tbuckley/cabot-search huggingface dataset:
Mevalonate-Dependent Inhibition of Transendothelial Migration and Chemotaxis of Human Peripheral Blood Neutrophils by Pravastatin
Authors: Stefan Dunzendorfer, Dorothea Rothbucher, Peter Schratzberger, Norbert Reinisch, Christian M. Kähler, Christian J. Wiedermann
Journal: Circulation Research (1997)

Pravastatin, a hydrophilic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, has been reported to beneficially affect atherogenesis, plaque stability, and transient myocardial ischemia in significant coronary artery disease by influencing lipid metabolism and by intracellular signaling via mevalonate pathway products other than cholesterol. Leukocytes are implicated to play a pathophysiological role in these events. We were interested in finding out whether pravastatin could affect transendothelial migration (TEM), chemotaxis, and respiratory burst activity of the neutrophil ex vivo. In addition, effects on monocyte and T-lymphocyte chemotaxis were tested. For TEM assays, monolayers of human umbilical vein endothelial cells (HUVECs) were grown to confluence on polycarbonate filters bearing 5-microns pores in Transwell (Costar) culture plate inserts. Chemotaxis experiments were performed using modified Boyden chambers with cellulose nitrate micropore filters. Respiratory burst activity was measured fluorometrically. Treatment of neutrophils and monocytes with pravastatin at 2 to 200 mumol/L and 10 to 1000 mumol/L, respectively, significantly decreased chemotaxis triggered by fMet-Leu-Phe. This effect was abolished in the presence of mevalonic acid (500 mumol/L); no effect of pravastatin was seen on T-lymphocyte chemotaxis triggered by interleukin-8. Preincubation of neutrophils with pravastatin (200 mumol/L) also resulted in a significant reduction in the number of neutrophils that transmigrated a tumor necrosis factor-stimulated or lipopolysaccharide-stimulated HUVEC monolayer. At none of the concentrations tested (2 pmol/L to 200 mumol/L) did pravastatin affect neutrophil respiratory burst activity. We conclude that pravastatin may alter monocyte chemotaxis and neutrophil-endothelial interactions in migratory responses at concentrations obtained in vivo with cholesterol-lowering doses.
Modulation of miR-29 expression by alpha-fetoprotein is linked to the hepatocellular carcinoma epigenome
Authors: Sonya Parpart, Stephanie Roessler, Fei Dong, Vinay Rao, Atsushi Takai, Junfang Ji, Lun-Xiu Qin, Qing-Hai Ye, Hu-Liang Jia, Zhao-You Tang, Xin Wei Wang
Journal: Hepatology (2014)

Globally, hepatocellular carcinoma (HCC) accounts for 70%-85% of primary liver cancers and ranks as the second leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP + and AFP − tumors differ biologically. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage ( P &lt; 0.043). Using microarray-based global microRNA (miRNA) profiling, we found that miRNA-29 (miR-29) family members were the most significantly ( P &lt; 0.001) down-regulated miRNAs in AFP + tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation ( P &lt; 0.001) between miR-29 and DNMT3A gene expression, suggesting that they might be functionally antagonistic. Moreover, global DNA methylation profiling reveals that AFP + and AFP − HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP + HCC. Experimentally, we found that AFP expression in AFP − HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP + cells, inhibits miR-29a expression and induces DNMT3A expression in AFP − HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus, and this effect is mediated through c-MYC binding to the transcript of miR-29a/b-1. Furthermore, AFP expression promotes tumor growth of AFP − HCC cells in nude mice. Conclusion : Tumor biology differs considerably between AFP + HCC and AFP − HCC; AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC. (Hepatology 2014;60:872–883)
Heat Shock Protein 70 Promotes Cell Survival by Inhibiting Lysosomal Membrane Permeabilization
Authors: Jesper Nylandsted, Mads Gyrd-Hansen, Agnieszka Danielewicz, Nicole Fehrenbacher, Ulrik Lademann, Maria Høyer-Hansen, Ekkehard Weber, Gabriele Multhoff, Mikkel Rohde, Marja Jäättelä
Journal: The Journal of Experimental Medicine (2004)

