tbuckley/cabot-search huggingface dataset:
Incidence, Mechanisms, Predictors, and Clinical Impact of Acute and Late Stent Malapposition After Primary Intervention in Patients With Acute Myocardial Infarction
Authors: Ning Guo, Akiko Maehara, Gary S. Mintz, Yong He, Kai Xu, Xiaofan Wu, Alexandra J. Lansky, Bernhard Witzenbichler, Giulio Guagliumi, Bruce Brodie, Mirle A. Kellett, Ovidiu Dressler, Helen Parise, Roxana Mehran, Gregg W. Stone
Journal: Circulation (2010)

The incidence and mechanisms of acute and late stent malapposition after primary stent implantation in ST-segment elevation myocardial infarction remain unclear.The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial was a dual-arm, factorial, randomized trial comparing paclitaxel-eluting stents (PES) and otherwise equivalent bare metal stents (BMS) in ST-segment elevation myocardial infarction patients. The intravascular ultrasound substudy enrolled 241 patients with 263 native coronary lesions (201 PES, 62 BMS) with baseline and 13-month follow-up imaging. Postintervention acute stent malapposition (ASM) occurred in 34.3% PES- and 40.3% BMS-treated lesions. Of these, 39.1% PES- and 40.0% BMS-treated lesions resolved at follow-up, especially within the stent body (66.7%); complete resolution was accompanied by a reduction in external elastic membrane area. An ASM area >1.2 mm(2) best separated persistent from resolved ASM. At follow-up, a higher frequency of late stent malapposition was detected in PES-treated lesions (46.8%) mainly because of more late acquired stent malapposition (30.8%) compared with BMS-treated lesions. Late acquired stent malapposition area correlated to the decrease of peri-stent plaque in the subset of lesions without positive remodeling and only to change in external elastic membrane in the group with positive remodeling. Independent predictors of late acquired stent malapposition were plaque/thrombus protrusion (odds ratio, 5.60; 95% confidence interval [CI], 2.32 to 13.54) and PES use (odds ratio, 6.32; 95% CI, 2.15 to 18.62).The incidence of ASM was similar in PES- and BMS-treated lesions, but late acquired stent malapposition was more common in PES-treated lesions. The reason for resolved ASM was negative remodeling, with larger ASM areas separating persistent from resolved ASM. Late acquired stent malapposition was due mainly to positive remodeling and plaque/thrombus resolution.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.
Insulin-Like Growth Factor-I, Regulating Aromatase Expression through Steroidogenic Factor 1, Supports Estrogen-Dependent Tumor Leydig Cell Proliferation
Authors: Rosa Sirianni, Adele Chimento, Rocco Malivindi, Ignazio Mazzitelli, Sebastiano Andò, Vincenzo Pezzi
Journal: Cancer Research (2007)

