP-13-deficient mice after BDL. To clarify the mechanism of this suppression, samples from 5-day BDL mice were used for evaluation of liver injury. Compared with those in WT animals, serum ALT and the number of hepatic neutrophils were reduced in MMP-13-deficient mice. Increased expression of the mRNA of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) was significantly suppressed in livers of MMP-13-deficient mice. Upregulation of fibrogenic markers, for example, transforming growth factor beta1 (TGF-β1), was also significantly suppressed in livers of MMP-13-deficient mice versus in WT mice. In conclusion , distinct from the known function of interstitial collagenase to reduce liver fibrosis by degrading the extracellular matrix, MMP-13 contributes to accelerating fibrogenesis in cholestatic livers by mediating the initial inflammation of the liver.
Plasminogen Activator Inhibitor-1 Promotes Formation of Endothelial Microparticles With Procoagulant Potential
Authors: Sergey V. Brodsky, Kazimierz Malinowski, Marc Golightly, Jolyon Jesty, Michael S. Goligorsky
Journal: Circulation (2002)

Endothelial dysfunction is emerging as a common denominator for diverse and highly prevalent cardiovascular diseases. Increased level of plasminogen activator inhibitor-1 (PAI-1) and procoagulant activity have been recognized as hallmarks of endothelial dysfunction. This study was aimed at investigating cellular actions of PAI-1 and a potential link between PAI-1 and procoagulant state.Human umbilical vein endothelial cells treated with PAI-1 were subjected to laser confocal fluorescence microscopy, immunoprecipitation and Western blotting, and FACS analysis for isolation and identification of endothelial microparticles. PAI-1 treatment resulted in a reduced expression of uPAR, its colocalization with caveolin, and the concomitant increase of uPAR abundance in the culture medium. FACS analysis revealed that PAI-1 rapidly and dose-dependently increased the number of endothelial microparticles expressing uPAR and alpha(V)beta3 integrin. This process was attenuated by pretreatment with neutralizing anti-uPAR antibodies. PAI-1 knockout mice showed a significantly decreased number of circulating endothelial microparticles than wild-type mice; however, PAI-1-deficient animals responded to infusion of PAI-1 with a more pronounced rise in the number of microparticles. PAI-1 treatment increased the number of microparticles stained with Annexin V, evidence for the expression of anionic phospholipids. This was accompanied by the accelerated generation of thrombin.The data disclose a novel effect of PAI-1 to dose-dependently promote formation of endothelial microparticles with the reduced transmembrane asymmetry of phospholipids. This phenomenon may be responsible for the observed increase in in vitro thrombin generation. These findings could potentially link these hallmarks of endothelial dysfunction-elevated levels of PAI-1 and propensity toward thrombosis.
The c-FLIP–NH2 terminus (p22-FLIP) induces NF-κB activation
Authors: Alexander Golks, Dirk Brenner, Peter H. Krammer, Inna N. Lavrik
Journal: The Journal of Experimental Medicine (2006)

c-FLIP proteins (isoforms: c-FLIPL, c-FLIPS, and c-FLIPR) play an essential role in the regulation of death receptor–induced apoptosis. Here, we demonstrate that the cytoplasmic NH2-terminal procaspase-8 cleavage product of c-FLIP (p22-FLIP) found in nonapoptotic malignant cells, primary T and B cells, and mature dendritic cells (DCs) strongly induces nuclear factor κB (NF-κB) activity by interacting with the IκB kinase (IKK) complex via the IKKγ subunit. Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-κB activation and life/death decisions in lymphocytes and DCs.
Comment on “A Peptidomimetic Targeting White Fat Causes Weight Loss and Improved Insulin Resistance in Obese Monkeys”
Authors: Leoluca Criscione
Journal: Science Translational Medicine (2012)