Heat shock protein 70 (Hsp70) is a potent survival protein whose depletion triggers massive caspase-independent tumor cell death. Here, we show that Hsp70 exerts its prosurvival function by inhibiting lysosomal membrane permeabilization. The cell death induced by Hsp70 depletion was preceded by the release of lysosomal enzymes into the cytosol and inhibited by pharmacological inhibitors of lysosomal cysteine proteases. Accordingly, the Hsp70-mediated protection against various death stimuli in Hsp70-expressing human tumor cells as well as in immortalized Hsp70 transgenic murine fibroblasts occurred at the level of the lysosomal permeabilization. On the contrary, Hsp70 failed to inhibit the cytochrome c-induced, apoptosome-dependent caspase activation in vitro and Fas ligand-induced, caspase-dependent apoptosis in immortalized fibroblasts. Immunoelectron microscopy revealed that endosomal and lysosomal membranes of tumor cells contained Hsp70. Permeabilization of purified endo/lysosomes by digitonin failed to release Hsp70, suggesting that it is physically associated with the membranes. Finally, Hsp70 positive lysosomes displayed increased size and resistance against chemical and physical membrane destabilization. These data identify Hsp70 as the first survival protein that functions by inhibiting the death-associated permeabilization of lysosomes.
Birth weight, childhood socioeconomic environment, and cognitive development in the 1958 British birth cohort study
Authors: B. J M H Jefferis
Journal: BMJ (2002)

<h3>abstract</h3> <b>Objectives:</b> To examine the combined effect of social class and weight at birth on cognitive trajectories during school age and the associations between birth weight and educational outcomes through to 33 years. <b>Design</b>: Longitudinal, population based, birth cohort study. <b>Participants</b>: 10 845 males and females born during 3-9 March 1958 with information on birth weight, social class, and cognitive tests. <b>Main outcome measures</b>: Reading, maths, draw a man, copying designs, verbal and non-verbal ability tests at ages 7, 11, and 16, highest qualifications achieved by 33, and trajectories of maths standardised scores at 7-16 years. <b>Results</b>: The outcome of all childhood cognitive tests and educational achievements improved significantly with increasing birth weight. Analysis of maths scores at 7 and of highest qualifications achieved by 33 showed that the relations were robust to adjustment for potential confounding factors. For each kilogram increase in birth weight, maths z score increased by 0.17 (adjusted estimate 0.15, 95% confidence interval 0.10 to 0.21) for males and 0.21 (0.20, 0.14 to 0.25) for females. Trajectories of maths z scores between 7 and 16 years diverged for different social class groups: participants from classes I and II increased their relative position on the score with increasing age, whereas classes IV and V showed a relative decline with increasing age. Birth weight explained much less of the variation in cognition than did social class (range 0.5-1.5% <i>v</i> 2.9-12.5%). <b>Conclusions</b>: The postnatal environment has an overwhelming influence on cognitive function through to early adulthood, but these strong effects do not explain the weaker but independent association with birth weight.
Immunization of mice against African trypanosomiasis using anti-idiotypic antibodies.
Authors: D L Sacks, K M Esser, A Sher
Journal: The Journal of Experimental Medicine (1982)

Anti-idiotypic (anti-Id) antibodies were raised against three protective monoclonal antibodies, each with specificity for the variable antigen type (VAT) of a clone of Trypanosoma rhodesiense. The IgG1 fractions of each were pooled and administered to BALB/c mice 3-4 wk before homologous challenge. The course of primary parasitemia was altered in 19 of 30 anti-Id-treated animals. The immunity was manifested as either: (a) complete protection, (b) reduced parasitemia, or (c) selection against parasites bearing the original VAT. The three idiotypes (Id) were found in variable levels in serum during the course of infection in control animals. However, in all anti-Id-treated mice that displayed immunity, one Id in particular (7H11) was detectable much earlier in infection and in higher levels than in control mice or anti-Id-treated, nonimmune mice. Six of nine mice treated with the anti-7H11 Id alone also displayed immunity, manifested in this case exclusively as selection against parasites bearing the original VAT. The effect was again associated with the more rapid appearance of the Id after infection. Specificity of the anti-Id-induced immunity was supported by the failure of anti-7H11 Id treatment to alter the course of infection with a heterologous clone of T. rhodesiense. To our knowledge, this is the first report of the antigen-independent induction of antimicrobial immunity using anti-Id antibodies.
Vacuolar and plasma membrane stripping and autophagic elimination of <i>Toxoplasma gondii</i> in primed effector macrophages
Authors: Yun M. Ling, Michael H. Shaw, Carol Ayala, Isabelle Coppens, Gregory A. Taylor, David J.P. Ferguson, George S. Yap
Journal: The Journal of Experimental Medicine (2006)