Abstract The aim of this study was to investigate the role of estrogens in Leydig cell tumor proliferation. We used R2C rat Leydig tumor cells and testicular samples from Fischer rats with a developed Leydig tumor. Both experimental models express high levels of aromatase and estrogen receptor α (ERα). Treatment with exogenous 17β-estradiol (E2) induced proliferation of R2C cells and up-regulation of cell cycle regulators cyclin D1 and cyclin E, the expression of which was blocked by addition of antiestrogens. These observations led us to hypothesize an E2/ERα–dependent mechanism for Leydig cell tumor proliferation. In determining the molecular mechanism responsible for aromatase overexpression, we found that total and phosphorylated levels of transcription factors cyclic AMP–responsive element binding protein and steroidogenic factor 1 (SF-1) were higher in tumor samples. Moreover, we found that tumor Leydig cells produce high levels of insulin-like growth factor I (IGF-I), which increased aromatase mRNA, protein, and activity as a consequence of increased total and phosphorylated SF-1 levels. Specific inhibitors of IGF-I receptor, protein kinase C, and phosphatidylinositol 3-kinase determined a reduction in SF-1 expression and in IGF-I–dependent SF-1 recruitment to the aromatase PII promoter. The same inhibitors also inhibited aromatase expression and activity and, consequently, R2C cell proliferation. We can conclude that one of the molecular mechanisms determining Leydig cell tumorigenesis is an excessive estrogen production that stimulates a short autocrine loop determining cell proliferation. In addition, cell-produced IGF-I amplifies estrogen signaling through an SF-1–dependent up-regulation of aromatase expression. The identification of this molecular mechanism will be helpful in defining new therapeutic approaches for Leydig cell tumors. [Cancer Res 2007;67(17):8368–77]
The Emerging Role of Glutamate in the Pathophysiology and Treatment of Schizophrenia
Authors: D C Goff, J T Coyle
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. METHOD: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. RESULTS: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-d-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the symptomatic manifestations of schizophrenia, including negative symptoms and cognitive impairments, and increases dopamine release in the mesolimbic system. Agents that indirectly enhance NMDA receptor function via the glycine modulatory site reduce negative symptoms and variably improve cognitive functioning in schizophrenic subjects receiving typical antipsychotics. CONCLUSIONS: Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development.
Biochemical pathways in prokaryotes can be traced backward through evolutionary time.
Authors: R A Jensen
Journal: Molecular Biology and Evolution (1985)

For the first time, a credible prokaryotic phylogenetic tree is being assembled by Woese and others using quantitative sequence analysis of oligonucleotides in the highly conservative rRNA. This provides an evolutionary scale against which the evolutionary steps that led to the arrangement and regulation of contemporary biochemical pathways can be measured. This paper presents an emerging evolutionary picture of aromatic amino acid biosynthesis within a large superfamily assemblage of prokaryotes that is sufficiently developed to illustrate a new perspective that will be applicable to many other biochemical pathways.
Relation between <i>Helicobacter pylori</i> infection and gastrointestinal symptoms and syndromes
Authors: S Rosenstock, L Kay, C Rosenstock, L P Andersen, O Bonnevie, T Jørgensen
Journal: Gut (1997)

Background — Helicobacter pylori is a human pathogen that colonises the gastric mucosa and causes permanent gastric inflammation. Aims —To assess the symptoms of H pylori infection in an adult unselected population. Subjects —A random sample of 3589 adult Danes who were examined in 1982 and 1987 (n=2987). Methods —Abdominal symptoms within the preceding year were recorded at both attendances. Circulating IgG antibodies against H pylori in serum samples drawn in 1982 were measured by using in-house indirect enzyme linked immunosorbent assays (ELISA). Results —People with increased levels of IgG antibodies to H pylori were more likely than uninfected individuals to report heartburn (odds ratio (OR) = 1.26, 95% confidence interval (CI) 1.03–1.54) and abdominal pain characterised by daily length (OR = 1.33, 95% CI 0.92–1.91), nocturnal occurrence (OR = 1.62, 95% CI 1.19–2.19), spring aggravation (OR = 1.68, 95% CI 0.70–4.05), and no relation to meals (OR = 0.62, 95% CI 0.43–0.91) or stress (OR = 0.69, 95% CI 0.50–0.95). The inclusion of people with increased levels of IgG antibodies to H pylori , but without upper dyspepsia, at study entry significantly increased the likelihood of reporting upper dyspepsia at follow up (OR = 1.71, 95% CI 1.24–2.36). People with epigastric pain and increased levels of IgM antibodies to H pylori only indicative of acute H pylori infection were more likely to report nocturnal pain, heartburn, nausea, and vomiting. Conclusions — H pylori infection may precede the development of dyspepsia and is associated with a variety of gastrointestinal symptoms in people with no history of peptic ulcer disease.
Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer
Authors: J. Cortés, J. Baselga, Y.-H. Im, S.-A. Im, X. Pivot, G. Ross, E. Clark, A. Knott, S.M. Swain
Journal: Annals of Oncology (2013)
Ligation of protease-activated receptor 1 enhances v 6 integrin-dependent TGF- activation and promotes acute lung injury
Authors: R. G. Jenkins
Journal: Journal of Clinical Investigation (2006)

