tbuckley/cabot-search huggingface dataset:
The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis
Authors: Jie Zhang, Lang Chen, Elizabeth Delzell, Paul Muntner, William B Hillegass, Monika M Safford, Iris Yolanda Navarro Millan, Cynthia S Crowson, Jeffrey R Curtis
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> To examine the association of serum inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and serum lipid measures (low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol) with risk of myocardial infarction (MI) and ischaemic stroke (IS) among rheumatoid arthritis (RA) patients. <h3>Methods</h3> We conducted a retrospective cohort study using 2005–2010 data from a US commercial health plan. Eligible patients had two or more physician diagnoses of RA during a baseline period of at least 180 days with continuous medical and pharmacy coverage. We computed age-adjusted incidence rates of MI and IS, and used spline regression to assess non-linear associations and Cox-regression to quantify the independent association between the laboratory values and the outcomes. <h3>Results</h3> We identified 44 418 eligible RA patients (mean age 49 years; 76% women). CRP&gt;10 mg/L compared with &lt;1 mg/L was associated with increased MI risk (HR 2.12; 95% CI 1.02 to 4.38). ESR&gt;42 mm/h compared with &lt;14 mm/h was associated with increased risk of MI (HR 2.53; 95% CI 1.48 to 4.31) and IS (HR 2.51; 95% CI 1.33 to 4.75) risk. HDL-cholesterol ≥60 mg/dL (1.6 mmol/L) compared with &lt;40 mg/dL (1.0 mmol/L) was associated with reduced MI risk (HR 0.37; 0.21 to 0.66). The association between LDL and MI was not linear; the lowest risk was observed among patients with LDL between 70 mg/L (1.8 mmol/L) and 100 mg/L (2.6 mmol/L). We did not observe a significant association between LDL and IS. <h3>Conclusions</h3> This study provides evidence supporting the hypothesis that RA-related systemic inflammation plays a role in determining cardiovascular risk and a complex relationship between LDL and cardiovascular risk.
Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent.
Authors: C J Allegra, J A Kovacs, J C Drake, J C Swan, B A Chabner, H Masur
Journal: The Journal of Experimental Medicine (1987)

The therapy of Pneumocystis carinii (PC) pneumonia is often unsuccessful, particularly in patients with acquired immune deficiency syndrome (AIDS). Because of difficulties in growing the organism in vitro or obtaining purified organisms, current treatment choices have been made with little information on the metabolic effects of therapeutic agents on PC. This report quantitates the effects of the commonly used antifolates as well as the classic antineoplastic antifolate methotrexate and a lipid-soluble analogue, trimetrexate, on the target enzyme, dihydrofolate reductase (DHFR), in the PC organisms. Trimethoprim and pyrimethamine were found to be weak inhibitors (ID50 = 39,600 and 2,800 nM, respectively), while methotrexate and trimetrexate were potent reductase inhibitors (ID50 = 1.4 and 26.1 nM, respectively). transport studies with radiolabeled compounds showed that compounds with the classic folate structure (methotrexate and leucovorin) were not taken up by the intact PC organisms. In contrast, trimetrexate exhibited rapid uptake. These results suggest a major therapeutic advantage may be gained by combining a potent, readily transported PC DHFR inhibitor such as trimetrexate with the reduced folate leucovorin to achieve a highly potent antiprotozoan effect while preventing toxicity to mammalian cells.
Down-regulation of Rap1GAP via Promoter Hypermethylation Promotes Melanoma Cell Proliferation, Survival, and Migration
Authors: Hong Zheng, Ling Gao, Yunfeng Feng, Liya Yuan, Haibo Zhao, Lynn A. Cornelius
Journal: Cancer Research (2009)