A study reporting that a peptidomimetic adipotide reduces weight loss in obese monkeys by inducing apoptosis of blood vessels surrounding white adipose tissue may instead reflect a direct effect of adipotide on food consumption.
CHANGES IN CELLULAR ENZYME LEVELS AND EXTRACELLULAR RELEASE OF LYSOSOMAL ACID HYDROLASES IN MACROPHAGES EXPOSED TO GROUP A STREPTOCOCCAL CELL WALL SUBSTANCE
Authors: Philip Davies, Roy C. Page, A. C. Allison
Journal: The Journal of Experimental Medicine (1974)

Mouse peritoneal macrophages exposed to type-specific polysaccharide and peptidoglycan (PPG) from group A streptococci undergo marked morphologic and biochemical changes. The cells show increases in size and an increased number of lysosomes as demonstrated by vital staining with acridine orange. There are significant elevations in the levels of both lysosomal and nonlysosomal enzymes. Higher doses of PPG cause selective release of the hydrolases into the extracellular environment with no detectable loss of cell viability. The in vitro phenomena may be relevant to understanding the role of macrophages in chronic inflammation.
Trends of cutaneous melanoma in The Netherlands: increasing incidence rates among all Breslow thickness categories and rising mortality rates since 1989
Authors: L.M. Hollestein, S.A.W. van den Akker, T. Nijsten, H.E. Karim-Kos, J.W. Coebergh, E. de Vries
Journal: Annals of Oncology (2011)
The hematopoietic cell transplantation comorbidity index (HCT-CI) predicts clinical outcomes in lymphoma and myeloma patients after reduced-intensity or non-myeloablative allogeneic stem cell transplantation
Authors: L Farina, B Bruno, F Patriarca, F Spina, R Sorasio, M Morelli, R Fanin, M Boccadoro, P Corradini
Journal: Leukemia (2009)
Pregnancy and Maternal Outcomes Among Kidney Transplant Recipients
Authors: Vicki Levidiotis, Sean Chang, Stephen McDonald
Journal: Journal of the American Society of Nephrology (2009)

Fertility rates, pregnancy, and maternal outcomes are not well described among women with a functioning kidney transplant. Using data from the Australian and New Zealand Dialysis and Transplant Registry, we analyzed 40 yr of pregnancy-related outcomes for transplant recipients. This analysis included 444 live births reported from 577 pregnancies; the absolute but not relative fertility rate fell during these four decades. Of pregnancies achieved, 97% were beyond the first year after transplantation. The mean age at the time of pregnancy was 29 +/- 5 yr. Compared with previous decades, the mean age during the last decade increased significantly to 32 yr (P < 0.001). The proportion of live births doubled during the last decade, whereas surgical terminations declined (P < 0.001). The fertility rate (or live-birth rate) for this cohort of women was 0.19 (95% confidence interval 0.17 to 0.21) relative to the Australian background population. We also matched 120 parous with 120 nulliparous women by year of transplantation, duration of transplant, age at transplantation +/-5 yr, and predelivery creatinine for parous women or serum creatinine for nulliparous women; a first live birth was not associated with a poorer 20-yr graft or patient survival. Maternal complications included preeclampsia in 27% and gestational diabetes in 1%. Taken together, these data confirm that a live birth in women with a functioning graft does not have an adverse impact on graft and patient survival.
Relation of Left Ventricular Function, Mass, and Volume to NT-proBNP in Type 1 Diabetic Patients
Authors: Anne Sofie Astrup, Won Yong Kim, Lise Tarnow, René M. Botnar, Cheryl Simonsen, Lau Brix, Lotte Pietraszek, Peter Riis Hansen, Warren J. Manning, Hans-Henrik Parving
Journal: Diabetes Care (2008)

To measure left ventricular mass (LVM), left ventricular volumes, and left ventricular function (LVF) in a cohort of type 1 diabetic patients and to correlate measures of imaging to NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP).In a cross-sectional study, all patients with type 1 diabetes underwent cardiovascular magnetic resonance imaging. We included 63 patients with diabetic nephropathy and 73 patients with normoalbuminuria.All patients had normal global LVF. LVM was increased in patients with diabetic nephropathy compared with patients with persistent normoalbuminuria. Patients with nephropathy had smaller left ventricular volumes and increased levels of NT-proBNP. Linear regression analysis in patients with diabetic nephropathy showed that NT-proBNP and creatinine were associated with LVM.Increased LVM is identified in asymptomatic type 1 diabetic patients with nephropathy compared with normoalbuminuric patients. Elevated levels of NT-proBNP were associated with increased LVM, which are both markers of increased cardiovascular risk.
Survey of European clinical geneticists on awareness, experiences and attitudes towards direct-to-consumer genetic testing
Authors: Heidi Carmen Howard, Pascal Borry
Journal: Genome Medicine (2013)

