tbuckley/cabot-search huggingface dataset:
Natriuretic Peptide Testing in Heart Failure
Authors: Han-Na Kim, James L. Januzzi
Journal: Circulation (2011)

A 78-year-old woman with a history of morbid obesity, coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease (serum creatinine 2.0 mg/dL) presented to the emergency department with worsening dyspnea.Her ECG shows no acute ischemic changes; her chest radiograph reveals chronic emphysematous changes with mild bilateral infiltrates.Her lung examination is notable for diffuse wheezing, and she has chronic lower extremity edema.Her aminoterminal pro-B-type natriuretic peptide (NT-proBNP) level is 5500 pg/mL (upper limit of normal is Ͻ1800 pg/mL for age Ͼ75 years).Does this patient have acutely decompensated heart failure (ADHF)? Overview: Natriuretic Peptides in Acute DyspneaMany patients presenting with acute dyspnea (including those with ADHF) have multiple coexisting medical disorders that may complicate their diagnosis and management.Diagnostic uncertainty in the setting of acute dyspnea is associated with longer hospital length of stay, more diffuse diagnostic and therapeutic efforts, increased healthcare costs, and higher likelihood for repeat heart failure (HF) hospitalization or death. 1 The addition of testing for brain natriuretic peptide (BNP) or NT-proBNP to standard clinical assessment has been shown to be valuable for an accurate and efficient diagnosis and prognostication of HF, and the use of BNP or NT-proBNP may be associated with improved clinical outcomes. 2-
Evolution of Snake Venom Disintegrins by Positive Darwinian Selection
Authors: P. Juarez, I. Comas, F. Gonzalez-Candelas, J. J. Calvete
Journal: Molecular Biology and Evolution (2008)

PII-disintegrins, cysteine-rich polypeptides broadly distributed in the venoms of geographically diverse species of vipers and rattlesnakes, antagonize the adhesive functions of β1 and β3 integrin receptors. PII-disintegrins evolved in Viperidae by neofunctionalization of disintegrin-like domains of duplicated PIII-snake venom hemorrhagic metalloproteinase (SVMP) genes recruited into the venom proteome before the radiation of the advanced snakes. Minimization of the gene (loss of introns and coding regions) and the protein structures (successive loss of disulfide bonds) underpins the postduplication divergence of disintegrins. However, little is known about the underlying genetic mechanisms that have generated the structural and functional diversity among disintegrins. Phylogenetic inference and maximum likelihood–based codon substitution approaches were used to analyze the evolution of the disintegrin family. The topology of the phylogenetic tree does not parallel that of the species tree. This incongruence is consistent with that expected for a multigene family undergoing a birth-and-death process in which the appearance and disappearance of loci are being driven by selection. Cysteine and buried residues appear to be under strong purifying selection due to their role in maintaining the active conformation of disintegrins. Divergence of disintegrins is strongly influenced by positive Darwinian selection causing accelerated rate of substitution in a substantial proportion of surface-exposed disintegrin residues. Global and lineage-specific sites evolving under diversifying selection were identified. Several sites are located within the integrin-binding loop and the C-terminal tail, two regions that form a conformational functional epitope. Arginine-glycine-aspartic acid (RGD) was inferred to represent the ancestral integrin-recognition motif, which emerged from the subgroup of PIII-SVMPs bearing the RDECD sequence. The most parsimonious nucleotide substitution model required for the emergence of all known disintegrin's integrin inhibitory motifs from an ancestral RGD sequence involves a minimum of three mutations. The adaptive advantage of the emergence of motifs targeting β1 integrins and the role of positively selected sites located within nonfunctional disintegrin regions appear to be difficult to rationalize in the context of a predator–prey arms race. Perhaps, this represents a consequence of the neofunctionalization potential of the disintegrin domain, a feature that may underlie its recruitment into the venom proteome followed by its successful transformation into a toxin.
Gender-Based Differences in Cardiac Repolarization in Mouse Ventricle
Authors: Véronique Trépanier-Boulay, Chantale St-Michel, Annie Tremblay, Céline Fiset
Journal: Circulation Research (2001)