Melanoma is the most serious, highly aggressive form of skin cancer with recent dramatic increases in incidence. Current therapies are relatively ineffective, highlighting the need for a better understanding of the molecular mechanisms contributing to the disease. We have previously shown that activation of Rap1 promotes melanoma cell proliferation and migration through the mitogen-activated protein kinase pathway and integrin activation. In the present study, we show that expression of Rap1GAP, a specific negative regulator of Rap1, is decreased in human melanoma tumors and cell lines. Overexpression of Rap1GAP in melanoma cells blocks Rap1 activation and extracellular signal-regulated kinase (ERK) phosphorylation and inhibits melanoma cell proliferation and survival. In addition, overexpression of Rap1GAP also inhibits focal adhesion formation and decreases melanoma cell migration. Rap1GAP down-regulation is due to its promoter methylation, a mechanism of gene silencing in tumors. Furthermore, treatment of melanoma cells with the demethylating agent 5-aza-2'-deoxycytidine reinduces Rap1GAP expression, followed by decreased Rap1 activity, ERK phosphorylation, and cell proliferation and survival-changes that are significantly blunted in cells transfected by small interfering RNA-mediated Rap1GAP knockdown. Taken together, our findings indicate that down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.
Cancer Stem Cells and Radiotherapy: New Insights Into Tumor Radioresistance
Authors: Maximilian Diehn, Michael F. Clarke
Journal: JNCI Journal of the National Cancer Institute (2006)

EDITORIALS 1755 Solid tumors are histologically heterogeneous and include tumor cells, stroma, infl ammatory infi ltrates, and vascular structures. Furthermore, it has long been recognized that subpopulations of cancer cells exist within the tumors that resemble the developmental hierarchy of the normal tissue from which the tumor arose . In recent years, the cancer stem cell model of tumorigenesis has received increasing attention. This model posits that tumors are driven and maintained by a minority subpopulation of cells that have the capacity to self-renew (i.e., give rise to progeny with similar properties as themselves) and to generate the more differentiated progeny which make up the bulk of a tumor (1) . The former population has been termed cancer stem cells (CSCs), tumorigenic cancer cells, or tumor-initiating cells, by various investigators, to indicate that only they can give rise to new tumors when transplanted into immunodefi cient animals. Evidence for the existence of CSCs initially came from studies of acute myelogenous leukemia (AML), among which a subset of leukemic cells was identifi ed that gave rise to AML in immunodefi cient mice and that displayed a similar cell surface immunophenotype as normal hematopoietic stem cells (2) . Subsequently,
Effects of ursodeoxycholic acid treatment on nutrition and liver function in patients with cystic fibrosis and longstanding cholestasis.
Authors: J Cotting, M J Lentze, J Reichen
Journal: Gut (1990)

The prevalence of biliary and hepatic diseases is increasing in patients with cystic fibrosis as more of them reach adult life. There is no effective treatment or method of preventing cholestasis in cystic fibrosis, although beneficial effects have been ascribed to the tertiary bile acid, ursodeoxycholate, in other forms of chronic cholestasis. We evaluated prospectively the effects of a six month course of ursodeoxycholate (15-20 mg/kg per day) in eight, mostly adult, patients with cystic fibrosis and chronic cholestasis. Bile acid treatment improved inflammatory activity (average decrease in alanine aminotransferase, 60%, p less than 0.005) and cholestasis (alkaline phosphatase, 47%; p less than 0.01) in all patients. Quantitative liver function, measured by 45 minute sulphobromophthalein retention and by the 14C-aminopyrine breath test, improved in all patients while galactose elimination capacity showed a slight decrease. Patients9 nutritional state improved as evidenced by a 1.8 kg weight gain and an increase in muscle mass suggested by a 26% increase in 24 hour urinary creatinine excretion. Steatorrhea was not affected by bile acid treatment. Ursodeoxycholic acid may be beneficial in the treatment of chronic cholestasis in cystic fibrosis by improving liver function and also the patient9s nutritional state.
Systems Pharmacology: Network Analysis to Identify Multiscale Mechanisms of Drug Action
Authors: Shan Zhao, Ravi Iyengar
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Systems approaches have long been used in pharmacology to understand drug action at the organ and organismal levels. The application of computational and experimental systems biology approaches to pharmacology allows us to expand the definition of systems pharmacology to include network analyses at multiple scales of biological organization and to explain both therapeutic and adverse effects of drugs. Systems pharmacology analyses rely on experimental "omics" technologies that are capable of measuring changes in large numbers of variables, often at a genome-wide level, to build networks for analyzing drug action. A major use of omics technologies is to relate the genomic status of an individual to the therapeutic efficacy of a drug of interest. Combining pathway and network analyses, pharmacokinetic and pharmacodynamic models, and a knowledge of polymorphisms in the genome will enable the development of predictive models of therapeutic efficacy. Network analyses based on publicly available databases such as the U.S. Food and Drug Administration's Adverse Event Reporting System allow us to develop an initial understanding of the context within which molecular-level drug-target interactions can lead to distal effectors in a process that results in adverse phenotypes at the organ and organismal levels. The current state of systems pharmacology allows us to formulate a set of questions that could drive future research in the field. The long-term goal of such research is to develop polypharmacology for complex diseases and predict therapeutic efficacy and adverse event risk for individuals prior to commencement of therapy.
High-Resolution Mapping of DNA Breakpoints to Define True Recurrences Among Ipsilateral Breast Cancers
Authors: Marc A. Bollet, Nicolas Servant, Pierre Neuvial, Charles Decraene, Ingrid Lebigot, Jean-Philippe Meyniel, Yann De Rycke, Alexia Savignoni, Guillem Rigaill, Philippe Hupé, Alain Fourquet, Brigitte Sigal-Zafrani, Emmanuel Barillot, Jean-Paul Thiery
Journal: JNCI Journal of the National Cancer Institute (2007)

