tbuckley/cabot-search huggingface dataset:
Selective Targeting and Timing of Matrix Metalloproteinase Inhibition in Post-Myocardial Infarction Remodeling
Authors: William M. Yarbrough, Rupak Mukherjee, G. Patricia Escobar, Joseph T. Mingoia, Jeffrey A. Sample, Jennifer W. Hendrick, Kathryn B. Dowdy, Julie E. McLean, Abigail S. Lowry, Timothy P. O’Neill, Francis G. Spinale
Journal: Circulation (2003)

A cause-and-effect relationship exists between matrix metalloproteinase (MMP) induction and left ventricular (LV) remodeling after myocardial infarction (MI). Whether broad-spectrum MMP inhibition is necessary and the timing at which MMP inhibition should be instituted after MI remain unclear. This study examined the effects of MMP-1 and MMP-7-sparing inhibition (sMMPi) on regional and global LV remodeling when instituted before or after MI.Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to MI only (n=11) or sMMPi (PGE-530742, 10 mg/kg PO TID) begun 3 days before MI (n=11) or 3 days after MI (n=10). Eleven weight-matched noninstrumented pigs served as reference controls. At 10 days after MI, infarct size was similar between groups (47+/-3% of the area at risk). Marker area increased from baseline in the MI-only group (10+/-3%, P<0.05) but was unchanged with sMMPi. LV end-diastolic volume increased in the MI-only group (82+/-3 mL) compared with controls (56+/-3 mL, P<0.05) but was attenuated with pre-MI and post-MI sMMPi (69+/-3 and 69+/-4 mL, respectively, P<0.05). Collagen content increased in the infarct zone of the MI-only group (34+/-5%) compared with control (2+/-1%, P<0.05) but was reduced with pre-MI and post-MI sMMPi (24+/-1% and 23+/-2%, P<0.05). Collagen content increased in the border zone (12+/-2%) and decreased in the remote zone (3+/-1%) of the pre-MI sMMPi group compared with post-MI sMMPi values (7+/-1% and 5+/-1%, P<0.05).Inhibition of MMP-1 and -7 is not required to favorably influence LV remodeling after MI. Moreover, a temporal difference exists with respect to the timing of sMMPi and regional and global myocardial remodeling patterns after MI.
The need for political correctness in scientific writing
Authors: J. Le Fanu
Journal: BMJ (1998)

It is not immediately obvious why political correctness should feature so strongly as sacred cow number two on the hit list of visitors to the BMJ 's website. Certainly, spouses have become partners lest the unmarried should take offence, and prostitutes have been transformed into sex workers (not that they are likely to be much concerned either way about their job title). But this can be lived with, and there has been nothing in medicine to compare with “Gingerbread Person,” “Baa, Baa Green Sheep,” or the myriad other absurdities of the politically correct lexicon.

This verbal hygiene is, however, only the outer shell of political correctness. More serious is the censorship of significant facts and observations from scientific writing and which in turn explains why there is such a disparity between the everyday world as experienced by doctors and its bowdlerised, scarcely recognisable, reflection in the …
Differential patterns of intronic and exonic DNA regions with respect to RNA polymerase II occupancy, nucleosome density and H3K36me3 marking in fission yeast
Authors: Brian T Wilhelm, Samuel Marguerat, Sofia Aligianni, Sandra Codlin, Stephen Watt, Jürg Bähler
Journal: Genome biology (2011)

