tbuckley/cabot-search huggingface dataset:
Polymorphisms in<i>Cyclooxygenase-2</i>and<i>Epidermal Growth Factor Receptor</i>Are Associated with Progression-Free Survival Independent of K-ras in Metastatic Colorectal Cancer Patients Treated with Single-Agent Cetuximab
Authors: Georg Lurje, Fumio Nagashima, Wu Zhang, Dongyun Yang, Heung M. Chang, Michael A. Gordon, Anthony El-Khoueiry, Hatim Husain, Peter M. Wilson, Robert D. Ladner, David J. Mauro, Christiane Langer, Eric K. Rowinsky, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Recently, an objective response rate of 12% was reported in a phase II study of cetuximab in patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) refractory to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (IMC-0144). In this large molecular correlates study, we tested whether K-ras mutation status and polymorphisms in genes involved in the EGFR-signaling pathway were associated with clinical outcome in IMC-0144. Experimental Design: We analyzed all available tissue samples from 130 of 346 mCRC patients enrolled in the IMC-0144 phase II clinical trial of cetuximab. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissues, and K-ras mutation status and the genotypes were analyzed using PCR-RFLP, direct DNA-sequencing, and 5′-end [γ-33P] ATP–labeled PCR-protocols. Results: The PFS of patients with cyclooxygenase-2 (COX-2) −765 G&amp;gt;C [C/C; risk ratio (RR), 0.31; 95% confidence interval (95% CI), 0.12-0.84; P = 0.032], COX-2 +8473 T&amp;gt;C (C/C; RR, 0.67; 95% CI, 0.40-1.13; P = 0.003), EGF +61 A&amp;gt;G (G/G; RR, 0.57; 95% CI, 0.34-0.95; P = 0.042), and EGFR +497 G&amp;gt;A (A/G; RR, 0.82; 95% CI, 0.56-1.20; P = 0.017) genotypes was significantly longer compared with those with other genotypes. In addition, patients whose tumors did not have K-ras mutations showed better RR, PFS, and overall survival than patients with K-ras mutations. In multivariable analysis, COX-2 +8473 T&amp;gt;C (adjusted P = 0.013) and EGFR +497 G&amp;gt;A (adjusted P = 0.010) remained significantly associated with progression-free survival, independent of skin rash toxicity, K-ras mutation status, and Eastern Cooperative Group performance status. Conclusions: Polymorphisms in COX-2 and EGFR may be useful independent molecular markers to predict clinical outcome in patients with mCRC treated with single-agent cetuximab, independent of skin rash toxicity, K-ras mutation, and Eastern Cooperative Oncology Group performance status.
Mental Health, Social Functioning, and Attitudes of Kosovar Albanians Following the War in Kosovo
Authors: Barbara Lopes Cardozo
Journal: JAMA (2000)

The 1998-1999 war in Kosovo had a direct impact on large numbers of civilians. The mental health consequences of the conflict are not known.To establish the prevalence of psychiatric morbidity associated with the war in Kosovo, to assess social functioning, and to identify vulnerable populations among ethnic Albanians in Kosovo.Cross-sectional cluster sample survey conducted from August to October 1999 among 1358 Kosovar Albanians aged 15 years or older in 558 randomly selected households across Kosovo.Nonspecific psychiatric morbidity, posttraumatic stress disorder (PTSD) symptoms, and social functioning using the General Health Questionnaire 28 (GHQ-28), Harvard Trauma Questionnaire, and the Medical Outcomes Study Short-Form 20 (MOS-20), respectively; feelings of hatred and a desire for revenge among persons surveyed as addressed by additional questions.Of the respondents, 17.1% (95% confidence interval [CI], 13.2%-21.0%) reported symptoms that met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for PTSD; total mean score on the GHQ-28 was 11.1 (95% CI, 9.9-12.4). Respondents reported a high prevalence of traumatic events. There was a significant linear decrease in mental health status and social functioning with increasing amount of traumatic events (P</=.02 for all 3 survey tools). Populations at increased risk for psychiatric morbidity as measured by GHQ-28 scores were those aged 65 years or older (P =.006), those with previous psychiatric illnesses or chronic health conditions (P<.001 for both), and those who had been internally displaced (P =.009). Populations at risk for poorer social functioning were living in rural areas (P =.001), were unemployed (P =.046) or had a chronic illness (P =.01). Respondents scored highest on the physical functioning and role functioning subscales of the MOS-20 and lowest on the mental health and social functioning subscales. Eighty-nine percent of men and 90% of women reported having strong feelings of hatred toward Serbs. Fifty-one percent of men and 43% of women reported strong feelings of revenge; 44% of men and 33% of women stated that they would act on these feelings.Mental health problems and impaired social functioning related to the recent war are important issues that need to be addressed to return the Kosovo region to a stable and productive environment. JAMA. 2000;284:569-577
Flow-Induced [Ca2+]i Increase Depends on Nucleotide Release and Subsequent Purinergic Signaling in the Intact Nephron
Authors: Mikkel Erik Juul Jensen, Elvin Odgaard, Mette Høgh Christensen, Helle A. Praetorius, Jens Leipziger
Journal: Journal of the American Society of Nephrology (2007)

