tbuckley/cabot-search huggingface dataset:
A Selective Sweep Driven by Pyrimethamine Treatment in Southeast Asian Malaria Parasites
Authors: S. Nair
Journal: Molecular Biology and Evolution (2003)

Malaria parasites (Plasmodium falciparum) provide an excellent system in which to study the genomic effects of strong selection in a recombining eukaryote because the rapid spread of resistance to multiple drugs during the last the past 50 years has been well documented, the full genome sequence and a microsatellite map are now available, and haplotype data can be easily generated. We examined microsatellite variation around the dihydrofolate reductase (dhfr) gene on chromosome 4 of P. falciparum. Point mutations in dhfr are known to be responsible for resistance to the antimalarial drug pyrimethamine, and resistance to this drug has spread rapidly in Southeast (SE) Asia after its introduction in 1970s. We genotyped 33 microsatellite markers distributed across chromosome 4 in 61 parasites from a location on the Thailand/Myanmar border. We observed minimal microsatellite length variation in a 12-kb (0.7-cM) region flanking the dhfr gene and diminished variation for approximately 100 kb (6 cM), indicative of a single origin of resistant alleles. Furthermore, we found the same or similar microsatellite haplotypes flanked resistantdhfr alleles sampled from 11 parasite populations in five SE Asian countries indicating recent invasion of a single lineage of resistant dhfr alleles in locations 2,000 km apart. Three features of these data are of especial interest. (1) Pyrimethamine resistance is generally assumed to have evolved multiple times because the genetic basis is simple and resistance can be selected easily in the laboratory. Yet our data clearly indicate a single origin of resistant dhfr alleles sampled over a large region of SE Asia. (2) The wide valley (∼6 cM) of reduced variation around dhfr provides “proof-of-principle” that genome-wide association may be an effective way to locate genes under strong recent selection. (3) The width of the selective valley is consistent with predictions based on independent measures of recombination, mutation, and selection intensity, suggesting that we have reasonable estimates of these parameters. We conclude that scanning the malaria parasite genome for evidence of recent selection may prove an extremely effective way to locate genes underlying recently evolved traits such as drug resistance, as well as providing an opportunity to study the dynamics of selective events that have occurred recently or are currently in progress.
Oxaliplatin Plus Irinotecan Compared With Irinotecan Alone as Second-Line Treatment After Single-Agent Fluoropyrimidine Therapy for Metastatic Colorectal Carcinoma
Authors: Daniel G. Haller, Mace L. Rothenberg, Alfred O. Wong, Piotr M. Koralewski, Wilson H. Miller, Gyorgy Bodoky, Nassir Habboubi, Carlos Garay, Luis O. Olivatto
Journal: Journal of Clinical Oncology (2008)

Purpose To determine whether irinotecan plus oxaliplatin (IROX) is superior to irinotecan alone in patients with metastatic colorectal cancer (CRC) previously treated with single-agent fluoropyrimidines. Patients and Methods A phase III, randomized, open-label, multicenter study of patients with metastatic or recurrent CRC that had progressed or recurred during or after adjuvant or first-line fluoropyrimidines (fluorouracil/leucovorin or capecitabine, the latter only for metastatic CRC). Patients received IROX (irinotecan 200 mg/m 2 plus oxaliplatin 85 mg/m 2 ) or irinotecan alone (350 mg/m 2 ) every 3 weeks. Results At the data cutoff (when 447 of 628 randomly assigned patients had died), median overall survival was 13.4 months (95% CI, 12.4 to 14.7 months) and 11.1 month (95% CI, 10.0 to 12.7 months) in the IROX and irinotecan groups, respectively (hazard ratio = 0.78; 95% CI, 0.65 to 0.94; P = .0072). Overall response rate (22% v 7%, respectively; P &lt; .0001), median time to progression (5.3 v 2.8 months, respectively; P &lt; .0001), and improvement in tumor-related symptoms (32% v 19%, respectively; P = .0072) were also improved with IROX as compared with irinotecan. With the exception of granulocytopenia (25% v 13%), diarrhea (28% v 23%), and sensory disturbances (5% v 0%), grade 3 to 4 toxicities were comparable between the IROX and irinotecan groups, respectively. Conclusion IROX is an effective treatment for metastatic CRC that has progressed after first-line fluoropyrimidine therapy. IROX improves efficacy compared with irinotecan alone, providing an additional option in the postadjuvant or second-line treatment setting for patients who experience treatment failure with single-agent fluoropyrimidine therapy.
The postponed compensatory pause as a manifestation of positive feedback in atrioventricular conduction.
Authors: L B Goldberg, M N Levy, J Edelstein
Journal: Circulation (1975)

