tbuckley/cabot-search huggingface dataset:
Sex Differences in Cardiac Catheterization
Authors: S S Rathore, J Chen, Y Wang, M J Radford, V Vaccarino, H M Krumholz
Journal: JAMA (2001)

Many studies indicate that women are less likely than men to undergo cardiac procedures after an acute myocardial infarction (AMI), raising concerns of sexual bias in clinical care. However, no data exist regarding the relationship between patient sex, physician sex, and use of cardiac procedures.To determine whether sex differences in cardiac catheterization after AMI were greater when patients were treated by male attending physicians compared with female attending physicians.Analysis of data from the Cooperative Cardiovascular Project, a retrospective medical record review. A total of 104 >231 Medicare fee-for-service beneficiaries who were hospitalized in US acute care hospitals for an AMI between January 1994 and February 1995.Use of cardiac catheterization within 60 days of admission, compared between the 4 groups of patient sex-physician sex combinations.Women underwent fewer cardiac catheterizations than men when treated by either male physicians (38.6% vs 50.8%; P =.001) or female physicians (34.8% vs 45.8%; P =.001). Sex differences in procedure use were not greater when a patient and physician were of different sexes (P for interaction =.85). After potential confounders in multivariable analysis were accounted for, women were less likely to undergo cardiac catheterization (risk ratio, 0.90 [95% confidence interval (CI), 0.88-0.92]), regardless of the treating physician's sex. Patients treated by male physicians were more likely to undergo cardiac catheterization (risk ratio, 1.06 [95%CI, 1.02-1.10]) than those treated by female physicians, regardless of patient sex.Women who have had an AMI undergo a cardiac catheterization less often than men, whether treated by a male or female physician. These results suggest that factors other than sexual bias by male physicians toward women account for sex differences in cardiac procedure use.
Abstract A20: DARPP-32-mediated EGFR protein stability leads to gefitinib resistance in gastric cancer
Authors: Shoumin Zhu, Abbes Belkhiri, Wael El-Rifai
Journal: Clinical Cancer Research (2012)

Abstract Background: Gastric cancer is an aggressive tumor that is often resistant to chemotherapeutics. The 17q amplicon genes, including dopamine and cAMP-regulated phosphoprotein MW 32 kDa (DARPP-32), are overexpressed in two-thirds of gastric adenocarcinomas and may induce chemotherapy resistance via abrogation of apoptosis. EGFR plays an important role in tumor growth and activation of the PI3K pathway. Gefitinib (Iressa) is a specific and effective EGFR inhibitor that has shown antitumor activity in clinical trials against several gastrointestinal cancers, including gastric cancers. However, molecular mechanisms that mediate resistance to gefitinib remain poorly understood. Methods and Results: The expression of DARPP-32 in the multistep carcinogenesis cascade was examined using IHC analysis on 533 samples. The composite expression score, calculated from immunostaining patterns, progressively increased significantly from normal or gastritis to metaplasia, dysplasia, and adenocarcinoma (p&amp;lt;0.001). Using clonogenic survival assays, and ATP-GLO cell viability assays, we found that overexpression of DARPP-32 leads to a 3-fold increase in gefitinib resistance in MKN-28 cells (25 μM gefitinib, treated overnight, P&amp;lt;0.01). We also found that DARPP-32 expressing MKN-28 cells had activated the PI3K-AKT pathway as compared to control cells. We next examined the binding of DARPP-32 to EGFR and ERBB3. The three-way co-immunoprecipitation experiments demonstrated the existence of DARPP-32, EGFR, and ERBB3 in the same protein complex. The enhanced EGFR-ERBB3 heterodimerization promotes phosphorylation of ERBB3, then activated the PI3K-AKT pathway, as indicated by p-p85 (Tyr458) subunit of PI3K and p-AKT (Ser473) levels. Following treatment with gefitinib (25 μM) overnight, MKN-28 cells expressing DARPP-32 displayed stable protein levels of EGFR. In contrast, control cells exhibited a significant reduction in EGFR protein levels, suggesting that DARPP-32 promotes stability and suppresses degradation of EGFR protein. After the gefitinib treatment of DARPP-32-expressing MKN-28 cells, p-ERBB3 and activated PI3K-AKT pathway were maintained at higher levels than in control cells. The knockdown of endogenous DARPP-32 by lentiviral DARPP-32 shRNA in SNU-16 cell lines reversed these signaling effects and increased sensitivity to gefitinib (p&amp;lt;0.01). Conclusion: Our results suggest that DARPP-32 overexpression may participate in the transition to intestinal metaplasia and progression to neoplasia. The in vitro studies indicate that DARPP-32 plays a role in increasing the stability of EGFR protein by delaying gefitinib-induced EGFR degradation; maintaining EGFR-ERBB3 heterodimerization promotes phosphorylation of ERBB3, which regulates the PI3K/Akt pathway. DARPP-32 may have potential as a predictive biomarker in gastric cancer prognosis and clinical response to treatment.
Increased Matrix Metalloproteinase-9 in the Airway after Allergen Challenge
Authors: ELIZABETH A. BECKY KELLY, WILLIAM W. BUSSE, NIZAR N. JARJOUR
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Persistent asthma is associated with airway inflammation, tissue damage, and deposition of extracellular matrix (ECM) proteins, which may be mediated, in part, through release of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1). To investigate the role of allergen in the induction of MMP-9 and TIMP-1, bronchoscopy and segmental bronchoprovocation (SBP) with saline (SAL) and antigen (AG) were performed in 17 allergic subjects. Bronchoalveolar lavage (BAL) was done 5 min and 48 h after challenge and concentrations of MMP-9 and TIMP-1 in BAL fluid (BALF) were measured by ELISA. Forty-eight hours after AG challenge, concentrations of MMP-9 and TIMP-1 were increased in the airway, but not in serum. Zymography demonstrated that MMP-9 was the predominant metalloproteinase and was present in a latent proform. MMP-9 immunoreactivity was associated primarily with neutrophils, and concentrations of MMP-9 in BALF correlated with airway neutrophils and, to a lesser extent, with alveolar macrophages. These data suggest that AG challenge leads to generation of factors, including MMP-9, that may be associated with the initiation of bronchial injury, which may then lead to remodeling in asthma.
Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus-associated oral lichen planus
Authors: M. Carrozzo, P. Francia Di Celle, S. Gandolfo, M. Carbone, D. Conrotto, M.E. Fasano, S. Roggero, S. Rendine, V. Ghisetti
Journal: British Journal of Dermatology (2001)