The advent of direct-to-consumer (DTC) genetic testing (GT) has sparked a number of debates regarding the scientific validity of tests, their broad health and ethical implications for society as well as their legal status. To date, relatively few empirical studies have been published regarding this phenomenon. We conducted a survey of European clinical geneticists to gauge their awareness of, experiences with, and attitudes towards DTC GT.We invited 300 clinical geneticists from 28 European countries to complete an online questionnaire. Statistical analyses of closed-ended questions were performed using the STATISTICA software package. Answers to open-ended questions were analysed for recurring themes.One hundred and thirty-one clinical geneticists answered our survey (response rate, 44%). Eighty-six percent (110/128) of respondents were aware of DTC GT, and over one-third had been contacted by at least one patient regarding these services. The majority (84%) of respondents did not agree with telephone medical supervision outside of an established doctor-patient relationship. The majority of clinical geneticists also found it unacceptable to provide non-face-to-face medical supervision for: (i) a presymptomatic test for a condition with very high penetrance; (ii) a predictive test for a condition that has a 'medium' penetrance of 50% to 60%; and (iii) carrier testing. For conditions that are neither treatable nor preventable and for disorders with serious health consequences, clinical geneticists were almost unanimous in expressing the unacceptability of offering such genetic tests outside of the traditional healthcare setting, without an established physician-patient relationship and without face-to-face medical supervision.A high percentage of European clinical geneticists are aware of DTC GT and the majority do not agree with the model of provision used by many commercial companies for certain severe or actionable health conditions. Despite this disagreement with the DTC model of provision, >85% of respondents said that they would offer genetic counselling to patients who asked for a consultation after having undergone DTC genetic testing. The understanding of the views and opinions of this expert stakeholder group should be considered in the attempts to shape responsible policy and guidelines for these services.
CC Chemokines and Interleukin-5 in Bronchial Lavage Fluid from Patients with Status Asthmaticus
Authors: ISABELLE TILLIE-LEBLOND, HAMIDA HAMMAD, SOPHIE DESURMONT, JÉRÔME PUGIN, BENOÎT WALLAERT, ANDRÉ-BERNARD TONNEL, PHILIPPE GOSSET
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

In status asthmaticus (SA), severe bronchial inflammation is associated with acute respiratory failure. Neutrophils are the prominent cells found in bronchi from SA patients, but eosinophils are also recruited within the first 48 h after the beginning of mechanical ventilation (MV). Interleukin (IL)-5 and CC chemokines have been directly implicated in the pathophysiology of allergic asthma. However, their involvement in SA had not been determined. The aim of this study was to evaluate the production of CC chemokines and of IL-5 in airways from ventilated patients with SA as compared with mild asthma (A), and to assess the role of these mediators in eosinophil recruitment. We measured levels of the chemokines monocyte chemotactic proteins (MCPs)-1 and -3; regulated on activation, normal T-cell expressed and secreted (RANTES); macrophage inflammatory peptide (MIP)-1alpha; and eotaxin; and of the cytokine IL-5 in bronchial lavage fluid (BLF) from 10 SA patients, four patients without respiratory disease but undergoing ventilation (V) who were receiving MV, 11 patients with A, and eight healthy volunteers (C). We further evaluated in vitro eosinophil chemotactic activity of BLF from the various groups. Levels of MCP-1, MIP-1alpha, RANTES, and IL-5 were significantly higher in the SA than in the V, A, and C groups. MCP-3 and eotaxin values were not significantly different in the SA and other groups; however, their levels, as well as those of MIP-1alpha, RANTES, and IL-5 correlated with eosinophil influx. Eosinophil chemotactic activity in BLF was increased in asthmatic subjects (A and SA groups) as compared with the other groups, and in SA patients as compared with A patients. Addition of neutralizing anti-IL-5, anti-MCP-3, anti-eotaxin, and anti-RANTES antibodies significantly inhibited the eosinophil chemotactic activity as compared with that of native BLF. This study shows that the levels of various CC chemokines and IL-5 are increased in airways of SA patients, and are potentially involved in eosinophil recruitment.
Cytotoxicity of Activated Natural Killer Cells against Pediatric Solid Tumors
Authors: Duck Cho, David R. Shook, Noriko Shimasaki, Yu-Hsiang Chang, Hiroyuki Fujisaki, Dario Campana
Journal: Clinical Cancer Research (2010)