Apicomplexan protozoan pathogens avoid destruction and establish a replicative niche within host cells by forming a nonfusogenic parasitophorous vacuole (PV). Here we present evidence for lysosome-mediated degradation of Toxoplasma gondii after invasion of macrophages activated in vivo. Pathogen elimination was dependent on the interferon γ inducible-p47 GTPase, IGTP, required PI3K activity, and was preceded by PV membrane indentation, vesiculation, disruption, and, surprisingly, stripping of the parasite plasma membrane. Denuded parasites were enveloped in autophagosome-like vacuoles, which ultimately fused with lysosomes. These observations outline a series of mechanisms used by effector cells to redirect the fate of a classically nonfusogenic intracellular pathogen toward a path of immune elimination.
GENETIC FACTORS UNDERLYING VARIABILITY IN METHADONE PLASMA LEVELS AND QTC PROLONGATION DURING METHADONE TREATMENT FOR OPIOID ADDICTION: THE MEMORIES TRIAL
Authors: Jeffrey L. Anderson, Eric Johnson, Marian Jacobsen, John Huntinghouse, Jeffrey Rollo, Stacey Knight, J. Muhlestein, john carlquist
Journal: Journal of the American College of Cardiology (2012)
Breast Cancer Risk After Caloric Restriction During the 1944-1945 Dutch Famine
Authors: S. G. Elias, P. H. M. Peeters, D. E. Grobbee, P. A. H. v. Noord
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Data from animal models suggest that caloric restriction may reduce the risk of breast cancer, although not all dietary regimens produce similar effects. We examined whether caloric restriction imposed as a consequence of the 1944–1945 Dutch famine reduced the risk of breast cancer in women participating in a Dutch breast cancer screening program. Methods: Between 1983 and 1986, approximately 15 000 women, aged 2 to 33 years during the 1944–1945 Dutch famine, responded to a questionnaire about their famine experience. A famine exposure score, graded as absent, moderate, or severe exposure, was derived from answers regarding hunger, cold, and weight loss. During follow-up until January 2000, 585 women with incident breast cancer were identified by the regional cancer registry. The relationship between famine exposure and breast cancer risk was assessed by weighted Cox regression models, in which person-years lived for the entire cohort was extrapolated from data from a random sample of 15% of the cohort. Results: Women who were severely exposed to the famine had a statistically significantly higher risk of breast cancer (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.09 to 2.01) than women who were not exposed. Women who were moderately exposed to the famine had a 13% increased risk of breast cancer (HR = 1.13, 95% CI = 0.92 to 1.38; Ptrend = 0.016). The association between famine exposure and breast cancer risk was stronger for women who were exposed between the ages of 2 and 9 years (severely exposed versus unexposed: HR = 2.01, 95% CI = 0.92 to 4.41) than for women who were exposed at older ages. Conclusions: The risk of breast cancer was increased in women who were severely exposed to a short but severe famine decades earlier. This result is compatible with data from the few animal studies investigating effects of short-term, transient caloric restriction.
Empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor prognosis in endemic areas
Authors: J-Y Wang
Journal: Thorax (2006)