The mouse heart has become a widely used model for genetic studies of heart diseases. Thus, understanding gender differences in mouse cardiac repolarization is crucial to the interpretation of such studies. The objective of this study was to evaluate whether there are gender differences in cardiac repolarization in mouse ventricle and to gain insights into the ionic and molecular mechanisms underlying these differences. Action potential durations (APDs) and K + currents in male and female ventricular myocytes were compared using a patch-clamp technique. APD 20 , APD 50 , and APD 90 were found to be significantly longer in females than males. Examination of the different K + currents revealed that a significantly lower current density exists in female ventricular myocytes compared with male myocytes for the ultrarapid delayed rectifier K + current, I Kur (at +30 mV, male, 33.2±2.9 pA/pF [n= 22]; female, 20.9±1.73 pA/pF [n= 19], P &lt;0.001). Consistent with these findings were the results of the ribonuclease protection assay, Western blots, and confocal analysis that showed a significantly lower expression level of Kv1.5 (coding for I Kur ) in female compared with male ventricle. The additional K + currents present in mouse ventricle exhibited no gender differences. In agreement with these electrophysiological data, no differences in the expression levels for the K + channels underlying these currents were detected between both sexes. This study demonstrates that adult mice exhibit gender differences in cardiac repolarization. The expression of Kv1.5 and of its corresponding K + current, I Kur , is significantly lower in female mouse ventricle, and as a result, the APD is lengthened.
Pathologic Complete Response to Neoadjuvant Chemotherapy of Breast Carcinoma Is Associated with the Disappearance of Tumor-Infiltrating Foxp3+ Regulatory T Cells
Authors: Sylvain Ladoire, Laurent Arnould, Lionel Apetoh, Bruno Coudert, Francois Martin, Bruno Chauffert, Pierre Fumoleau, François Ghiringhelli
Journal: Clinical Cancer Research (2008)

Abstract Purpose: T-cell infiltration is associated with good tumor prognosis in many cancers. To assess the capacity of neoadjuvant chemotherapy to affect T-cell infiltration in breast cancer, we evaluated CD3 and CD8 infiltrates, and the Foxp3 immunosuppressive T cells. Experimental Design: CD3+, CD8+, and Foxp3+ cell infiltrates were detected by immunohistochemistry in a series of 56 breast cancer patients before and after the end of neoadjuvant chemotherapy. Results: Poor prognostic factors (negative hormonal receptors, high tumor grade, and nodal involvement) were associated with a significantly higher number of CD3, CD8, and Foxp3 infiltrates before the beginning of chemotherapy. Chemotherapy resulted in a decrease in Foxp3 infiltrates, whereas the level of CD8 and CD3 infiltrates remained unchanged. Pathologic complete responses (pCR) had a drastic decrease of Foxp3+ cells, whereas these cells remained elevated in nonresponders. A cutoff criterion that combined high CD8 infiltration and no Foxp3 cell infiltration on surgical specimens is associated with pCR with a sensitivity of 75% and a specificity of 93%. The infiltrate of cytotoxic TiA1 and granzyme B–positive cells was dramatically enhanced after chemotherapy only in patients with pCR. By multivariate analysis, association of a high CD8 infiltration and no Foxp3 infiltration on final histologic specimens were independently associated with pCR. Conclusion: These findings indicate that pCR to neoadjuvant chemotherapy is associated with an immunologic profile combining the absence of immunosuppressive Foxp3 cells and the presence of a high number of CD8 T cells and cytotoxic cells. These results argue for the induction of an antitumor immune response by chemotherapy.
Prevalence of Regional Myocardial Thinning and Relationship With Myocardial Scarring in Patients With Coronary Artery Disease
Authors: Dipan J. Shah, Han W. Kim, Olga James, Michele Parker, Edwin Wu, Robert O. Bonow, Robert M. Judd, Raymond J. Kim
Journal: JAMA (2013)