Abstract Background The generation of mature mRNAs involves interconnected processes, including transcription by RNA polymerase II (Pol II), modification of histones, and processing of pre-mRNAs through capping, intron splicing, and polyadenylation. These processes are thought to be integrated, both spatially and temporally, but it is unclear how these connections manifest at a global level with respect to chromatin patterns and transcription kinetics. We sought to clarify the relationships between chromatin, transcription and splicing using multiple genome-wide approaches in fission yeast. Results To investigate these functional interdependencies, we determined Pol II occupancy across all genes using high-density tiling arrays. We also performed ChIP-chip on the same array platform to globally map histone H3 and its H3K36me3 modification, complemented by formaldehyde-assisted isolation of regulatory elements (FAIRE). Surprisingly, Pol II occupancy was higher in introns than in exons, and this difference was inversely correlated with gene expression levels at a global level. Moreover, introns showed distinct distributions of histone H3, H3K36me3 and FAIRE signals, similar to those at promoters and terminators. These distinct transcription and chromatin patterns of intronic regions were most pronounced in poorly expressed genes. Conclusions Our findings suggest that Pol II accumulates at the 3' ends of introns, leading to substantial transcriptional delays in weakly transcribed genes. We propose that the global relationship between transcription, chromatin remodeling, and splicing may reflect differences in local nuclear environments, with highly expressed genes being associated with abundant processing factors that promote effective intron splicing and transcriptional elongation.
Alteration of Gene Expression in Normal-Appearing Colon Mucosa of <b> <i>APC</i> </b> <b> <i>min</i> </b> Mice and Human Cancer Patients
Authors: Ling-Chun Chen, Chun-Yi Hao, Yanek S. Y. Chiu, Patrick Wong, Jane S. Melnick, Martin Brotman, John Moretto, Fredrick Mendes, Andrew P. Smith, James L. Bennington, Dan Moore, Nancy M. Lee
Journal: Cancer Research (2004)

Abstract The expression of many genes is altered in colon cancer, but the roles of these genes in carcinogenesis are unclear. Using real-time quantitative PCR, we demonstrated that several genes previously implicated in human colon cancer undergo altered expression in the APCmin mouse adenomatous polyp, a precursor of cancer, as well as in normal-appearing surrounding mucosa. The five genes that were most highly up-regulated in mouse polyp were also significantly up-regulated in polyp-free colon mucosa. Similar changes occurred in morphologically normal mucosa of surgical sections taken from human cancer patients, frequently extending to the margins. Thus, morphologically normal colon mucosa in APCmin mice and in human cancer patients is not metabolically normal. Altered gene expression in this tissue does not appear to result from a field effect because there was no correlation between extent of altered regulation and distance from polyp or tumor. Our data suggest that alterations of expression levels of these genes may be an early event in carcinogenesis and a marker of risk for the development of colon cancer.
RENAL INSUFFICIENCY IN PATIENTS WITH A TOTAL OCCLUSION OF A CORONARY ARTERY AFTER MYOCARDIAL INFARCTION
Authors: Judith S. Hochman, Ramin Hastings, Harmony R. Reynolds, Vladimir Dzavik, Dimitris Mikas, Lampros K. Michalis, Francois Schiele, Sandra A. Forman, Gervasio A, Lamas A. Lamas
Journal: Journal of the American College of Cardiology (2010)
Directed Vascular Expression of Human Cysteinyl Leukotriene 2 Receptor Modulates Endothelial Permeability and Systemic Blood Pressure
Authors: Yiqun Hui, Yan Cheng, Isabella Smalera, Wenying Jian, Lawrence Goldhahn, Garret A. FitzGerald, Colin D. Funk
Journal: Circulation (2004)

Background— The proinflammatory and vascular actions of cysteinyl leukotrienes (CysLTs) are mediated by 2 receptors: cysteinyl leukotriene 1 receptor (CysLT 1 R) and cysteinyl leukotriene 2 receptor (CysLT 2 R). However, the distinct contribution of CysLT 2 R to the vascular actions of CysLTs has not been addressed. Methods and Results— We generated an endothelial cell–specific human CysLT 2 R (EC-hCysLT 2 R) transgenic (TG) mouse model using the Tie2 promoter/enhancer. Strong expression of hCysLT 2 R in TG lung and endothelial cells, detected by real-time polymerase chain reaction, markedly enhanced CysLT-stimulated intracellular calcium mobilization compared with endogenous expression in cells from nontransgenic mice. The permeability response to exogenous LTC 4 and to endogenous CysLTs evoked by passive cutaneous anaphylaxis was augmented in TG mice. The rapid, systemic pressor response to intravenous LTC 4 was also diminished in TG mice coincidentally with augmented production of nitric oxide. Conclusions— The development of EC-hCysLT 2 R mice has permitted detection of distinct vascular effects of CysLTs, which can be mediated via the CysLT 2 R in vivo.
Comparison of triamcinolone acetonide nasal inhaler with astemizole in the treatment of ragweed-induced allergic rhinitis*
Authors: D BERNSTEIN, P CRETICOS, W BUSSE, R COHEN, D GRAFT, W HOWLAND, W LUMRY, A PEDINOFF, P RATNER, J LIM
Journal: Journal of Allergy and Clinical Immunology (1996)
Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension
Authors: M C Tamby
Journal: Thorax (2005)

