tbuckley/cabot-search huggingface dataset:
Nicotine induced gastric injury. A quantitative macroscopic and microscopic analysis of the protective effects of sucralfate and feeding.
Authors: W M Hui, H Joana, B W Chen, C H Cho, C T Luk, S K Lam
Journal: Gut (1991)

Nicotine, while an important component of cigarettes, does not cause gross gastric mucosal damage, although its microscopic effect remains unknown. We have evaluated the histology and the microvascular permeability of (a) the effect of nicotine alone or in combination with ethanol on the gastric mucosa of rats and (b) the effect of feeding and sucralfate on the mucosa of rats treated with nicotine and ethanol. Mucosal injury was assessed histologically by the depth of injury and microvascular permeability by the leakage of fluorescein isothiocyanate-labelled albumin. Our results show that nicotine induced microscopic mucosal damage and accentuated the damage induced by alcohol. The damaging effects on mucosa of nicotine and ethanol, alone or in combination, were reduced by pretreatment with sucralfate. Similarly, feeding reduced the degree of mucosal injury. Nicotine and ethanol increased leakage of albumin into the interstitium and the leakage was reduced after sucralfate pretreatment. This study substantiates the adverse effect of smoking on mucosal damage. Vascular factors are probably involved in the pathogenesis.
The Impact of Calcification on the Biomechanical Stability of Atherosclerotic Plaques
Authors: Hayden Huang, Renu Virmani, Hesham Younis, Allen P. Burke, Roger D. Kamm, Richard T. Lee
Journal: Circulation (2001)

Background —Increased biomechanical stresses in the fibrous cap of atherosclerotic plaques contribute to plaque rupture and, consequently, to thrombosis and myocardial infarction. Thin fibrous caps and large lipid pools are important determinants of increased plaque stresses. Although coronary calcification is associated with worse cardiovascular prognosis, the relationship between atheroma calcification and stresses is incompletely described. Methods and Results —To test the hypothesis that calcification impacts biomechanical stresses in human atherosclerotic lesions, we studied 20 human coronary lesions with techniques that have previously been shown to predict plaque rupture locations accurately. Ten ruptured and 10 stable lesions derived from post mortem coronary arteries were studied using large-strain finite element analysis. Maximum stress was not correlated with percentage of calcification, but it was positively correlated with the percentage of lipid ( P =0.024). When calcification was eliminated and replaced with fibrous plaque, stress changed insignificantly; the median increase in stress for all specimens was 0.1% (range, 0% to 8%; P =0.85). In contrast, stress decreased by a median of 26% (range, 1% to 78%; P =0.02) when lipid was replaced with fibrous plaque. Conclusions —Calcification does not increase fibrous cap stress in typical ruptured or stable human coronary atherosclerotic lesions. In contrast to lipid pools, which dramatically increase stresses, calcification does not seem to decrease the mechanical stability of the coronary atheroma.
Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal Cancers
Authors: Matthias Kloor, Christina Becker, Axel Benner, Stefan M. Woerner, Johannes Gebert, Soldano Ferrone, Magnus von Knebel Doeberitz
Journal: Cancer Research (2005)

Abstract In colorectal cancer, the immune response is particularly pronounced against tumors displaying the high microsatellite instability (MSI-H) phenotype. MSI-H tumors accumulate mutations affecting microsatellites located within protein encoding regions (coding microsatellites, cMS), which lead to translational shifts of the respective reading frames. Consequently, novel tumor-specific frameshift-derived neopeptides (FSP) are generated and presented by MSI-H tumor cells, thus eliciting effective cytotoxic immune responses. To analyze whether the immunoselective pressure was reflected by the phenotype of MSI-H colorectal cancer cells, we compared here the expression of antigen processing machinery (APM) components and human leukocyte antigen (HLA) class I antigen subunits in 20 MSI-H and 20 microsatellite-stable (MSS) colorectal cancer using a panel of newly developed APM component-specific monoclonal antibodies. In addition, we did a systematic analysis of mutations at cMS located within APM genes and β2-microglobulin (β2m). Total HLA class I antigen loss was observed in 12 (60.0%) of the 20 MSI-H lesions compared with only 6 (30.0%) of the 20 MSS colorectal cancer lesions. Moreover, total loss of membraneous HLA-A staining was significantly more frequent in MSI-H colorectal cancer (P = 0.0024). Mutations at cMS of β2m and genes encoding APM components (TAP1 and TAP2) were detected in at least 7 (35.0%) of 20 MSI-H colorectal cancers but in none of the MSS colorectal cancers (P = 0.0002). These data show that defects of HLA class I antigen processing and presentation seem to be significantly more frequent in MSI-H than in MSS colorectal cancer, suggesting that in MSI-H colorectal cancer the immunoselective pressure leads to the outgrowth of cells with defects of antigen presentation.
EphA4-Mediated Rho Activation via Vsm-RhoGEF Expressed Specifically in Vascular Smooth Muscle Cells
Authors: Hisakazu Ogita, Satoshi Kunimoto, Yuji Kamioka, Hirofumi Sawa, Michitaka Masuda, Naoki Mochizuki
Journal: Circulation Research (2003)