Flow induces cytosolic Ca(2+) increases ([Ca(2+)](i)) in intact renal tubules, but the mechanism is elusive. Mechanical stimulation in general is known to promote release of nucleotides (ATP/UTP) and trigger auto- and paracrine activation of P2 receptors in renal epithelia. It was hypothesized that the flow-induced [Ca(2+)](i) response in the renal tubule involves mechanically stimulated nucleotide release. This study investigated (1) the expression of P2 receptors in mouse medullary thick ascending limb (mTAL) using P2Y(2) receptor knockout (KO) mice, (2) whether flow increases induce [Ca(2+)](i) elevations in mTAL, and (3) whether this flow response is affected in mice that are deplete of the main purinergic receptor. [Ca(2+)](i) was imaged in perfused mTAL with fura-2 or fluo-4. It is shown that luminal and basolateral P2Y(2) receptors are the main purinergic receptor in this segment. Moreover, the data suggest presence of basolateral P2X receptors. Increases of tubular flow were imposed by promptly rising the inflow pressure, which triggered a marked increase of [Ca(2+)](i). This [Ca(2+)](i) response was significantly reduced in P2Y(2) receptor KO tubules (fura-2 ratio increase WT 0.44 +/- 0.09 [n = 28] versus KO 0.16 +/- 0.04 [n = 13]). Furthermore, the flow response was greatly inhibited with luminal and basolateral scavenging of extracellular ATP (apyrase 7.5 U/ml) or blockage of P2 receptors (suramin 300 microM). The flow response could still be elicited in the absence of extracellular Ca(2+). These results strongly suggest that increase of tubular flow elevates [Ca(2+)](i) in intact renal epithelia. This flow response is caused by release of bilateral nucleotides and subsequent activation of P2 receptors.
THE INCIDENCE AND NATURAL HISTORY OF MITRAL REGURGITATION FOLLOWING SURGICAL REPAIR OF TOTAL ANOMALOUS PULMONARY VENOUS DRAINAGE
Authors: Diana Magee, Devin Chetan, Yasuhiro Kotani, Jae-Sung Son, Mark Friedberg, Christopher Caldarone, Glen van Arsdell, John Coles, Osami Honjo
Journal: Journal of the American College of Cardiology (2013)
Quantifying the major mechanisms of recent gene duplications in the human and mouse genomes: a novel strategy to estimate gene duplication rates
Authors: Deng Pan, Liqing Zhang
Journal: Genome biology (2007)