To develop new therapies for children with solid tumors, we tested the cytotoxicity of natural killer (NK) cells expanded by coculture with K562-mb15-41BBL cells. We sought to identify the most sensitive tumor subtypes, clarify the molecular interactions regulating cytotoxicity, and determine NK antitumor potential in vivo.We tested in vitro cytotoxicity of expanded NK cells against cell lines representative of Ewing sarcoma (EWS; n = 5), rhabdomyosarcoma (n = 4), neuroblastoma (n = 3), and osteosarcoma (n = 3), and correlated the results with expression of inhibitory and activating NK receptor ligands. We also compared expanded and primary NK cells, determined the effects of activating receptor ligation and of chemotherapeutic drugs, and assessed the therapeutic effect of NK cell infusions in xenografts.In 45 experiments, EWS and rhabdomyosarcoma cell lines were remarkably sensitive to expanded NK cells, with median cytotoxicities at 1:1 effector/target ratio of 87.2% and 79.1%, respectively. Cytotoxicity was not related to levels of expression of NK receptor ligands, nor was it affected by pretreatment of target cells with daunorubicin or vincristine, but was markedly inhibited by preincubation of NK cells with a combination of antibodies against the NK-activating receptors NKGD2 and DNAM-1. Expanded NK cells were considerably more cytotoxic than unstimulated NK cells, and eradicated EWS cells engrafted in nonobese diabetic/severe combined immunodeficient Il2rgnull mice.Among pediatric solid tumors, EWS and rhabdomyosarcoma are exquisitely sensitive to expanded NK cells. The NK expansion method described here has been adapted to large-scale conditions and supports a phase I clinical study including patients with these malignancies.
Interferon- therapy in two patients with progressive chronic pulmonary aspergillosis
Authors: P. Kelleher, A. Goodsall, A. Mulgirigama, H. Kunst, D. C. Henderson, R. Wilson, A. Newman-Taylor, M. Levin
Journal: European Respiratory Journal (2006)

Infection by Aspergillus species causes a wide spectrum of pulmonary disease in humans. In two patients with semi-invasive Aspergillus-induced lung disease, significantly reduced levels of interferon-γ secretion by peripheral blood mononuclear cells were found after in vitro stimulation with the T-cell mitogen phytohaemagglutinin. Despite anti-fungal therapy, both patients exhibited progressive disease, and adjunctive interferon-γ therapy was associated with significant clinical improvement. The data suggest that impaired production of interferon-γ can be seen in patients with chronic pulmonary aspergillosis. Adjunctive cytokine therapy with interferon-γ may be useful in patients with progressive disease despite adequate anti-fungal therapy.
Congenital Absence of the Left Pericardium
Authors: WILLIAM NASSER, HARVEY FEIGENBAUM, CHARLES HELMEN
Journal: Circulation (1966)