A study was conducted to evaluate the effect of the empirical use of fluoroquinolones on the timing of antituberculous treatment and the outcome of patients with tuberculosis in an endemic area.All patients with culture confirmed tuberculosis aged > or =14 years diagnosed between July 2002 and December 2003 were included and their medical records were reviewed.Seventy nine (14.4%) of the 548 tuberculosis patients identified received a fluoroquinolone (FQ group), 218 received a non-fluoroquinolone antibiotic (AB group), and 251 received no antibiotics before antituberculous treatment. Fifty two (65.8%) experienced clinical improvement after fluoroquinolone use. In the FQ group the median interval from the initial visit to starting antituberculous treatment was longer than in the AB group and in those who received no antibiotics (41 v 16 v 7 days), and the prognosis was worse (hazard ratio 6.88 (95% CI 1.84 to 25.72)). More patients in the FQ and AB groups were aged >65 years (53.2% and 61.0% v 31.5%), had underlying disease (53.2% and 46.8% v 34.3%), and were hypoalbuminaemic (67.2% and 64.9% v 35.1%). Of the nine mycobacterial isolates obtained after fluoroquinolone use from nine patients whose initial isolates were susceptible to ofloxacin, one (11.1%) was resistant to ofloxacin (after fluoroquinolone use for 7 days). Independent factors for a poor prognosis included empirical fluoroquinolone use, age >65, underlying disease, hypoalbuminaemia, and lack of early antituberculous treatment.14.4% of our patients with tuberculosis received a fluoroquinolone before the diagnosis. With a 34 day delay in antituberculous treatment and more frequent coexistence of underlying disease and hypoalbuminaemia, empirical fluoroquinolone treatment was associated with a poor outcome. Mycobacterium tuberculosis isolates could obtain ofloxacin resistance within 1 week.
Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia
Authors: John C. Byrd, Jennifer R. Brown, Susan O'Brien, Jacqueline C. Barrientos, Neil E. Kay, Nishitha M. Reddy, Steven Coutre, Constantine S. Tam, Stephen P. Mulligan, Ulrich Jaeger, Steve Devereux, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Florence Cymbalista, Christopher Pocock, Patrick Thornton, Federico Caligaris-Cappio, Tadeusz Robak, Julio Delgado, Stephen J. Schuster, Marco Montillo, Anna Schuh, Sven de Vos, Devinder Gill, Adrian Bloor, Claire Dearden, Carol Moreno, Jeffrey J. Jones, Alvina D. Chu, Maria Fardis, Jesse McGreivy, Fong Clow, Danelle F. James, Peter Hillmen
Journal: New England Journal of Medicine (2014)

In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.
Specifically Binding of L-ficolin to N-glycans of HCV Envelope Glycoproteins E1 and E2 Leads to Complement Activation
Authors: Jun Liu, Mohammed A M Ali, Yinghua Shi, Yinglan Zhao, Fenglin Luo, Jin Yu, Tian Xiang, Jie Tang, Dongqing Li, Quan Hu, Wenzhe Ho, Xiaolian Zhang
Journal: Cellular and Molecular Immunology (2009)
Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up
Authors: Y. Peker, J. Carlson, J. Hedner
Journal: European Respiratory Journal (2006)

An increased incidence of cardiovascular disease has previously been reported in middle-aged males during a follow-up period of 7 yrs. The aim of the present study was to address the incidence of coronary artery disease (CAD) in a larger sample without any heart disease at baseline. The population comprised 308 snorers (245 males and 63 females) with a mean± sd age of 49.0±9.9 yrs in 1991. Data were collected via the Swedish Hospital Discharge Register, National Cause of Death Registry, clinical charts and questionnaires. Over 7 yrs, CAD was observed in 17 (16.2%) of 105 patients with obstructive sleep apnoea (OSA; overnight (6 h) oxygen desaturations ≥30 events) compared with 11 (5.4%) of 203 snorers without OSA. OSA diagnosis at baseline was associated with an increased risk of development of CAD in a multivariate model. In the OSA group, CAD was confirmed in 16 (24.6%) of 65 incompletely treated patients compared with one (3.9%) of 26 efficiently treated subjects. Efficient treatment of OSA reduced this risk. It is concluded that middle-aged sleep apnoeics are at high risk of developing coronary artery disease if they are not treated efficiently, which should be considered in cardiovascular disease prevention models.
Presence of the Metabolic Syndrome Is Not a Better Predictor of Cardiovascular Disease Than the Sum of Its Components in HIV-Infected Individuals
Authors: Signe W. Worm, Caroline A. Sabin, Peter Reiss, Wafaa El-Sadr, Antonella d'Arminio Monforte, Christian Pradier, Rodolphe Thiebaut, Matthew Law, Martin Rickenbach, Stephane De Wit, Jens D. Lundgren, Nina Friis-Møller
Journal: Diabetes Care (2008)