Recent controlled studies have confirmed that hepatitis C virus (HCV) is the main correlate of liver disease in patients with lichen planus (LP), mainly in southern Europe and Japan. However, a low prevalence of HCV infection has been found in LP patients in England and northern France, and significant differences in serum HCV RNA levels or HCV genotypes have not been found between LP patients and controls. Thus host rather than viral factors may be prevalent in the pathogenesis of HCV-related LP. The HLA-DR allele may influence both the outcome of HCV infection and the appearance of symptoms outside the liver.To assess whether major histocompatibility complex class II alleles play a part in the development of HCV-related LP.Intermediate-resolution DRB typing by hybridization with oligonucleotide probes was performed in 44 consecutive Italian oral LP (OLP) patients with HCV infection (anti-HCV and HCV RNA positive), in an age, sex and clinically comparable disease control group of 60 Italian OLP patients without HCV infection (anti-HCV and HCV RNA negative), and in 145 healthy unrelated Italian bone marrow donors without evidence of liver disease or history of LP and with negative tests for HCV.Patients with exclusive OLP and HCV infection possessed the HLA-DR6 allele more frequently than patients with exclusive OLP but without HCV infection (52% vs. 18%, respectively; Pc (Pcorrected) = 0.028, relative risk = 4.93). We did not find any relationship between mucocutaneous LP, HCV infection and HLA-DR alleles.HCV-related OLP therefore appears to be a distinctive subset particularly associated with the HLA class II allele HLA-DR6. This could partially explain the peculiar geographical heterogeneity of the association between HCV and LP.
A Targeted Deletion of a Region Upstream from the Jκ Cluster Impairs κ Chain Rearrangement In Cis in Mice and in the 103/bcl2 Cell Line
Authors: Laurentiu Cocea, Annie De Smet, Mahasti Saghatchian, Simon Fillatreau, Laurent Ferradini, Stéphane Schurmans, Jean-Claude Weill, Claude-Agnès Reynaud
Journal: The Journal of Experimental Medicine (1999)