A patient with hypertensive cardiovascular disease was found to have unusual varieties of premature atrial and ventricular contractions. If the premature atrial contraction resulted in a greatly prolonged P-R interval, such that the increment in P-R exceeded the decrement in the preceding R-P, the next sinus P wave, occurring after a normal P-P interval, was found to be blocked. Also, numerous interpolated ventricular extrasystoles were observed in which the postextrasystolic P-R intervals were markedly prolonged and in which the compensatory pauses were postponed for one or two beats. We also present data from one dog in which a premature atrial activation produced a chain reaction such that complete A-V block occurred three beats later. We propose that the chain reaction which evoked the delayed block in the dog and the postponed compensatory pauses in the patient reflects the operation of a positive feedback mechanism in A-V conduction. Positive feedback is initiated by an extremely long P-R, which results in a very short R-P before the next cycle. This then leads to a still longer P-R, which then elicits a still shorter R-P. Block ultimately supervenes when the atrial activation wave arrives at the A-V junction during its effective refractory period.
Surgical Management of Mitral Regurgitation After Repair of Endocardial Cushion Defects : Early and Midterm Results
Authors: A. M. Moran, S. Daebritz, J. F. Keane, J. E. Mayer
Journal: Circulation (2000)

Mitral regurgitation (MR) represents the principal indication for reoperation in patients after repair of atrioventricular septal defects (AVSD). Reports of mitral valvuloplasty (MVP) in such patients are few; the alternative, mitral valve replacement (MVR), necessitates commitment to future valve replacement and long-term anticoagulation. We sought to determine the outcome of those patients who underwent either MVP or MVR between January 1, 1988, and December 31, 1998, for significant MR after repair of AVSD. Furthermore, we sought to identify (a) morphological predictors necessitating MVR, and (b) predictors of future reoperation within the MVP group.Retrospective review of clinical, operative, and echocardiographic data were performed. There were 46 patients identified (37 MVP and 9 MVR). The median age at initial AVSD repair was 0.6 years, and the age at subsequent mitral valve operation was 2.8 years. The early postoperative mortality rate was 2.2%, and survival at 1 and 10 years was 89.9% and 86.6%, respectively. A high rate of complete heart block was noted within the MVR group (37.5%). Freedom from later mitral valve reoperation for both groups was similar. No significant morphological predictors necessitating MVR were found. Predictors of reoperation within the MVP group included the presence of moderate or worse MR in the early postoperative period. In both groups New York Heart Association class, degree of MR, growth, and ventricular volumes improved.Mitral valve surgery significantly improves clinical status, with a sustained improvement in ventricular chamber size. MR can be successfully managed in patients after repair of AVSD independent of morphological type. Overall survival is acceptable, and further reoperation within the MVP group is influenced by early outcome of repair.
Preoperative imaging of parathyroid glands with technetium-99m-labelled sestamibi and iodine-123 subtraction scanning in secondary hyperparathyroidism
Authors: Elif Hindie, Pablo Urena, Christian Jeanguillaume, Didier Melliere, Jean-Michel Berthelot, Victorio Menoyo-Calonge, Dominique Chiappini-Briffa, Anne Janin, Pierre Galle
Journal: The Lancet (1999)
Epithelial Progeny of Estrogen-Exposed Breast Progenitor Cells Display a Cancer-like Methylome
Authors: Alfred S.L. Cheng, Aedín C. Culhane, Michael W.Y. Chan, Chinnambally R. Venkataramu, Mathias Ehrich, Aejaz Nasir, Benjamin A.T. Rodriguez, Joseph Liu, Pearlly S. Yan, John Quackenbush, Kenneth P. Nephew, Timothy J. Yeatman, Tim H-M. Huang
Journal: Cancer Research (2008)