Activation of latent TGF-beta by the alpha(v)beta6 integrin is a critical step in the development of acute lung injury. However, the mechanism by which alpha(v)beta6-mediated TGF-beta activation is regulated has not been identified. We show that thrombin, and other agonists of protease-activated receptor 1 (PAR1), activate TGF-beta in an alpha(v)beta6 integrin-specific manner. This effect is PAR1 specific and is mediated by RhoA and Rho kinase. Intratracheal instillation of the PAR1-specific peptide TFLLRN increases lung edema during high-tidal-volume ventilation, and this effect is completely inhibited by a blocking antibody against the alpha(v)beta6 integrin. Instillation of TFLLRN during high-tidal-volume ventilation is associated with increased pulmonary TGF-beta activation; however, this is not observed in Itgb6-/- mice. Furthermore, Itgb6-/- mice are also protected from ventilator-induced lung edema. We also demonstrate that pulmonary edema and TGF-beta activity are similarly reduced in Par1-/- mice following bleomycin-induced lung injury. These results suggest that PAR1-mediated enhancement of alpha(v)beta6-dependent TGF-beta activation could be one mechanism by which activation of the coagulation cascade contributes to the development of acute lung injury, and they identify PAR1 and the alpha(v)beta6 integrin as potential therapeutic targets in this condition.
A Large Cohort Study of Nonsteroidal Anti-inflammatory Drug Use and Melanoma Incidence
Authors: M. M. Asgari, S. S. Maruti, E. White
Journal: JNCI Journal of the National Cancer Institute (2008)

Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. However, few published epidemiological studies have examined the association between NSAID use and melanoma risk. We examined whether NSAID use was associated with melanoma risk among 63 809 men and women in the Vitamins and Lifestyle (VITAL) cohort study. Participants self-reported NSAID use (low-dose aspirin, regular or extra-strength aspirin, and nonaspirin NSAIDs) during the previous 10 years and data related to their melanoma risk factors on a baseline questionnaire. After linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident melanoma were identified through December 31, 2005. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by NSAID use as categorized by overall use, duration of use, and dose (expressed as average number of days of use during the past 10 years). All statistical tests were two-sided. After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. When use of at least 4 d/wk was compared with nonuse, no melanoma risk reduction was detected for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), for any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), for regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or for nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). Moreover, NSAID use was not associated with tumor invasion ( Pinteraction = .38), tumor thickness ( Ptrend = .98), or risk of metastasis (HR = 1.09, 95% CI = 0.32 to 3.62). NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.
A prospective study of rock climbing injuries.
Authors: J P Wyatt, G W McNaughton, P T Grant
Journal: British Journal of Sports Medicine (1996)

To study the rate, causes, and nature of rock climbing injuries presenting to an accident and emergency (A&E) department.Patients presenting with rock climbing injuries to an urban A&E department were studied prospectively for one year.19 rock climbers presented during the year, at a rate of one per 2774 A&E attendances. Fourteen climbers were injured on outdoor cliffs and five on the local indoor climbing wall, where the safety mats were noted to be in poor condition. Eighteen climbers had been injured during falls, 17 hitting the ground. Twelve of these climbers sustained fractures, four of which were missed on initial attendance. The remaining climber sustained the characteristic A2 pulley finger injury, which was treated conservatively with a good result.The risks of rock climbing in Britain would be reduced if lead climbers arranged protection at earlier stages of climbs. Sports centres with climbing walls should regularly inspect and repair their safety equipment. It is important for staff in A&E departments to appreciate the large forces involved in any climbing fall, in order that significant injuries are not missed. Those treating injured climbers should also be aware of the specific injuries to which elite climbers are predisposed.
Genetic PTX3 Deficiency and Aspergillosis in Stem-Cell Transplantation
Authors: Cristina Cunha, Franco Aversa, João F. Lacerda, Alessandro Busca, Oliver Kurzai, Matthias Grube, Jürgen Löffler, Johan A. Maertens, Alain S. Bell, Antonio Inforzato, Elisa Barbati, Bruno Almeida, Pedro Santos e Sousa, Anna Barbui, Leonardo Potenza, Morena Caira, Fernando Rodrigues, Giovanni Salvatori, Livio Pagano, Mario Luppi, Alberto Mantovani, Andrea Velardi, Luigina Romani, Agostinho Carvalho
Journal: New England Journal of Medicine (2014)