We have shown previously that a mutation of the KI-KII site immediately 5′ to Jκ1 on the mouse immunoglobulin light chain κ locus reduces the rearrangement level in cis, although it does not affect transcription. Here we deleted by homologous recombination in mouse embryonic stem cells a 4-kb DNA fragment, located immediately upstream of the KI-KII element, which contains the promoter of the long germline transcript. Analysis of gene-targeted heterozygous mouse splenic B cells showed a strong decrease in rearrangement for the allele bearing the deletion. When both the KI-KII mutation and the 4-kb deletion were present on the same allele, the overall reduction in rearrangement was stronger than with the 4-kb deletion alone underlying the role of these two elements in the regulation of rearrangement. The same deletion was performed by homologous recombination on one allele of the rearrangement- inducible mouse 103/bcl2-hygroR pre-B cell line, and resulted in a similar reduction in the induction of rearrangement of the mutated allele. This result validates this cell line as an in vitro model for studying the incidence of gene-targeted modifications of the κ locus on the regulation of rearrangement.
Bronchiectasis consequent upon foreign body retention
Authors: E. U. Kurklu, M. A. Williams, B. T. le Roux
Journal: Thorax (1973)

<b>Kürklü, E. U., Williams, M. A., and le Roux, B. T. (1973).</b><i>Thorax</i>, <b>28</b>, 601-602. <b>Bronchiectasis consequent upon foreign body retention.</b> A series of patients in whom bronchiectasis was related to long retention of an intrabronchial foreign body is reported. The surgical rules which apply to management of intrabronchial foreign bodies by bronchotomy are restated.
Ultimate erythropoietic repopulating abilities of fetal, young adult, and old adult cells compared using repeated irradiation.
Authors: D E Harrison, C M Astle, C Lerner
Journal: The Journal of Experimental Medicine (1984)

Erythropoietic repopulating abilities of fetal liver cells and young and old adult marrow cells were compared as follows: Equal numbers of cells from a donor of each age were mixed with a constant portion of cells pooled from genetically distinguishable competitors. These mixtures were transplanted into stem cell-depleted recipients, and the proportions of recipient hemoglobin that were donor type measured the relative effectiveness of early erythropoietic precursor cells from the various donors (Fig. 1). At intervals of 3-6 mo, recipients were sublethally irradiated, requiring a new round of competitive repopulation. When B6 mice were used as donors, with WBB6F1 competitors and recipients, the highest levels of stem cell activity were found using old donors (Tables I, III). This was true even with unirradiated, immune-competent W/Wv recipients (Table III). When donors and recipients were WBB6F1 hybrids, with B6 competitors, fetal cells initially gave higher levels of repopulating ability, and they were similar to the adult and old marrow cells after 400 d and after recovery from two sublethal irradiations (Table II). These effects were mostly insignificant and probably reflect small differences in initial stem cell concentrations that are brought out by the sensitivity of the competitive repopulation assay. Clearly, ultimate erythropoietic stem cell proliferative capacities did not decline as a result of the proliferation required between 15 d of fetal life and old age. Repopulating abilities of 12-d fetal liver cells were not detectable. We also showed that the proportions of newly synthesized hemoglobins made by the two types of stem cells in tetraparental mice remained nearly constant when tested at 3-d intervals over 30 d. Minimum numbers of stem cells producing erythrocytes over a single 3-d period were calculated as 62 and 128, but these are too low, since variances were similar in the tetraparental mice and in the F1 hybrid control. This contradicts the hypothesis that erythropoietic stem cells reserve limited proliferative capacities by proliferating one or a few at a time. We suggest that erythropoietic stem cells have essentially unlimited proliferative capacities and are found in approximately equal concentrations in the primary erythropoietic organs after 15 or 16 d of fetal life.
Improving Antitumor Immune Responses by Circumventing Immunoregulatory Cells and Mechanisms
Authors: Gregory Lizée, Laszlo G. Radvanyi, Willem W. Overwijk, Patrick Hwu
Journal: Clinical Cancer Research (2006)