Abstract Estrogen imprinting is used to describe a phenomenon in which early developmental exposure to endocrine disruptors increases breast cancer risk later in adult life. We propose that long-lived, self-regenerating stem and progenitor cells are more susceptible to the exposure injury than terminally differentiated epithelial cells in the breast duct. Mammospheres, containing enriched breast progenitors, were used as an exposure system to simulate this imprinting phenomenon in vitro. Using MeDIP-chip, a methylation microarray screening method, we found that 0.5% (120 loci) of human CpG islands were hypermethylated in epithelial cells derived from estrogen-exposed progenitors compared with the non–estrogen-exposed control cells. This epigenetic event may lead to progressive silencing of tumor suppressor genes, including RUNX3, in these epithelial cells, which also occurred in primary breast tumors. Furthermore, normal tissue in close proximity to the tumor site also displayed RUNX3 hypermethylation, suggesting that this aberrant event occurs in early breast carcinogenesis. The high prevalence of estrogen-induced epigenetic changes in primary tumors and the surrounding histologically normal tissues provides the first empirical link between estrogen injury of breast stem/progenitor cells and carcinogenesis. This finding also offers a mechanistic explanation as to why a tumor suppressor gene, such as RUNX3, can be heritably silenced by epigenetic mechanisms in breast cancer. [Cancer Res 2008;68(6):1786–96]
True to the power of one? Cognition, argument, and reasoning
Authors: Drew Michael Khlentzos, Bruce Stevenson
Journal: Behavioral and Brain Sciences (2011)

Abstract While impressed by much of what Mercier &amp; Sperber (M&amp;S) offer through their argumentative hypothesis, we question whether the specific competencies entailed in each system are adequate. In particular, whether system 2 might not require independent reasoning capabilities. We explore the adequacy of the explanations offered for confirmation bias and the Wason selection task.
Chemoattractants MDC and TARC are secreted by malignant B-cell precursors following CD40 ligation and support the migration of leukemia-specific T cells
Authors: Paolo Ghia, Pietro Transidico, J. Pedro Veiga, Christoph Schaniel, Federica Sallusto, Kouji Matsushima, Stephen E. Sallan, Antonius G. Rolink, Alberto Mantovani, Lee M. Nadler, Angelo A. Cardoso
Journal: Blood (2001)
Response to: ‘Towards optimal cut-off trough levels of adalimumab and etanercept for a good therapeutic response in rheumatoid arthritis. Results of the INMUNOREMAR study’ by Sanmartiet al
Authors: Der-Yuan Chen, Yi-Ming Chen
Journal: Annals of the Rheumatic Diseases (2015)

Response to: 'Towards optimal cut-off trough levels of adalimumab and etanercept for a good therapeutic response in rheumatoid arthritis.Results of the INMUNOREMAR study' by Sanmarti et alWe thank Sanmarti et al 1 for their interest in our study 2 and the confirmation of our results in Caucasian patients with rheumatoid arthritis (RA).We agree that monitoring of serum drug trough levels would help to optimise anti-tumor necrosis factor (TNF)-α therapy for patients with RA in clinical practice.The serum drug trough levels in our patients with RA who showed good therapeutic response were very close to those observed by Sanmarti et al, 1 possibly reflecting a similar status in pharmacokinetics in different ethnic populations.However, the drug trough levels may vary with different detection methods, dosing and timing of the used drug or concomitant disease-modifying antirheumatic drugs 2-4 and may be further complicated by the presence of antidrug antibodies. 5lthough not yet addressed in the updated 2013 European League Against Rheumatism recommendation, 6 the determination of drug trough levels would be a valuable guide for clinicians to optimise dosing of biologics according to a personalised treatment algorithm 2 3 7 and avoid overtreatment for patients with RA receiving anti-TNF-α therapy. 2 3 8 For example, Pouw et al 3 have identified the therapeutic range of adalimumab trough levels at 5-8 μg/mL for maximal clinical response, providing a useful reference for downtitration of adalimumab dose.However, the optimal cut-off trough levels of adalimumab and etanercept which can predict a good therapeutic response in patients with RA should still be validated in longitudinal and larger scale studies.
Effect of an action plan with ongoing support by a case manager on exacerbation-related outcome in patients with COPD: a multicentre randomised controlled trial
Authors: J. C. A. Trappenburg, E. M. Monninkhof, J. Bourbeau, T. Troosters, A. J. P. Schrijvers, T. J. M. Verheij, J.-W. J. Lammers
Journal: Thorax (2011)