<h3>Importance</h3>Regional left ventricular (LV) wall thinning is believed to represent chronic transmural myocardial infarction and scar tissue. However, recent case reports using delayed-enhancement cardiovascular magnetic resonance (CMR) imaging raise the possibility that thinning may occur with little or no scarring.<h3>Objective</h3>To evaluate patients with regional myocardial wall thinning and to determine scar burden and potential for functional improvement.<h3>Design, Setting, and Patients</h3>Investigator-initiated, prospective, 3-center study conducted from August 2000 through January 2008 in 3 parts to determine (1) in patients with known coronary artery disease (CAD) undergoing CMR viability assessment, the prevalence of regional wall thinning (end-diastolic wall thickness ≤5.5 mm), (2) in patients with thinning, the presence and extent of scar burden, and (3) in patients with thinning undergoing coronary revascularization, any changes in myocardial morphology and contractility.<h3>Main Outcomes and Measures</h3>Scar burden in thinned regions assessed using delayed-enhancement CMR and changes in myocardial morphology and function assessed using cine-CMR after revascularization.<h3>Results</h3>Of 1055 consecutive patients with CAD screened, 201 (19% [95% CI, 17% to 21%]) had regional wall thinning. Wall thinning spanned a mean of 34% (95% CI, 32% to 37% [SD, 15%]) of LV surface area. Within these regions, the extent of scarring was 72% (95% CI, 69% to 76% [SD, 25%]); however, 18% (95% CI, 13% to 24%) of thinned regions had limited scar burden (≤50% of total extent). Among patients with thinning undergoing revascularization and follow-up cine-CMR (n = 42), scar extent within the thinned region was inversely related to regional (r = −0.72, P &lt; .001) and global (r = −0.53, P &lt; .001) contractile improvement. End-diastolic wall thickness in thinned regions with limited scar burden increased from 4.4 mm (95% CI, 4.1 to 4.7) to 7.5 mm (95% CI, 6.9 to 8.1) after revascularization (P &lt; .001), resulting in resolution of wall thinning. On multivariable analysis, scar extent had the strongest association with contractile improvement (slope coefficient, −0.03 [95% CI, −0.04 to −0.02]; P &lt; .001) and reversal of thinning (slope coefficient, −0.05 [95% CI, −0.06 to −0.04]; P &lt; .001).<h3>Conclusions and Relevance</h3>Among patients with CAD referred for CMR and found to have regional wall thinning, limited scar burden was present in 18% and was associated with improved contractility and resolution of wall thinning after revascularization. These findings, which are not consistent with common assumptions, warrant further investigation.
Effect of Positive Bone Marrow EBV <i>In situ</i> Hybridization in Staging and Survival of Localized Extranodal Natural Killer/T-Cell Lymphoma, Nasal-Type
Authors: Jeeyun Lee, Cheolwon Suh, Jooryung Huh, Hyun Jung Jun, Kihyun Kim, Chulwon Jung, Keunchil Park, Yeon Hee Park, Young Hyeh Ko, Won Seog Kim
Journal: Clinical Cancer Research (2007)

The aim of the study was to determine the effect of EBV-encoded RNA-1 in situ hybridization (EBER-1 ISH) in bone marrow specimens on survival outcome in patients with clinical stage I/II natural killer/T-cell lymphoma.We systematically did EBER-1 ISH on 182 archival bone marrow tissues from 91 patients who were diagnosed of stage I/II natural killer/T-cell lymphoma and analyzed the correlation between bone marrow EBER-1 ISH status and survival. We defined minimal bone marrow involvement and definite bone marrow involvement to distinguish the subgroups who revealed EBV-positive cells from normal marrow by EBER-1 ISH from those who showed typical neoplastic cells in bone marrow biopsies.In total, 17 of the 91 (18.7%) patients showed positivity for EBER-1 ISH at least in one of the bilateral bone marrow biopsies with 14 minimal bone marrow involvements and 3 definite bone marrow involvements. Patients with positive bone marrow EBER-1 ISH showed significantly poorer overall survival than those who were negative for bone marrow EBER-1 ISH (median survival, 16.1 months versus not reached; P = 0.045).Considering a high proportion of stage I/II patients (15.4%) with minimal in bone marrow specimens, bone marrow EBER-1 ISH should be routinely done in all patients with localized disease for more accurate staging.
Alternate Healthy Eating Index 2010 and risk of chronic obstructive pulmonary disease among US women and men: prospective study
Authors: R. Varraso, S. E. Chiuve, T. T. Fung, R. G. Barr, F. B. Hu, W. C. Willett, C. A. Camargo
Journal: BMJ (2015)