Abstract Although numerous immunotherapeutic strategies have been studied in patients with cancer, consistent induction of clinical responses remains a formidable challenge. Cancer vaccines are often successful at generating elevated numbers of tumor-specific T lymphocytes in peripheral blood, however, despite this, tumors usually continue to grow unabated. Recent evidence suggests that endogenous regulatory cells, known to play a major role in the induction of immune tolerance to self and prevention of autoimmunity, as well as suppressive myeloid cells invoked in the tumor-bearing state, may be largely responsible for preventing effective antitumor immune responses. This review will focus on the major regulatory cell subtypes, including CD4+CD25+ T-regulatory cells, type 1 regulatory T cells, natural killer T cells, and immature myeloid cells. Studies in humans and in animal models have shown a role for all of these cells in tumor progression, although the mechanisms by which they act to suppress immunity remain largely undefined. Elucidation of the dominant molecular mechanisms mediating immune suppression in vivo will allow more precise targeting of the relevant regulatory cell populations, as well as the development of novel strategies and clinical reagents that will directly block molecules that induce the suppression of antitumor immunity.
Concordant genotype of upper and lower airways P aeruginosa and S aureus isolates in cystic fibrosis
Authors: J G Mainz, L Naehrlich, M Schien, M Kading, I Schiller, S Mayr, G Schneider, B Wiedemann, L Wiehlmann, N Cramer, W Pfister, B C Kahl, J F Beck, B Tummler
Journal: Thorax (2009)

<h3>Rationale:</h3> Lower airway (LAW) infection with <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i> is the leading cause of morbidity in cystic fibrosis (CF). The upper airways (UAW) were shown to be a gateway for acquisition of opportunistic bacteria and to act as a reservoir for them. Therefore, tools for UAW assessment within CF routine care require evaluation. <h3>Objectives:</h3> The aims of the study were non-invasive assessment of UAW and LAW microbial colonisation, and genotyping of <i>P aeruginosa</i> and <i>S aureus</i> strains from both segments. <h3>Methods:</h3> 182 patients with CF were evaluated (age 0.4–68 years, median 17 years). LAW specimens were preferably sampled as expectorated sputum and UAW specimens by nasal lavage. <i>P aeruginosa</i> and <i>S aureus</i> isolates were typed by informative single nucleotide polymorphisms (SNPs) or by <i>spa</i> typing, respectively. <h3>Results:</h3> Of the typable <i>S aureus</i> and <i>P aeruginosa</i> isolates from concomitant UAW- and LAW-positive specimens, 31 of 36 patients were carrying identical <i>S aureus spa</i> types and 23 of 24 patients identical <i>P aeruginosa</i> SNP genotypes in both compartments. Detection of <i>S aureus</i> or <i>P aeruginosa</i> in LAW specimens was associated with a 15- or 88-fold higher likelihood also to identify <i>S aureus</i> or <i>P aeruginosa</i> in a UAW specimen from the same patient. <h3>Conclusions:</h3> The presence of identical genotypes in UAW and LAW suggests that the UAW play a role as a reservoir of <i>S aureus</i> and <i>P aeruginosa</i> in CF. Nasal lavage appears to be suitable for non-invasive UAW sampling, but further longitudinal analyses and comparison with invasive methods are required. While UAW bacterial colonisation is typically not assessed in regular CF care, the data challenge the need to discuss diagnostic and therapeutic standards for this airway compartment. <h3>Trial registration number:</h3> NCT00266474.
Evolution of the major histocompatibility complex: independent origin of nonclassical class I genes in different groups of mammals.
Authors: A L Hughes, M Nei
Journal: Molecular Biology and Evolution (1989)

The class I major histocompatibility complex genes are composed of classical and nonclassical genes, the latter being largely nonfunctional. To understand the evolutionary relationships of the two groups of class I genes, a phylogenetic analysis of DNA sequences was conducted using 45 genes from six mammalian and one avian species. The results indicate that nonclassical genes in one species are more closely related to classical genes from the same species than to nonclassical genes from a species belonging to a different order or family. This indicates that the differentiation of classical and nonclassical genes occurs rather rapidly in the genome. Classical genes are apparently duplicated with a high frequency in the evolutionary process, and many of the duplicated genes seem to degenerate into nonclassical genes as a result of deleterious mutation. The nonclassical Qa genes in the mouse have sequences homologous to regulatory sequences involved in the universal expression of classical class I genes, but they have accumulated numerous nucleotide substitutions in these sequences. The pattern of nucleotide substitution in nonclassical genes is different from that in classical genes. In nonclassical genes, the rate of nonsynonymous substitution is higher in the antigen recognition site than in other gene regions, as is true of classical genes. However, unlike the case of classical genes, the nonsynonymous rate does not always exceed the synonymous rate in the antigen recognition site. Nonclassical proteins further differ from classical proteins in having amino acid replacements in conserved antigen recognition site positions. These observations are consistent with the hypothesis that nonclassical genes have originated from classical genes but have lost classical class I function because of deleterious mutation.
Single Nucleotide Polymorphisms of Gemcitabine Metabolic Genes and Pancreatic Cancer Survival and Drug Toxicity
Authors: Taro Okazaki, Milind Javle, Motofumi Tanaka, James L. Abbruzzese, Donghui Li
Journal: Clinical Cancer Research (2009)