<h3>Background</h3> An individualised action plan (AP) is a potentially effective method of helping patients with chronic obstructive pulmonary disease (COPD) to recognise and anticipate early exacerbation symptoms. This multicentre randomised controlled trial evaluates the hypothesis that individualised APs reduce exacerbation recovery time. <h3>Methods</h3> Two hundred and thirty-three patients with COPD (age 65±10 years, forced expiratory volume in 1 s 56±21% predicted) were randomised to receive either an individualised AP (n=111) or care as usual (n=122). The AP provides individualised treatment prescriptions (pharmaceutical and non-pharmaceutical) related to a colour-coded symptom status to enhance an adequate response to periods of symptom deterioration (reinforced at 1 and 4 months). Exacerbation onset was defined using the Anthonisen symptom diary card algorithm. Every 3 days the Clinical COPD Questionnaire (CCQ) was assessed to evaluate the longitudinal course of health status. The primary outcome was health status recovery in the event of an exacerbation. <h3>Results</h3> During the 6-month follow-up period there was no difference in exacerbation rates and healthcare utilisation between the two groups. Cox-adjusted survival analysis including frailty showed enhanced health status recovery (HR 1.58; 95% CI 0.96 to 2.60) and reduced length of the exacerbation (HR 1.30; 95% CI 0.92 to 1.84). The mean difference in symptom recovery time was −3.68 days (95% CI −7.32 to −0.04). Mixed model repeated measure analysis showed that an AP decreased the impact of exacerbations on health status both in the prodromal and early post-onset periods. Between-group differences in CCQ scores were above the minimal clinically relevant difference of 0.4 points (3.0±0.7 vs 3.4±0.9; p≤0.01). <h3>Conclusion</h3> This study shows that an individualised AP, including ongoing support by a case manager, decreases the impact of exacerbations on health status and tends to accelerate recovery. APs can be considered a key component of self-management programmes in patients with COPD.
Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer
Authors: Lauren J. Bayne, Gregory L. Beatty, Nirag Jhala, Carolyn E. Clark, Andrew D. Rhim, Ben Z. Stanger, Robert H. Vonderheide
Journal: Cancer Cell (2012)
Effectiveness of TNF inhibitor switch in RA: results from the national Swedish register
Authors: Katerina Chatzidionysiou, Johan Askling, Jonas Eriksson, Lars Erik Kristensen, Ronald van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Switching to a second tumour necrosis factor inhibitor (TNFi) after discontinuation of a first in rheumatoid arthritis (RA) is a common strategy. The reason for the switch from the first TNFi could potentially influence the response to therapy. Data on direct comparisons between TNFi after switching are limited. <h3>Methods</h3> The national Swedish register was used. RA patients who switched to a second TNFi (infliximab, etanercept or adalimumab) after failure of a TNFi as first-ever biologic were identified. Effectiveness of treatment was compared across the three drugs according to the first TNFi used, the reason for discontinuing and the drug survival. Drug survival across TNFi used as second biologic was compared. <h3>Results</h3> Half of all patients starting infliximab, adalimumab or etanercept during the period 2005–2012 discontinued treatment for various reasons. Of these patients, a third switched within 2 months to a second TNFi (infliximab, etanercept or adalimumab). Around 35% of all patients achieved low disease activity or remission at 6 months. Regarding the switching strategy, best results were observed among patients who switched from infliximab to etanercept because of (secondary) inefficacy. Etanercept as second TNFi was associated with longer drug survival compared with infliximab. <h3>Conclusions</h3> Switching to a second TNFi after the failure of the first may lead to good clinical results. The inter-drug differences in drug survival on the second TNFi mirror those reported previously for the first TNFi, suggesting that these differences are not solely due to channelling bias.
Induction of Aromatase Expression in Cervical Carcinomas: Effects of Endogenous Estrogen on Cervical Cancer Cell Proliferation
Authors: Hareesh B. Nair, Roopa Luthra, Nameer Kirma, Ya-Guang Liu, Lisa Flowers, Dean Evans, Rajeshwar Rao Tekmal
Journal: Cancer Research (2005)