The rate of gene duplication is an important parameter in the study of evolution, but the influence of gene conversion and technical problems have confounded previous attempts to provide a satisfying estimate. We propose a new strategy to estimate the rate that involves separate quantification of the rates of two different mechanisms of gene duplication and subsequent combination of the two rates, based on their respective contributions to the overall gene duplication rate. Previous estimates of gene duplication rates are based on small gene families. Therefore, to assess the applicability of this to families of all sizes, we looked at both two-copy gene families and the entire genome. We studied unequal crossover and retrotransposition, and found that these mechanisms of gene duplication are largely independent and account for a substantial amount of duplicated genes. Unequal crossover contributed more to duplications in the entire genome than retrotransposition did, but this contribution was significantly less in two-copy gene families, and duplicated genes arising from this mechanism are more likely to be retained. Combining rates of duplication using the two mechanisms, we estimated the overall rates to be from approximately 0.515 to 1.49 × 10-3 per gene per million years in human, and from approximately 1.23 to 4.23 × 10-3 in mouse. The rates estimated from two-copy gene families are always lower than those from the entire genome, and so it is not appropriate to use small families to estimate the rate for the entire genome. We present a novel strategy for estimating gene duplication rates. Our results show that different mechanisms contribute differently to the evolution of small and large gene families.
Contribution of Fc receptor IIIA gene 158V/F polymorphism and copy number variation to the risk of ACPA-positive rheumatoid arthritis
Authors: M M Thabet, T W J Huizinga, R B Marques, G Stoeken-Rijsbergen, A M Bakker, F A Kurreeman, S J White, R E M Toes, A H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Background:</h3> Fcγ receptors (FcγRs) are potent immune modulators. FcγR genes encompass a complex region, polymorphic by both single nucleotide polymorphisms (SNPs) and copy number variation (CNV). The heterogeneity of rheumatoid arthritis (RA) combined with the genetic complexity of FcγR genes may be the cause of inconsistent findings in previous RA studies on FcγR SNPs. There is increasing evidence that anti-citrullinated peptide antibody (ACPA)-positive RA and ACPA-negative RA have a different genetic background. <h3>Objective:</h3> To investigate whether FcγRIIIA 158V/F SNP associates differently with ACPA-positive and ACPA-negative RA and to assess if the <i>FcγRIIIA</i> gene CNV affects the association of the FcγRIIIA 158V/F SNP with RA and whether the <i>FcγRIIIA</i> gene CNV confers risk for RA. <h3>Methods:</h3> 945 patients with RA and 388 healthy controls, all Dutch-Caucasians, were included in the study. FcγRIIIA 158V/F SNP was genotyped using Sequenom. CNV of the <i>FcγRIIIA</i> gene was determined in 456 patients with RA and 285 controls using multiplex ligation-dependent probe amplification. Associations between genotypes and RA were analysed, stratifying for the presence/absence of ACPA and CNV. <h3>Results:</h3> In all patients with RA the FcγRIIIA 158V/F SNP was not associated with RA. In ACPA-positive RA (n = 358), the VV genotype was more prevalent in cases than in controls (18.4% vs 13.2%, OR = 1.5, p = 0.05). After stratification for CNV the VV genotype was associated with RA in general (n = 426) (OR = 1.6, 95% CI 0.97 to 2.6, p = 0.05) and with ACPA-positive RA (n = 135) (OR = 2.1, 95% CI 1.2 to 3.8, p = 0.009) but not with ACPA-negative RA. The distribution of CNV was not significantly different between patients with RA and controls. <h3>Conclusion:</h3> The FcγRIIIA 158 VV genotype confers risk for ACPA-positive RA; this association increased slightly after correction for CNV of the <i>FcγRIIIA</i> gene. CNV itself is not associated with RA susceptibility.
Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload
Authors: Gloria C. Preza, Piotr Ruchala, Rogelio Pinon, Emilio Ramos, Bo Qiao, Michael A. Peralta, Shantanu Sharma, Alan Waring, Tomas Ganz, Elizabeta Nemeth
Journal: Journal of Clinical Investigation (2011)

Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders.
Abnormal exercise hemodynamics in patients with normal systolic function late after aortic valve replacement.
Authors: E S Monrad, O M Hess, T Murakami, H Nonogi, W J Corin, H P Krayenbuehl
Journal: Circulation (1988)