To distinguish new primary breast cancers from true recurrences, pangenomic analyses of DNA copy number alterations (CNAs) using single-nucleotide polymorphism arrays have proven useful.The pangenomic profiles of 22 pairs of primary breast carcinoma (ductal or lobular) and ipsilateral breast cancers from the same patients were analyzed. Hierarchical clustering was performed using CNAs and DNA breakpoint information. A partial identity score developed using DNA breakpoint information was used to quantify partial identities between two tumors. The nature of ipsilateral breast cancers (true recurrence vs new primary tumor) as defined using the clustering methods and the partial identity score was compared with that based on clinical characteristics. Metastasis-free survival was compared among patients with primary tumors and true recurrences as defined using the partial identity score and by clinical characteristics. All statistical tests were two-sided.All methods agreed on the nature of ipsilateral breast cancers for 14 pairs of samples. For five pairs, the clinical definition disagreed with both clustering methods. For three pairs, the two clustering methods were discordant and the one using DNA breakpoints agreed with the clinical definition. The partial identity score confirmed the nature of ipsilateral breast cancers as defined by clustering of DNA breakpoints in 21 of 22 pairs. The difference in metastasis-free survival of patients with new primary tumors and those with true recurrences was not statistically significant when tumors were defined based on clinical and histologic characteristics (5-year metastasis-free survival: 76%, 95% confidence interval [CI] = 52% to 100% for new primary tumors and 38%, 95% CI = 17% to 83% for true recurrences; P = .18; new primary tumor vs true recurrence, hazard ratio = 2.8, 95% CI = 0.6 to 13.7), but the difference was statistically significant when tumors were defined using the partial identity score (5-year metastasis-free survival: 100% for new primary tumors and 29%, 95% CI = 11% to 78% for true recurrences; P = .01).DNA breakpoint information more often agreed with the clinical determination than CNAs in this population. The partial identity score, which was calculated based on DNA breakpoints, allows statistical discrimination between new primary tumors and true recurrences that could outperform the clinical determination in terms of prognosis.
Blood Lipids and First-Ever Ischemic Stroke/Transient Ischemic Attack in the Bezafibrate Infarction Prevention (BIP) Registry
Authors: David Tanne, Nira Koren-Morag, Eran Graff, Uri Goldbourt
Journal: Circulation (2001)