It is much debated whether the metabolic syndrome contributes additional information over and above that provided by the individual components of the syndrome alone. Among HIV-infected individuals, we investigated whether any particular combinations of the components included in the definition of the metabolic syndrome are associated with a higher risk of cardiovascular disease (CVD).We followed 33,347 HIV-infected individuals in a prospective observational study. The effect of combinations of components of the metabolic syndrome (low HDL cholesterol, high triglycerides, high BMI, hypertension, and diabetes) on the risk of CVD was assessed by Poisson regression incorporating interactions between each component pair and adjusting for age, sex, family history of CVD, smoking status, calendar year, and exposure to antiretroviral therapy. We reduced the risk of type 1 errors by randomly splitting the data set for training (70% of sample) and validation (remaining 30%).In the training data set, 671 patients experienced a CVD event over 110,652 person-years. Unadjusted, the presence of metabolic syndrome at study enrollment (>or=3 of the factors) was associated with a 2.89 higher risk of CVD (95% CI 2.34-3.59; P = 0.0001) compared with individuals without the metabolic syndrome. After adjustment for the individual components, the metabolic syndrome as an entity no longer predicted the risk of CVD (adjusted relative risk 0.85; 95% CI 0.61-1.17; P = 0.32). No significant positive interactions were found among the components of the metabolic syndrome.The presence of the metabolic syndrome in HIV-infected individuals did not appear to increase the CVD risk over and above that conferred by the components of the syndrome separately.
Nonhuman Primate Models for SARS
Authors: Bart L Haagmans, Albert D. M. E Osterhaus
Journal: PLoS Medicine (2006)

Severe acute respiratory syndrome (SARS) first emerged in Guangdong Province, the People's Republic of China, in November 2002. The disease was characterised by a rapidly progressive atypical pneumonia [ 1]. In addition to other pathogens, a coronavirus not previously discovered was identified in patients with SARS. Reproduction of a similar disease in cynomolgus macaques with this virus completed Koch's postulates, implicating SARS coronavirus (SARS-CoV) as the aetiologic agent [ 2, 3].
Amplicon Mapping and Expression Profiling Identify the Fas-Associated Death Domain Gene as a New Driver in the 11q13.3 Amplicon in Laryngeal/Pharyngeal Cancer
Authors: Johan H. Gibcus, Lorian Menkema, Mirjam F. Mastik, Mario A. Hermsen, Geertruida H. de Bock, Marie-Louise F. van Velthuysen, Robert P. Takes, Klaas Kok, Cesar A. Álvarez Marcos, Bernard F.A.M. van der Laan, Michiel W.M. van den Brekel, Johannes A. Langendijk, Philip M. Kluin, Jacqueline E. van der Wal, Ed Schuuring
Journal: Clinical Cancer Research (2007)

Amplification of the 11q13 region is a frequent event in human cancer. The highest incidence (36%) is found in head and neck squamous cell carcinomas. Recently, we reported that the amplicon size in 30 laryngeal and pharyngeal carcinomas with 11q13 amplification is determined by unique genomic structures, resulting in the amplification of a set of genes rather than a single gene.To investigate which gene(s) drive the 11q13 amplicon, we determined the smallest region of overlap with amplification and the expression levels of all genes within this amplicon.Using array-based comparative genomic hybridization analysis, we detected a region of approximately 1.7 Mb containing 13 amplified genes in more than 25 of the 29 carcinomas. Quantitative reverse transcription-PCR revealed that overexpression of 8 potential driver genes including, cyclin D1, cortactin, and Fas-associated death domain (FADD), correlated significantly with DNA amplification. FADD protein levels correlated well with DNA amplification, implicating that FADD is also a candidate driver gene in the 11q13 amplicon. Analysis of 167 laryngeal carcinomas showed that increased expression of FADD (P = 0.007) and Ser(194) phosphorylated FADD (P = 0.011) were associated with a worse disease-specific survival. FADD was recently reported to be involved in cell cycle regulation, and cancer cells expressing high levels of the Ser(194) phosphorylated isoform of FADD proved to be more sensitive to Taxol-induced cell cycle arrest.Because of the frequent amplification of the 11q13 region and concomitant overexpression of FADD in head and neck squamous cell carcinomas, we hypothesize that FADD is a marker to select patients that might benefit from Taxol-based chemoradiotherapy.