We studied the hemodynamic response to supine bicycle exercise in 20 patients late (10 +/- 2 years) after aortic valve replacement (for aortic stenosis in 12 patients, aortic insufficiency in six patients, and for combined stenosis and insufficiency in two patients). The pulmonary artery wedge pressure was obtained with a pulmonary artery balloon catheter, and left ventriculography was performed by digital-subtraction angiography after injection of radiographic contrast into the pulmonary artery. These patients were compared with 11 control subjects with no or minimal cardiac disease studied routinely for evaluation of chest pain in whom left ventricular end-diastolic pressure and a direct contrast ventriculogram were obtained. Compared with the control population, the study population had similar left heart filling pressures (7 +/- 3 vs 9 +/- 3 mm Hg, NS), but higher left ventricular ejection fractions (75 +/- 7% vs 67 +/- 7%, p less than .02) and higher left ventricular muscle mass indexes (106 +/- 28 vs 85 +/- 9 g/m2, p less than .01). Elevated myocardial muscle mass led to lower systolic wall stress in the study population than in the control subjects (254 +/- 65 vs 320 +/- 49 10(3).dynes/cm2, p less than .01) and might explain the higher ejection fraction observed. Fourteen patients had a normal response to exercise (with left heart filling pressures of 16 +/- 4 vs 18 +/- 2 mm Hg for control subjects, NS; and left ventricular ejection fraction of 77 +/- 8% vs 73 +/- 5% for control subjects, NS). However, while the remaining six patients had a normal exercise left ventricular ejection fraction (72 +/- 9%, NS), they had an abnormal rise in left heart filling pressure (33 +/- 8 mm Hg, p less than .01). Preoperatively these patients also had higher left ventricular mid- and end-diastolic pressures at similar diastolic volumes, suggesting a decrease in chamber compliance. Thus, late after aortic valve replacement there is a subgroup of patients who, despite normal hemodynamics and normal left ventricular systolic function as assessed by the left ventricular ejection fraction at rest, have an abnormal response to exercise characterized primarily by a substantial rise in left heart filling pressures. Preoperatively this group also has a decrease in diastolic chamber compliance despite nearly normal left ventricular ejection fractions. This abnormality appears to result from a primary derangement of diastolic function that is not evident at rest.
Phenformin (Dibotin) in polyarthritis.
Authors: G D Kersley
Journal: Annals of the Rheumatic Diseases (1968)

Since 1956biguanides havereceived attention as oralhypoglycaemic agents(Krall andBradley, 1959). Ungar,Madison, andCarter (1960), using phenformin (Dibotin, phenethyl biguanide), showed their effect on peripheral utilization ofglucose, Butterfield, Fry,andHolling (1958) having previously demonstrated increased uptake ofinsulin in hepatic andperipheral tissues. Since thenthedrug hasbeenusedwithsulphonylureas fororal control of diabetes andwithinsulin inbrittle diabetics and whentheyarepartly insulin resistant. Fearnley andChakrabarti (1964) showedthat phenformin increased fibrinolytic activity inocclusive heart disease andFearnley, Chakrabarti, and Hocking (1965) usedthis druginrheumatoid arthritis inhopes ofremoving fibrin fromtheinflammatory lesions. Inafollow-up oftwenty cases treated with phenformin 100mg.andethyloestrenol 8-16mg. for5 to14months, (Fearnley, Chakrabarti, and Evans, 1966), they found someclinical improvement intwelve. Inseventeen patients there wasa20to 63percentreduction ofplasma fibrinogen andin twelve theerythrocyte sedimentation rate(ESR) decreased byover30percent. Material andMethods Inviewofthese results itwasdecided tocarry outa double-blind cross-over trial; 26patients withrheumatoid arthritis wereselected andallocated randomly tostart treatment either with100mg.phenformin tablets orwith placebo tablets of identical appearance. Allwere patients withtypical, active, sero-positive, rheumatoid arthritis andthroughout thetrial nochange wasmadein treatment except inthenumberofanalgesic tablets. The numbertaken ineachperiod wasrecorded butthere was little variation andthis didnotinfluence thetrial. Thepatients' conditions wereassessed before treatment andafter 6weeksoneachmedication, theassessment including thepatients' estimate ofpainandstiffness (graded 0-3), strength ofgrip, ring-size measurement oftheworstaffected finger, ESR,haemoglobin, and weight. Infourpatients, whoalsohaddiabetes, bloodsugar estimations weremadethree hoursafter thesamelight breakfast.
Genomic Approaches to Understanding Mammary Tumor Progression in Transgenic Mice and Responses to Therapy
Authors: Jeffrey E. Green, Kartiki Desai, Yumei Ye, Claudine Kavanaugh, Alfonso Calvo, Jung-Im Huh
Journal: Clinical Cancer Research (2004)