Despite unclear associations between blood lipids, including fractionated cholesterol and triglycerides, and stroke, recent evidence demonstrates that lipid-modifying agents decrease the risk of stroke in patients with coronary heart disease (CHD).Patients with documented CHD who were screened for but not included in the Bezafibrate Infarction Prevention study and had no history of stroke or transient ischemic attack (TIA) (n=11 177) were followed up. At baseline, medical histories were obtained and blood lipids assessed at a central study laboratory. During a 6- to 8-year follow-up period, 941 patients were identified as having nonhemorrhagic cerebrovascular disease, of whom 487 had verified ischemic stroke (per clinical findings and brain CT) or TIA. Patients experiencing an ischemic stroke/TIA had higher mean levels of triglycerides, lower levels of HDL cholesterol, and lower percentages of cholesterol contained in the HDL cholesterol moiety (%HDL; P<0.01 for all). In a logistic regression model, the adjusted ORs for developing an ischemic stroke/TIA were 1.27 (95% CI 1.01 to 1.60) associated with triglycerides >200 mg/dL and 0.87 (95% CI 0.78 to 0.97) associated with a 5% decrease in %HDL. The increased risk associated with high triglycerides was found across subgroups of age, sex, patient characteristics, and cholesterol fractions.High triglycerides constitute an independent risk factor for ischemic stroke/TIA across subgroups of age, sex, patient characteristics, and cholesterol fractions, whereas high %HDL was an independent protective factor among patients with CHD. These findings support the role of blood lipids, including triglycerides, as important modifiable stroke risk factors.
HIV Coreceptor Downregulation as Antiviral Principle: SDF-1α–dependent Internalization of the Chemokine Receptor CXCR4 Contributes to Inhibition of HIV Replication
Authors: Ali Amara, Sylvie Le Gall, Olivier Schwartz, Jean Salamero, Monica Montes, Pius Loetscher, Marco Baggiolini, Jean-Louis Virelizier, Fernando Arenzana-Seisdedos
Journal: The Journal of Experimental Medicine (1997)

Ligation of CCR5 by the CC chemokines RANTES, MIP-1α or MIP-1β, and of CXCR4 by the CXC chemokine SDF-1α, profoundly inhibits the replication of HIV strains that use these coreceptors for entry into CD4+ T lymphocytes. The mechanism of entry inhibition is not known. We found a rapid and extensive downregulation of CXCR4 by SDF-1α and of CCR5 by RANTES or the antagonist RANTES(9-68). Confocal laser scanning microscopy showed that CCR5 and CXCR4, after binding to their ligands, are internalized into vesicles that qualify as early endosomes as indicated by colocalization with transferrin receptors. Internalization was not affected by treatment with Bordetella pertussis toxin, showing that it is independent of signaling via Gi-proteins. Removal of SDF-1α led to rapid, but incomplete surface reexpression of CXCR4, a process that was not inhibited by cycloheximide, suggesting that the coreceptor is recycling from the internalization pool. Deletion of the COOH-terminal, cytoplasmic domain of CXCR4 did not affect HIV entry, but prevented SDF-1α–induced receptor downregulation and decreased the potency of SDF-1α as inhibitor of HIV replication. Our results indicate that the ability of the coreceptor to internalize is not required for HIV entry, but contributes to the HIV suppressive effect of CXC and CC chemokines.
Strengthening intercellular communication to prevent atrial fibrillation
Authors: M. B. Thomsen
Journal: Cardiovascular Research (2011)

This editorial refers to ‘Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model’ by O. Bikou et al. , pp. 218–217, this issue. 

Many complex pathophysiological mechanisms underlie atrial fibrillation (AF). The classical view of AF is of a trigger causing abnormal impulse formation and a substrate-supporting reentrant impulse conduction which combines to sustain the arrhythmia. Furthermore, time seems to be important in the development of the disease, such that short episodes of AF gradually prime the atria for longer lasting and eventually perpetuating episodes of AF.1 Multiple reentrant wavelets are suggested to underlie the persistent episodes, in which a short refractory period and slow conduction velocity unite to maintain the reentrant circuits.2 Additionally, a high-frequency firing source may cause AF via non-homogeneous spreading of the propagating wave front in a manner called fibrillatory conduction.