The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown.
Signal Transducers and Activators of Transcription-3 Binding to the Fibroblast Growth Factor Receptor Is Activated by Receptor Amplification
Authors: Anna A. Dudka, Steve M.M. Sweet, John K. Heath
Journal: Cancer Research (2010)

Abstract Fibroblast growth factor receptors (FGFR) are cell surface tyrosine kinases that function in cell proliferation and differentiation. Aberrant FGFR signaling occurs in diverse cancers due to gene amplification, but the associated oncogenic mechanisms are poorly understood. Using a proteomics approach, we identified signal transducers and activators of transcription-3 (STAT3) as a receptor-binding partner that is mediated by Tyr677 phosphorylation on FGFR. Binding to activated FGFR was essential for subsequent tyrosine phosphorylation and nuclear translocation of STAT3, along with activation of its downstream target genes. Tyrosine phosphorylation of STAT3 was also dependent on concomitant FGFR-dependent activity of SRC and JAK kinases. Lastly, tyrosine (but not serine) phosphorylation of STAT3 required amplified FGFR protein expression, generated either by enforced overexpression or as associated with gene amplification in cancer cells. Our findings show that amplified FGFR expression engages the STAT3 pathway, and they suggest therapeutic strategies to attack FGFR-overexpressing cancers. Cancer Res; 70(8); 3391–401. ©2010 AACR.
Genetic and Epigenetic Analysis of von Hippel-Lindau (<i>VHL</i>) Gene Alterations and Relationship with Clinical Variables in Sporadic Renal Cancer
Authors: Rosamonde E. Banks, Prasanna Tirukonda, Claire Taylor, Nick Hornigold, Dewi Astuti, Dena Cohen, Eamonn R. Maher, Anthea J. Stanley, Patricia Harnden, Adrian Joyce, Margaret Knowles, Peter J. Selby
Journal: Cancer Research (2006)

Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumor suppressor gene are common in sporadic conventional renal cell carcinoma (cRCC). Further insight into the clinical significance of these changes may lead to increased biological understanding and identification of subgroups of patients differing prognostically or who may benefit from specific targeted treatments. We have comprehensively examined the VHL status in tissue samples from 115 patients undergoing nephrectomy, including 96 with sporadic cRCC. In patients with cRCC, loss of heterozygosity was found in 78.4%, mutation in 71%, and promoter methylation in 20.4% of samples. Multiplex ligation-dependent probe amplification identified intragenic copy number changes in several samples including two which were otherwise thought to be VHL-noninvolved. Overall, evidence of biallelic inactivation was found in 74.2% of patients with cRCC. Many of the mutations were novel and approximately two-thirds were potentially truncating. Examination of these and other published findings confirmed mutation hotspots affecting codons 117 and 164, and revealed a common region of mutation in codons 60 to 78. Gender-specific differences in methylation and mutation were seen, although not quite achieving statistical significance (P = 0.068 and 0.11), and a possible association between methylation and polymorphism was identified. No significant differences were seen between VHL subgroups with regard to clinicopathologic features including stage, grade, tumor size, cancer-free and overall survival, with the exception of a significant association between loss of heterozygosity and grade, although a possible trend for survival differences based on mutation location was apparent.
First-Line Chemotherapy for Non–Small-Cell Lung Cancer: Is There a Superior Regimen Based on Histology?
Authors: Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2008)