<b>Background:</b> It has previously been shown that IgG antibodies from patients with limited cutaneous systemic sclerosis (SSc) bind to specific microvascular endothelial cell antigens. Since patients with limited cutaneous SSc are prone to develop pulmonary arterial hypertension (PAH), and since endothelial cell activation is involved in the pathogenesis of idiopathic PAH (IPAH), a study was undertaken to examine the presence of anti-endothelial cell antibodies in patients with idiopathic or SSc associated PAH. <b>Methods:</b> PAH was confirmed by right heart catheterisation (mean pulmonary artery pressure at rest &gt;25 mm Hg). Serum IgG and IgM reactivities were analysed by immunoblotting on human macrovascular and microvascular lung and dermal endothelial cells from patients with IPAH (n = 35), patients with PAH associated with SSc (n = 10), patients with diffuse (n = 10) or limited cutaneous (n = 10) SSc without PAH, and 65 age and sex matched healthy individuals. <b>Results:</b> IgG antibodies from patients with IPAH bound to a 36 kDa band in macrovascular endothelial cell extracts with a higher intensity than IgG from other patient groups and controls. IgG antibodies from patients with IPAH bound more strongly to a 58 kDa band in microvascular dermal endothelial cells and to a 53 kDa band in microvascular lung endothelial cells than IgG antibodies from other patients and controls. IgG antibodies from patients with limited cutaneous SSc with or without PAH, but not from other groups or from healthy controls, bound to two major bands (75 kDa and 85 kDa) in microvascular endothelial cells. <b>Conclusion:</b> IgG antibodies from patients with idiopathic or SSc associated PAH express distinct reactivity profiles with macrovascular and microvascular endothelial cell antigens.
β-Catenin Contributes to Lung Tumor Development Induced by EGFR Mutations
Authors: Sohei Nakayama, Natasha Sng, Julian Carretero, Robert Welner, Yuichiro Hayashi, Mihoko Yamamoto, Alistair J. Tan, Norihiro Yamaguchi, Hiroyuki Yasuda, Danan Li, Kenzo Soejima, Ross A. Soo, Daniel B. Costa, Kwok-Kin Wong, Susumu S. Kobayashi
Journal: Cancer Research (2014)

Abstract The discovery of somatic mutations in EGFR and development of EGFR tyrosine kinase inhibitors (TKI) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here, we show that β-catenin is essential for development of EGFR-mutated lung cancers. β-Catenin was upregulated and activated in EGFR-mutated cells. Mutant EGFR preferentially bound to and tyrosine phosphorylated β-catenin, leading to an increase in β-catenin–mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacologic inhibition of β-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth, and genetic deletion of the β-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that β-catenin plays an essential role in lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs. Cancer Res; 74(20); 5891–902. ©2014 AACR.
Whole-Exome Sequencing Reveals Defective <i>CYP3A4</i> Variants Predictive of Paclitaxel Dose-Limiting Neuropathy
Authors: María Apellániz-Ruiz, Mi-Young Lee, Lara Sánchez-Barroso, Gerardo Gutiérrez-Gutiérrez, Isabel Calvo, Laura García-Estévez, María Sereno, Jesús García-Donás, Beatriz Castelo, Eva Guerra, Luis J. Leandro-García, Alberto Cascón, Inger Johansson, Mercedes Robledo, Magnus Ingelman-Sundberg, Cristina Rodríguez-Antona
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Paclitaxel, a widely used chemotherapeutic drug, can cause peripheral neuropathies leading to dose reductions and treatment suspensions and decreasing the quality of life of patients. It has been suggested that genetic variants altering paclitaxel pharmacokinetics increase neuropathy risk, but the major causes of interindividual differences in susceptibility to paclitaxel toxicity remain unexplained. We carried out a whole-exome sequencing (WES) study to identify genetic susceptibility variants associated with paclitaxel neuropathy. Experimental Design: Blood samples from 8 patients with severe paclitaxel-induced peripheral neuropathy were selected for WES. An independent cohort of 228 cancer patients with complete paclitaxel neuropathy data was used for variant screening by DHPLC and association analysis. HEK293 cells were used for heterologous expression and characterization of two novel CYP3A4 enzymes. Results: WES revealed 2 patients with rare CYP3A4 variants, a premature stop codon (CYP3A4*20 allele) and a novel missense variant (CYP3A4*25, p.P389S) causing reduced enzyme expression. Screening for CYP3A4 variants in the independent cohort revealed three additional CYP3A4*20 carriers, and two patients with missense variants exhibiting diminished enzyme activity (CYP3A4*8 and the novel CYP3A4*27 allele, p.L475V). Relative to CYP3A4 wild-type patients, those carrying CYP3A4 defective variants had more severe neuropathy (2- and 1.3-fold higher risk of neuropathy for loss-of-function and missense variants, respectively, P = 0.045) and higher probability of neuropathy-induced paclitaxel treatment modifications (7- and 3-fold higher risk for loss-of-function and missense variants, respectively, P = 5.9 × 10−5). Conclusion: This is the first description of a genetic marker associated with paclitaxel treatment modifications caused by neuropathy. CYP3A4 defective variants may provide a basis for paclitaxel treatment individualization. Clin Cancer Res; 21(2); 322–8. ©2014 AACR.
Alternative Lengthening of Telomeres Is Characterized by High Rates of Telomeric Exchange
Authors: J. Arturo Londoño-Vallejo, Héra Der-Sarkissian, Lucien Cazes, Silvia Bacchetti, Roger R. Reddel
Journal: Cancer Research (2004)