Scores of genetically engineered mice have been generated in the quest to understand mechanisms of breast cancer development and progression. More recently, there has been a growing trend for using such models for testing various therapeutic strategies and agents. The application of these mouse models for these purposes requires that they be characterized in ways that demonstrate they possess important similarities to human breast cancer. In particular, detailed comparisons of the features of the models to human breast cancer must include attention to the histological phenotypes, chromosomal and molecular alterations, and the predictive value of the models for preclinical testing. Whereas these models have become important tools for the study of breast cancer, the great majority of existing mouse mammary cancer models develop tumors that are estrogen receptor negative, with relatively few models demonstrating metastatic spread to the lungs, and none developing metastases to bone. This review focuses on recent studies using genomic approaches to further understand the oncogenic processes occurring in mouse models of mammary cancer and to compare these changes with those identified in human breast cancer. Gene expression profiling is being applied to help define pharmacological responses that occur in vivo. Detailed genomic analyses will provide important information for selecting models for specific experimental purposes, contribute to the understanding of oncogene-specific expression signatures and potential therapeutic targets, and further define mechanisms of chemoprevention and chemotherapy.
Relationship Between Malpractice Claims and Cesarean Delivery
Authors: A. Russell Localio
Journal: JAMA (1993)

To investigate whether an association exists between the probability of a cesarean delivery and the level of malpractice claims risk faced by hospitals and physicians.Survey of computerized discharge data linked with physician and hospital malpractice claims records based on stratified, random sample of hospitals.Acute care hospitals in New York State in 1984.All deliveries (60 490) at 31 hospitals.After controlling for the clinical risk of a cesarean delivery, patient socioeconomic status, and physician and hospital characteristics, cesarean delivery was positively associated with physician malpractice premiums (odds ratio [OR], 3.00; 95% confidence interval [CI], 2.13 to 4.24 for the difference between upstate and New York City levels), with the number of physician claims opened per 100 physicians at the hospital level (OR, 1.15; 95% CI, 1.02 to 1.30 for a 1-SD change), and with the number of hospital claims opened per 1000 discharges (OR, 1.26; 95% CI, 1.10 to 1.43 for a 1-SD change). Measures of physician-perceived risk of suit also showed a significant association with cesarean delivery (OR, 1.96; 95% CI, 1.53 to 2.52, upstate vs New York City). Within hospitals, there was no significant association (OR, 1.15; P = .126) between the odds of cesarean delivery and the claims history (none vs one or more) of an individual physician.Results support previous speculations of a positive association between malpractice claims risk and the rate of cesarean delivery.
Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-controlled trial
Authors: Steven J Reynolds, Fred Makumbi, Kevin Newell, Noah Kiwanuka, Paschal Ssebbowa, George Mondo, Iga Boaz, Maria J Wawer, Ronald H Gray, David Serwadda, Thomas C Quinn
Journal: The Lancet Infectious Diseases (2012)
Cationic amphiphiles prevent calcium leak induced by ATP depletion in myocardial cells.
Authors: J R Clague, J A Post, G A Langer
Journal: Circulation Research (1993)

Excessive calcium influx is important in the irreversible injury of cardiac myocytes and other cell types. The mechanism is unknown, but possibilities include L-type channels, Na(+)-Ca2+ exchange, sarcolemmal (SL) defects, and calcium leak channels. In this study, metabolic inhibition was used to induce ATP depletion and augmented calcium influx in cultured cardiac myocytes. Inhibition of the L-type calcium channel and Na(+)-Ca2+ exchanger had no significant effect on the calcium leak. There was no significant lactate dehydrogenase release, indicating that the leak did not occur through major SL defects. No alterations in the asymmetric distribution of SL phospholipids were demonstrated. Phospholipid rearrangements were therefore not responsible. The leak was unaffected by 0.5 mM cadmium and 1 microM nifedipine but was augmented by 50 microM nifedipine, characteristics in common with calcium leak channels. Insertion of the cationic amphiphiles dodecyltrimethylammonium bromide or polymyxin B sulfate into the SL had a profound inhibitory effect on the calcium leak. The anionic amphiphile sodium dodecyl sulfate had the opposite effect, and the neutral amphiphile lauryl acetate had no effect. These results suggest that an alteration in the SL surface charge affects calcium leak. It is proposed that the augmented calcium influx occurs via calcium leak channels and that these can be modulated by charged amphiphiles.