<b>Objective</b> To investigate the association between the Alternate Healthy Eating Index 2010 (AHEI-2010)—a measure of diet quality—and the risk of chronic obstructive pulmonary disease (COPD). <b>Design</b> Prospective cohort study. <b>Setting</b> Participants in the Nurses’ Health Study and the Health Professionals Follow-up Study, United States. <b>Participants</b> 73 228 female nurses from 1984 to 2000 and 47 026 men from 1986 to 1998, who completed biennial questionnaires. <b>Main outcome measures</b> The primary outcome was the self report of newly diagnosed COPD. Multivariable Cox proportional hazards models were adjusted for age, physical activity, body mass index, total energy intake, smoking, second hand tobacco exposure (only in the Nurses’ Health Study), race/ethnicity, physician visits, US region, spouse’s highest educational attainment (only in the Nurses’ Health Study), and menopausal status (only in the Nurses’ Health Study). <b>Results</b> Over the study period, 723 cases of newly diagnosed COPD occurred in women and 167 in men. In the pooled analysis, a significant negative association was seen between the risk of newly diagnosed COPD and fifths of the AHEI-2010: hazard ratios were 0.81 (95% confidence interval 0.51 to 1.29) for the second fifth, 0.98 (0.80 to 1.18) for the third fifth, 0.74 (0.59 to 0.92) for the fourth fifth, and 0.67 (0.53 to 0.85) for participants who ate the healthiest diet according to the AHEI-2010 (that is, were in the highest fifth), compared with those who ate the less healthy diet (participants in the lowest fifth). Similar findings were observed among ex-smokers and current smokers. <b>Conclusions</b> A higher AHEI-2010 diet score (reflecting high intakes of whole grains, polyunsaturated fatty acids, nuts, and long chain omega-3 fats and low intakes of red/processed meats, refined grains, and sugar sweetened drinks) was associated with a lower risk of COPD in both women and men. These findings support the importance of a healthy diet in multi-interventional programs to prevent COPD.
A Kinome-Wide Screen Identifies the Insulin/IGF-I Receptor Pathway as a Mechanism of Escape from Hormone Dependence in Breast Cancer
Authors: Emily M. Fox, Todd W. Miller, Justin M. Balko, Maria G. Kuba, Violeta Sánchez, R. Adam Smith, Shuying Liu, Ana María González-Angulo, Gordon B. Mills, Fei Ye, Yu Shyr, H. Charles Manning, Elizabeth Buck, Carlos L. Arteaga
Journal: Cancer Research (2011)

Estrogen receptor α (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF-7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-I receptor (IGF-IR) inhibited growth of 3 of 4 LTED cell lines. Inhibition of InsR and IGF-IR with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-IR monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-I gene expression signature predicted recurrence-free survival in patients with ER(+) breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-IR should be more effective than targeting IGF-IR alone in abrogating resistance to endocrine therapy in breast cancer.
Level of human TCRBV3S1 (V beta 3) expression correlates with allelic polymorphism in the spacer region of the recombination signal sequence.
Authors: D N Posnett, C S Vissinga, C Pambuccian, S Wei, M A Robinson, D Kostyu, P Concannon
Journal: The Journal of Experimental Medicine (1994)

One of the causes of variations in the expressed human T cell receptor (TCR) BV (V beta) repertoire is genetic variation in the germline DNA. Herein evidence is provided that allelic polymorphism may affect recombination frequency for a specific V gene. Two alleles of the TCR BV3 differ only at a single nucleotide position (C/T) within the 23-bp spacer region of the recombination signal sequence. These alleles are associated with variable percentages of BV3 cells in the peripheral blood, as shown in families and in unrelated normal donors. Individuals homozygous for allele 2 have a mean of 8.1% BV3 cells, heterozygous individuals have a mean of 4.7% BV3 cells, and homozygotes for allele 1 have a mean of 1.2% BV3 cells in CD3+ CD4+ peripheral blood T cells. Since the correlation is tight in unrelated individuals and other genetic differences were not found in the vicinity of BV3, we suggest that the spacer region sequence itself modifies recombination efficiency. This allelic system provides an example of a novel mechanism by which cis-acting genetic elements may affect recombination in a natural in vivo system.
A Pharmacodynamic Study of Docetaxel in Combination with the P-glycoprotein Antagonist Tariquidar (XR9576) in Patients with Lung, Ovarian, and Cervical Cancer
Authors: Ronan J. Kelly, Deborah Draper, Clara C. Chen, Robert W. Robey, William D. Figg, Richard L. Piekarz, Xiaohong Chen, Erin R. Gardner, Frank M. Balis, Aradhana M. Venkatesan, Seth M. Steinberg, Tito Fojo, Susan E. Bates
Journal: Clinical Cancer Research (2010)