Irrespective of the suggested underlying mechanism, atrial structural, mechanical, and electrophysiological remodelling provide the bridge leading from short, isolated …
Effect of a Single Mass Antibiotic Distribution on the Prevalence of Infectious Trachoma
Authors: Jaya D. Chidambaram, Wondu Alemayehu, Muluken Melese, Takele Lakew, Elizabeth Yi, Jenafir House, Vicky Cevallos, Zhaoxia Zhou, Kathryn Maxey, David C. Lee, Brett L. Shapiro, Muthiah Srinivasan, Travis Porco, John P. Whitcher, Bruce D. Gaynor, Thomas M. Lietman
Journal: JAMA (2006)

ContextThe World Health Organization recommends mass antibiotic distributions in its strategy to eliminate blinding trachoma as a public health concern.Some hypothesize that a single distribution is sufficient to control the ocular strains of chlamydia that cause trachoma.Others believe infection will inevitably return and periodic treatments or other measures are essential.Objective To determine whether ocular chlamydial infection returns to the community up to 24 months after a single mass antibiotic distribution in a hyperendemic region of Ethiopia. Design, Setting, and ParticipantsLongitudinal cohort study conducted March 2003 to March 2005 in the Gurage Zone of Ethiopia.Eight randomly selected villages were assessed for ocular chlamydial infection.Fifteen untreated villages were randomly chosen at 12 months to allow assessment of a secular trend.Intervention A single dose of oral azithromycin was offered to all residents of the 8 selected villages who were aged 1 year or older.Main Outcome Measure Prevalence of ocular chlamydial infection in all children aged 1 to 5 years from each intervention village prior to treatment and 2, 6, 12, 18, and 24 months after mass antibiotic treatment, and also in untreated villages enrolled at 12 months. ResultsFive hundred fifteen children were examined for ocular chlamydial infection at baseline.For the follow-up examinations, the mean participation rate was 83%.The mean prevalence of infection in children aged 1 to 5 years decreased from 43.5% (95% confidence interval [CI], 35.0%-52.0%) to 5.1% (95% CI, 1.1%-9.2%)after treatment.On average, infection returned gradually over 24 months to 11.3% (95% CI, 4.5%-18.1%;P=.001).In 7 of 8 villages, infection was higher at 24 months than at 2 months.In the remaining village, no infection could be identified at any point after treatment.Villages enrolled at 12 months had significantly fewer infections than those enrolled 12 months earlier, suggesting a secular trend (PϽ.001).Conclusions Ocular chlamydial infection was not eliminated in children aged 1 to 5 years after a single mass azithromycin distribution; it slowly returned over 24 months, although not to baseline levels.Repeated treatments or other effective measures will be necessary for elimination.
Association between body mass index and asthma, rhinitis and eczema in Chinese school children
Authors: Ning Song, Mohammed Shamssain, Jin Zhang, Shuting Hao, Jitao Guan, Jianling Wu, Chunling Fu, Xixin Yan
Journal: European Respiratory Journal (2012)

This study aimed to investigate the association between the prevalence of allergic diseases in children and body mass index (BMI). 10338 Chinese children(5095 boys and 5243 girls, aged 6-18 years) were assessed using an ISAAC questionnaire. BMI was calculated and overweight or obesity was defined using the International Obesity Task Force (IOTF) definitions. There was significantly higher prevalence rates of exercise-induced wheezing (4.2% vs 3.1%, p 65th percentile) than other children, respectively. The prevalence of overweight or higher BMI subjects was significantly greater in the atopic group (18.2% vs 14.0%, p<0.001; 37.2% vs 32.6%, p< 0.001), respectively. The obese asthmatic children had a significantly higher prevalence of sleep disturbances due to wheezing than non-obese asthmatics (p<0.01). They also reported more speech disturbances (23.1% vs 9.5%, p = 0.082) and a higher number of wheezing attacks in the past 12 months (more than 12, 15.4% vs 8.4%, p = 0.106) than the non-obese asthmatic children. Most of the obese atopic children were already overweight or obese at the time of the diagnosis (66.6%). None of the associations were significantly different for boys or girls. The study shows that there is some evidence of an association between excess body weight or obesity and atopy particularly asthma and that being overweight might increase the likelihood of asthma and other allergic conditions.