Epidemiologic studies have implicated estrogenic exposure as well as human papilloma virus (HPV) infection in cervical carcinogenesis, and some studies have suggested that estrogen and HPV may play synergistic roles in cervical tumorigenesis. In this study, we report a novel finding that approximately 35% of cervical carcinomas tested (n = 19) express aromatase, the enzyme responsible for converting androgen to estrogen, the rate-limiting and final step in estrogen biosynthesis. On the other hand, no aromatase expression was detected in precancerous (n = 42) or normal cervical (n = 17) tissue samples. Increased aromatase was associated with increases in estrogen receptors (ER-alpha and ER-beta) and a decrease in progesterone receptor levels, suggesting that in situ estrogen signaling via ER may be involved in tumor growth. Stable overexpression of aromatase in HPV+ cervical cancer cells resulted in increased cellular proliferation, anchorage-independent growth, and ER expression and activity. In contrast, little change in ER was observed in HPV- cells. Steroid hormone receptor expression observed in vitro paralleled that seen in cervical carcinomas expressing aromatase. Aromatase overexpression also induced the expression of cyclin D1, proliferating cell nuclear antigen, and the HPV oncogenes, E6 and E7. Furthermore, the data underscores the importance of steroid receptor (estrogen and progesterone receptors) regulation in cervical carcinogenesis. To our knowledge, this is the first report demonstrating the induction of aromatase expression in cervical carcinomas, and opens the possibility that aromatase inhibitors may be potential therapeutic agents in cervical carcinomas expressing aromatase.
Cardiodynamic Effects of Experimental Bundle-Branch Block in the Dog
Authors: JAMES R. WENNEMARK, DAVID F. BLAKE, PAUL KEZDI
Journal: Circulation Research (1962)

Electrical-mechanical relationships of the canine heart were studied using simultaneous right and left intraveutricular pressures. In the control tracings, there was usually some asynchrony in the onset of ventricular isometric contraction with the right ventricle following the left ventricle. Right bundle-branch block and left bundle-branch block produced a delay in the onset of isometric contraction of the homolateral ventricle. A change in contour of the right intraventricular curve was frequently seen with right, bundle-branch block.
INTERACTIONS OF C-REACTIVE PROTEIN WITH THE COMPLEMENT SYSTEM
Authors: Joan Siegel, Rosemarie Rent, Henry Gewurz
Journal: The Journal of Experimental Medicine (1974)

Protamine sulfate was found to consume large amounts of C selectively during preincubation with sera of individuals in the "acute phase". Marked depletion of C1, C4, and C2 with minimal, if any, depletion of C3-9, was observed. The consumption was time and temperature dependent, occurring most rapidly and extensively at 37 degrees C, 0.10 M relative salt concentration and pH 7.5-8.0; it required calcium ions. It was mediated by a heat-stable nondialyzable factor which separated with C-reactive protein (CRP) during fractionation and purification, correlated with serum CRP levels, and, like other known reactivities of CRP, was inhibited by phosphoryl choline. Preparations of CRP purified either from serum or ascites resulted in consumption of large amounts of C1, C4, and C2 when preincubated with normal serum and protamine. We conclude that CRP is a potent activator of the C system at the level of C1, and that polycations such as protamine sulfate are substrates of CRP which can bring about this activation. It seems not unlikely that one role of CRP in health and disease involves its ability to interact with the C system.
Vitamin B12 Deficiency Associated With Concomitant Metformin and Proton Pump Inhibitor Use
Authors: Amanda N. Long, Christopher L. Atwell, Wonsuk Yoo, Solomon S. Solomon
Journal: Diabetes Care (2012)

Metformin and proton pump inhibitors have been implicated in decreasing levels of vitamin B12 independently. The purpose of this study was to evaluate the effect of concomitant use of metformin and proton pump inhibitors on the incidence of vitamin B12 deficiency.

A retrospective chart review was done using the computerized patient record system at the Memphis VA Medical Center for 614 patients with type 2 diabetes and previously collected vitamin B12 levels. Patients were excluded if they were over the age of 60 years; on a vegetarian diet; had been diagnosed with pernicious anemia, documented by a positive Schilling test or anti-intrinsic factor antibody, or pancreatic exocrine insufficiency; had undergone a gastrectomy or bowel resection; or had been treated with supplemental calcium, H2 blocker, or B12 within 3 months of data collection. The vitamin B12 levels were assessed …