Abstract Telomere maintenance activity is a hallmark of cancer. In some telomerase-negative tumors, telomeres become lengthened by alternative lengthening of telomeres (ALT), a recombination-mediated DNA replication process in which telomeres use other telomeric DNA as a copy template. Using chromosome orientation fluorescence in situ hybridization, we found that postreplicative exchange events involving a telomere and another TTAGGG-repeat tract occur at remarkably high frequencies in ALT cells (range 28–280/100 metaphases) and rarely or never in non-ALT cells, including cell lines with very long telomeres. Like the ALT phenotype itself, the telomeric exchanges were not suppressed when telomerase was activated in ALT cells. These exchanges are telomere specific because there was no correlation with sister chromatid exchange rates at interstitial locations, and they were not observed in non-ALT Bloom syndrome cells with very high sister chromatid exchange rates.
Femoral Head Osteonecrosis in Pediatric and Young Adult Patients With Leukemia or Lymphoma
Authors: Evguenia J. Karimova, Shesh N. Rai, Scott C. Howard, Michael Neel, Lunetha Britton, Ching-Hon Pui, Sue C. Kaste
Journal: Journal of Clinical Oncology (2007)

Osteonecrosis of the capital femoral epiphysis is a significant late toxicity of treatment for childhood leukemia and lymphoma. We determined clinical and imaging risk factors predicting clinical joint outcomes of femoral head osteonecrosis in pediatric patients with leukemia or lymphoma.We reviewed retrospectively medical records and magnetic resonance imaging scans of 80 patients with osteonecrosis of the capital femoral epiphysis. Logistic regression was used to examine relationships between risk factors and outcomes of joint surface collapse and arthroplasty. We used Kaplan-Meier survival curves to display the time to joint surface collapse and arthroplasty based on selected predictors.Median time between primary diagnosis and diagnosis of osteonecrosis of the hip was 1.7 years (range, 0.1 to 17.5 years). Twenty-three patients (29%) underwent arthroplasty in 36 hips at a mean of 1.3 years (range, 0.5 to 8.6 years) after diagnosis of osteonecrosis. Median age at time of first arthroplasty was 20.1 years (range, 15.1 to 35.4 years). Joint outcome of osteonecrosis was predicted solely by lesion size at diagnosis of osteonecrosis. The worst prognosis was associated with lesions occupying more than 30% of the femoral head volume; 80% of hips with these lesions collapsed within 2 years of diagnosis and 50% required arthroplasty.Lesion size of osteonecrosis is the best predictor of clinical joint outcome of hip osteonecrosis in survivors of pediatric hematologic malignancy. Lesions occupying more than 30% of the femoral head have high likelihood of joint deterioration necessitating arthroplasty at a young age.
Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes
Authors: Mallika Singh, Christopher L. Murriel, Leisa Johnson
Journal: Cancer Research (2012)