P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to show meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third-generation, potent, noncompetitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel.
Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat.
Authors: J M Langrehr, N Murase, P M Markus, X Cai, P Neuhaus, W Schraut, R L Simmons, R A Hoffman
Journal: Journal of Clinical Investigation (1992)

The present study was designed to determine whether .N = O produced in vivo during the rejection of histoincompatible tissues might permit serum NO2-/NO3- levels to serve as markers of a rejection reaction. Rat syngeneic and allogeneic liver, heart, bone marrow/spleen cell, small bowel, skin, and sponge matrix grafts were performed and the stable end-products of .N = O, NO2-/NO3-, were serially assayed in the serum of the grafted animals. A significant rise of serum NO2-/NO3- levels in the allografted animals preceded the onset of clinical signs of rejection or graft-versus-host disease, with the exception of the skin and sponge matrix graft models, where elevated serum NO2-/NO3- levels were never observed. In all transplant models, normal serum NO2-/NO3- levels were observed at all times in animals that received syngeneic grafts. Furthermore, treatment of allograft recipients with the immunosuppressive agents FK 506 or cyclosporine A inhibited .N = O production. Determination of serum creatinine levels demonstrated that the elevated serum NO2-/NO3- levels were not caused by kidney dysfunction. Serum NO2-/NO3- levels might be useful early serum markers of the initiation of a rejection reaction or graft-versus-host disease when functional markers of graft dysfunction are not apparent.
<i>IL13</i> Promoter Polymorphism –1112C/T Modulates the Adverse Effect of Tobacco Smoking on Lung Function
Authors: Alireza Sadeghnejad, Deborah A Meyers, Matteo Bottai, David A Sterling, Eugene R Bleecker, Jill A Ohar
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Although the duration and amount of cigarette smoking correlate with reduction in pulmonary function, there is still variation among individual responses. IL-13 is involved in pulmonary inflammation, remodeling, and susceptibility to chronic obstructive pulmonary disease (COPD).Objectives: We investigated whether the relationships between smoking and the lung function measures FEV1 and FEV1/FVC ratio are modulated by IL13 polymorphisms.Methods: Smokers (≥20 pack-years), aged at least 40 years old (n = 1,073), were genotyped for three single nucleotide polymorphisms (SNPs; –1112C/T [rs1800925], +2044G/A [rs20541, R130Q], and +2525G/A [rs1295685]) in the IL13 gene. Linear, quantile, and logistic regression methods were used to assess the effect of cigarette smoking (pack-years), IL13 polymorphisms, and their interaction on %predicted FEV1 and FEV1/FVC ratio. Age, sex, and current smoking status were included as confounders.Measurements and Main Results: The number of pack-years smoked was associated with a lower value for both %predicted FEV1 and FEV1/FVC (P < 0.001).The three SNPs were not associated with lung function measures; however, there was a significant combined effect between smoking and the promoter polymorphism –1112C/T on %predicted FEV1 (P for interaction < 0.03 for mean %predicted FEV1 and < 0.0001 for 90th percentile %predicted FEV1). Every 20–pack-year increment in smoking was associated with a 2.4% reduction in mean %predicted FEV1 in the common homozygous (CC) or heterozygous (CT) promoter genotypes, and an 8.2% reduction in mean %predicted FEV1 in minor allele homozygotes (TT, recessive model).Conclusions: An IL13 polymorphism in the promoter region may modulate the adverse effects of cigarette smoking on pulmonary function in long-term cigarette smokers.
Value of procalcitonin for diagnosis of early onset pneumonia in hypothermia-treated cardiac arrest patients
Authors: Nicolas Mongardon, Virginie Lemiale, Sébastien Perbet, Florence Dumas, Stéphane Legriel, Sylvie Guérin, Julien Charpentier, Jean-Daniel Chiche, Jean-Paul Mira, Alain Cariou
Journal: Intensive Care Medicine (2009)