Lung cancer remains a formidable challenge. In the United States, death from lung cancer accounts for approximately 25% of all cancer deaths and exceeds the second, third, fourth, and fifth most common causes of cancer death combined. It is a leading cause of
The Sperm Proteins from Amphioxus Mirror Its Basal Position among Chordates and Redefine the Origin of Vertebrate Protamines
Authors: J. M. Eirin-Lopez, L. J. Frehlick, M. Chiva, N. Saperas, J. Ausio
Journal: Molecular Biology and Evolution (2008)

The sperm nuclear basic proteins (SNBPs) that participate in chromatin condensation in spermatozoa belong to 3 groups: histone (H), protamine-like (PL), and protamine (P) type. They share a common origin with histone H1 resulting from the segregation of PL components, corresponding to different regions of an H1 precursor molecule (N-terminal, winged-helix, C-terminal domains), becoming independent and following a subsequent process of parallel vertical evolution (H <--> PL <--> P). In the present work, we describe the sequence and primary structure of the main SNBP component in the sperm of the cephalochordate Branchiostoma floridae (amphioxus), revealing that it represents the deuterostome counterpart of the PL-III SNBP component from molluscs corresponding to the H1 N-terminal region. Until now, this has been a missing piece needed to complete the evolutionary history of SNBPs in metazoan genomes. The discovery of this PL lineage in deuterostomes definitively validates the parallel vertical evolution of SNBPs across metazoans, giving further support to the "basal" position of amphioxus among chordates, with respect to tunicates. Sequence analyses suggest that later on in evolution, the appearance of positively selected arginine-rich protamines, derived from the H1 C-terminal region, led to the extinction of this PL lineage in the genomes of early protostomes and deuterostomes. Given that tunicates are now viewed as a sister group of vertebrates, the lysine to arginine transition responsible for the origin of vertebrate protamines must be set a step back from tunicates.
Association Between Short Leukocyte Telomere Length, Endotoxemia, and Severe Periodontitis in People With Diabetes: A Cross-Sectional Survey
Authors: Stefano Masi, Nikolaos Gkranias, KaWa Li, Klelia D. Salpea, Mohamed Parkar, Marco Orlandi, Jean E. Suvan, Heng L. Eng, Stefano Taddei, Kalpesh Patel, Ulpee Darbar, Nikos Donos, John E. Deanfield, Steve Hurel, Steve E. Humphries, Francesco D’Aiuto
Journal: Diabetes Care (2014)

OBJECTIVE Shortened leukocyte telomere length (LTL) and diagnosis of periodontitis are associated with an increased risk of complications and mortality in diabetes. This study investigated the association between LTL, endotoxemia, and severity of periodontitis in a large cohort of people with diabetes. RESEARCH DESIGN AND METHODS Six hundred thirty individuals (371 with type 2 and 259 with type 1 diabetes) were recruited from the University College Hospital in London, U.K. During a baseline visit, blood was collected for standard biochemical tests and DNA extraction, while a dental examination was performed to determine diagnosis and extent of periodontitis. LTL was measured by real-time PCR, and endotoxemia was assessed by the limulus amoebocyte lysate method. RESULTS Two hundred fifty-five individuals were diagnosed with gingivitis, 327 with periodontitis (114 with moderate and 213 with severe disease), and 48 with edentulous. Diagnosis of periodontitis was associated with shorter LTL (P = 0.04). A negative association between LTL and endotoxemia was found in the severe periodontitis and type 2 diabetes groups (P = 0.01 for both). Shorter LTL was associated with increased extent of periodontitis (P = 0.01) and increased insulin resistance (homeostatic model assessment). Multiple adjustments for biochemical, anthropometric, and medication-use variables did not affect the results. CONCLUSIONS LTL is associated with endotoxemia and diagnosis of periodontitis in people with diabetes. LTL shortening might represent a novel biological pathway accounting for previous epidemiological data that documented higher prevalence of diabetes and its complications in people with periodontitis and vice versa.