To show whether single nucleotide polymorphisms (SNP) of drug metabolic genes were associated with toxicity of 2',2'-difluoro 2'-deoxycytidine (gemcitabine)-based chemoradiotherapy and overall survival (OS) of patients with pancreatic cancer.We evaluated 17 SNPs of the CDA, dCK, DCTD, RRM1, hCNT1, hCNT2, hCNT3, and hENT1 genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled in clinical trials at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to January 2006, with follow-up until April 2009. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. The association of genotypes with toxicity or OS was tested, respectively, by logistic regression and Cox regression analysis.None of the 17 SNPs, individually, had a significant association with OS. A combined genotype effect of CDA A-76C, dCK C-1205T, DCTD T-47C, hCNT3 C-69T, hENT1 T-549C, and hENT1 C913T on OS was observed. Patients carrying 0 to 1 (n = 43), 2 to 3 (n = 77), or 4 to 6 (n = 30) variant alleles had median survival time of 31.5, 21.4, and 17.5 months, respectively. The hazard ratio of dying was 1.71 (95% confidence interval, 1.06-2.76) and 3.16 (95% confidence interval, 1.77-5.63) for patients carrying two to three or four to six at-risk genotypes (P = 0.028 and P < 0.001), respectively, after adjusting for clinical predictors. CDA C111T, dCK C-1205T, dCK A9846G, and hCNT3 A25G, individually and jointly, had a significant association with neutropenia toxicity.These observations suggest that polymorphic variations of drug metabolic genes were associated with toxicity of gemcitabine-based therapy and OS of patients with resectable pancreatic cancer.
ACCF/AHA/HRS/SCAI Clinical Competence Statement on Physician Knowledge to Optimize Patient Safety and Image Quality in Fluoroscopically Guided Invasive Cardiovascular Procedures
Authors: John W. Hirshfeld, Stephen Balter, Jeffrey A. Brinker, Morton J. Kern, Lloyd W. Klein, Bruce D. Lindsay, Carl L. Tommaso, Cynthia M. Tracy, Louis K. Wagner, Mark A. Creager, Michael Elnicki, John W. Hirshfeld, Beverly H. Lorell, George P. Rodgers, Cynthia M. Tracy, Howard H. Weitz
Journal: Circulation (2005)
External Validity of a Trial Comprised of Elderly Patients With Hormone Receptor-Positive Breast Cancer
Authors: W. van de Water, M. Kiderlen, E. Bastiaannet, S. Siesling, R. G. J. Westendorp, C. J. H. van de Velde, J. W. R. Nortier, C. Seynaeve, A. J. M. de Craen, G.-J. Liefers
Journal: JNCI Journal of the National Cancer Institute (2014)

Inclusion in trials is selective, and thus results may not be generalizable to the general population. The aim of this study was to investigate the external validity of randomized clinical trial outcomes for elderly breast cancer patients. We compared characteristics and outcomes of breast cancer patients (n = 1325) who participated in a randomized clinical trial (Tamoxifen Exemestane Adjuvant Multinational trial) with unselected breast cancer patients of corresponding age from the general population (n = 1056). Dutch patients aged 65 years or older at diagnosis of hormone receptor–positive breast cancer without distant metastases, with either nodal involvement, a tumor greater than 3cm, or a 1 to 3cm histological grade III tumor, who completed local therapy were included. Analyses were stratified by age (65–74 years; ≥75 years). Primary outcome was overall mortality. Multivariable Cox proportional hazards models were used to assess the association between covariables and overall mortality. All statistical tests were two-sided. Irrespective of age, patients who participated in the trial had fewer comorbid diseases, a higher socioeconomic status, and smaller tumors (all P < .001). In patients aged 65 to 74 years, those who participated in the trial had a similar overall mortality to patients from the general population (multivariable hazard ratio [HR] = 1.08; 95% confidence interval [CI] = 0.73 to 1.60). Alternatively, in patients aged 75 years or older, those who participated in the trial had a lower overall mortality (multivariable HR = 0.72; 95% CI = 0.55 to 0.95; P = .02) than patients in the general population. Breast cancer trial participants aged 75 years or older do not represent elderly breast cancer patients of corresponding age from the general population, which hampers the external validity of a trial.