A case of complete absence of the left pericardium, suspected from plain chest x-rays and proved by diagnostic left pneumothorax, has been reported. The significance of the pericardium in relation to cardiac function is discussed. Because absence of the left pericardium is a benign and relatively asymptomatic anomaly that usually requires no treatment, it behooves the clinician and radiologist to become cognizant of its presence.
Health conditions and health-policy innovations in Brazil: the way forward
Authors: Cesar G Victora, Mauricio L Barreto, Maria do Carmo Leal, Carlos A Monteiro, Maria Ines Schmidt, Jairnilson Paim, Francisco I Bastos, Celia Almeida, Ligia Bahia, Claudia Travassos, Michael Reichenheim, Fernando C Barros
Journal: The Lancet (2011)
<i>HER2</i> and Chromosome 17 Effect on Patient Outcome in the N9831 Adjuvant Trastuzumab Trial
Authors: Edith A. Perez, Monica M. Reinholz, David W. Hillman, Kathleen S. Tenner, Matthew J. Schroeder, Nancy E. Davidson, Silvana Martino, George W. Sledge, Lyndsay N. Harris, Julie R. Gralow, Amylou C. Dueck, Rhett P. Ketterling, James N. Ingle, Wilma L. Lingle, Peter A. Kaufman, Daniel W. Visscher, Robert B. Jenkins
Journal: Journal of Clinical Oncology (2010)

We examined associations between tumor characteristics (human epidermal growth factor receptor 2 [HER2] protein expression, HER2 gene and chromosome 17 copy number, hormone receptor status) and disease-free survival (DFS) of patients in the N9831 adjuvant trastuzumab trial.All patients (N = 1,888) underwent chemotherapy with doxorubicin and cyclophosphamide, followed by weekly paclitaxel with or without concurrent trastuzumab. HER2 status was determined by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) at a central laboratory, Mayo Clinic, Rochester, MN. Patients with conflicting local positive HER2 expression results but normal central laboratory testing were included in the analyses (n = 103).Patients with HER2-positive tumors (IHC 3+, FISH HER2/centromere 17 ratio ≥ 2.0, or both) benefited from trastuzumab, with hazard ratios (HRs) of 0.46, 0.49, and 0.45, respectively (all P < .0001). Patients with HER2-amplified tumors with polysomic (p17) or normal (n17) chromosome 17 copy number also benefited from trastuzumab, with HRs of 0.52 and 0.37, respectively (P < .006). Patients who received chemotherapy alone and had HER2-amplified and p17 tumors had a longer DFS than those who had n17 (78% v 68%; P = .04), irrespective of hormone receptor status or tumor grade. Patients with HER2-normal tumors by central testing (n = 103) seemed to benefit from trastuzumab, but the difference was not statistically significant (HR, 0.51; P = .14). Patients with hormone receptor-positive or -negative tumors benefited from the addition of trastuzumab, with HRs of 0.42 (P = .005) and 0.60 (P = .0001), respectively.These results confirm that IHC or FISH HER2 testing is appropriate for patient selection for adjuvant trastuzumab therapy. Trastuzumab benefit seemed independent of HER2/centromere 17 ratio and chromosome 17 copy number.
Epithelioid Hemangioendothelioma of the Thoracic Aorta Resulting in Aortic Obstruction and Congestive Heart Failure
Authors: Jay H. Traverse, John R. Lesser, Bjorn P. Flygenring, Thomas H. Bracken, Olga M. Olevsky, Demetre M. Nicoloff, Thomas Flavin, Charles A. Horwitz, Robert G. Hauser
Journal: Circulation (1999)
Sex Differences in Response to Lithium Treatment
Authors: Adele C. Viguera, Leonardo Tondo, Ross J. Baldessarini
Journal: American Journal of Psychiatry (2000)

Although sex differences occur with some psychotropic drug treatments, they are not well defined for mood-stabilizing agents, including lithium. The authors' goal was to investigate whether there are differences between the sexes in response to lithium.Studies identified in a literature search were analyzed for reports of sex differences in clinical response to lithium in major affective syndromes.Data from 17 studies published in 1967-1998, involving 1,548 adults treated with lithium for a mean of 38.6 months (SD=30.5), yielded similar weighted response rates to lithium in 1,043 women (65.6% [N=684]) and 505 men (61.0% [N=308]).The results indicate little difference between the sexes in clinical response to lithium treatment of bipolar and related affective disorders.