The high failure rate of late-stage human clinical trials, particularly in oncology, predicates the need for improved translation of preclinical data from mouse tumor models into clinical predictions. Genetically engineered mouse models (GEMM) may fulfill this need, because they mimic spontaneous and autochthonous disease progression. Using oncogenic Kras-driven GEMMs of lung and pancreatic adenocarcinoma, we recently showed that these models can closely phenocopy human therapeutic responses to standard-of-care treatment regimens. Here we review the successful preclinical application of such GEMMs, as well as the potential for discovering predictive biomarkers and gaining mechanistic insights into clinical outcomes and drug resistance in human cancers.
Bronchoalveolar lavage alterations during prolonged ventilation of patients without acute lung injury
Authors: I. Tsangaris, M.E. Lekka, E. Kitsiouli, S. Constantopoulos, G. Nakos
Journal: European Respiratory Journal (2003)

Mechanical ventilation deteriorates previously injured lung, but little is known about its effect on healthy human lung. This work was designed to assess the effect of prolonged mechanical ventilation on bronchoalveolar lavage (BAL) fluid composition of patients without acute lung injury. Twenty-two ventilated patients (tidal volume 8–10 mL·kg −1 , positive end-expiratory pressure 3–5 cmH 2 O) without lung injury, who did not develop any complication from the respiratory system during the 2‐week study period, were studied. They were subjected to three consecutive BALs, the first during 36 h from intubation, the second at the end of the first week of mechanical ventilation and the third at the end of the second week of mechanical ventilation. Total BAL protein increased during mechanical ventilation (148±62, 381±288, 353±215 µg·mL −1 BAL for the first, second and third BAL, respectively). In contrast, BAL phospholipids decreased (2.7±1.1, 1.4±0.6, 1.2±0.7 µg·mL −1 BAL, respectively). Large surfactant aggregates were reduced and inflammatory markers, such as platelet activating factor (PAF), PAF-acetylhydrolase and neutrophils, significantly increased after 1 week, but partially remitted after 2 weeks of mechanical ventilation. In summary, this study demonstrates that prolonged mechanical ventilation even of patients without acute lung injury is associated with the presence of inflammatory markers and surfactant alterations.
CD40/CD154 Interactions at the Interface of Tolerance and Immunity
Authors: Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind, Randolph J. Noelle
Journal: Annual Review of Immunology (2004)

Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alpha CD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.
Degradation of cartilage proteoglycan by human leukocyte granule neutral proteases--a model of joint injury. I. Penetration of enzyme into rabbit articular cartilage and release of 35SO4-labeled material from the tissue.
Authors: A Janoff, G Feinstein, C J Malemud, J M Elias
Journal: Journal of Clinical Investigation (1976)

The present work was undertaken to explore the effect of two purified neutral proteases derived from human peripheral blood polymorphonuclear leukocytes (PMN) on articular cartilage as a model of joint injury. Human leukocyte elastase and chymotrypsin-like enzyme, purified by affinity chromatography, released 32SO4 from labeled rabbit articular cartilage slices in vitro. Release of isotope was initially delayed, suggesting that either a lag in enzyme penetration occurs or that size of degradation fragments is a limiting factor in diffusion of label out of the tissue. The release of 35SO4 was inhibited by preincubation of elastase and chymotrypsin-like enzyme with human alpha 1-anti-trypsin, or with their specific chloromethyl ketone inactivators, and the action of elastase was also inhibited by a monospecific antiserum to PMN elastase, freed of major serum proteinase inhibitors. Immunohistochemical staining procedures revealed the presence of PMN elastase inside the matrix of cartilage slices after a 20-min exposure of tissue to either the pure enzyme or crude PMN granule extract. Serum alpha 1-antitrypsin failed to penetrate into the cartilage slices under identical in vitro conditions. In association with the results reported in the accompanying paper, these findings suggest a model of cartilage matrix degradation by PMN neutral proteases in which local protease-antiprotease imbalance, coupled with different rates of penetration of protease and antiprotease into target tissue, plays a key role in accounting for matrix damage.