Rho-kinase, an effector of Rho GTPase, increases the contractility of vascular smooth muscle by phosphorylating myosin light chain (MLC) and by inactivating MLC phosphatase. A wide variety of extracellular stimuli activate RhoA via G protein–coupled receptors. In the present study, we demonstrate a novel cell-cell interaction–mediated Rho activation signaling pathway in vascular smooth muscle cells (VSMCs). Among many receptor tyrosine kinases, the Eph family receptors are unique in that they require cell-cell interaction to engage their ligands, ephrin. We found that a novel VSMC-specific guanine nucleotide exchange factor (GEF) for Rho (Vsm-RhoGEF/KIAA0915) was expressed specifically in VSMCs of several organs including the heart, aorta, liver, kidney, and spleen, as examined by the immunohistochemical analysis using a specific antibody against Vsm-RhoGEF. Based on the association of Vsm-RhoGEF with EphA4 in quiescent cells, we tested whether EphA4 and Vsm-RhoGEF were expressed in the same tissue and further studied the molecular mechanism of Vsm-RhoGEF regulation by EphA4. Immunohistochemical analysis showed that EphA4 and Vsm-RhoGEF expression overlapped in VSMCs. Additionally, tyrosine phosphorylation of Vsm-RhoGEF induced by EphA4 upon ephrin-A1 stimulation enhanced the Vsm-RhoGEF activity for RhoA. The requirement of Vsm-RhoGEF for ephrin-A1–induced assembly of actin stress fibers in VSMCs was shown by the overexpression of a dominant-negative form of VSM-RhoGEF and by the depletion of Vsm-RhoGEF using RNA interference. These results suggested that ephrin-A1–triggered EphA4-Vsm-RhoGEF-RhoA pathway is involved in the cell-cell interaction–mediated RhoA activation that regulates vascular smooth muscle contractility.
The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine
Authors: Ioannis Mavrikakis, Petros P Sfikakis, Emmanouil Mavrikakis, Kostantinos Rougas, Athanasios Nikolaou, Charalambos Kostopoulos, Myron Mavrikakis
Journal: Ophthalmology (2003)
HLA-A*0201-restricted cytolytic responses to the rtTA transactivator dominant and cryptic epitopes compromise transgene expression induced by the tetracycline on system
Authors: F. Ginhoux, S. Turbant, D.A. Gross, J. Poupiot, T. Marais, Y. Lone, F.A. Lemonnier, H. Firat, N. Perez, O. Danos, J. Davoust
Journal: Molecular Therapy (2004)

The tetracycline-controlled transcription system (Tet-on) is widely used to regulate gene expression in mammalian cells. In gene therapy applications, immune responses to Tet-on proteins such as the rtTA transcription factor have been reported, raising concerns about their occurrence in humans. To monitor the HLA class I cytolytic responses against Tet-on regulators, we characterized the immunogenic CD8+ epitopes within rtTA and tTS regulators using HLA-A*0201 class I transgenic mice. Epitope prediction programs, HLA-A*0201 binding assays, and peptide immunization were used to select a set of immunogenic peptides within rtTA and tTS sequences. To identify further the rejection epitopes, we expressed Tet-on protein components in vivo and found a single dominant rtTA186 CTL epitope in the rtTA tetracycline repressor domain. Target cells expressing rtTA were susceptible to CTL lysis, and rtTA expression compromised muscle transgene engraftment. To reduce the occurrence of immune responses to rtTA protein, we mutated the dominant rtTA186 epitope and found that this leads to the appearance of subdominant epitopes. As a result, we think that an epitope modification strategy is not applicable to blunt the immune response in this model. Moreover, the identification of HLA-A*0201 rtTA epitopes allowed us to demonstrate here that the delivery of the Tet-on system with weakly immunogenic rAAV vectors does not trigger primary CTL responses in mice, in contrast to DNA transfer. Altogether, the existence of HLA-A*0201 rtTA epitopes may lead to the occurrence of immune responses depending on vectors and local inflammation in gene therapy applications involving rtTA-based regulatory systems.
Cardiorespiratory adaptation of COPD patients to physical training on land and in water
Authors: J Perk, L Perk, C Boden
Journal: European Respiratory Journal (1996)

Physical training in water might be included in a comprehensive pulmonary rehabilitation programme, but data on the feasibility and safety of this technique in chronic obstructive pulmonary disease (COPD) patients are lacking. We studied cardiorespiratory parameters of 20 stable COPD patients (10 with forced expiratory volume in one second (FEV1) &lt; 35% of predicted value, and 10 with FEV1 &gt; or = 35% pred) on land and in a temperate-controlled pool (32 degrees C) both at rest and during a 15 min submaximal upper body muscle training programme. Compared to resting values on land, we found in water a decrease of systolic and diastolic blood pressure (14 and 6 mmHg, respectively), rate-pressure product (7%) and lung function (vital capacity (VC) 12%, FEV1 14%, peak expiratory flow (PEF) 18%). There were no differences in heart rate, breathing frequency or O2 saturation. The most strenuous exercise in water resulted in a slightly lower O2 saturation compared to work on land (95 and 93%, respectively), and an increase of Borg rating for dyspnoea from 4 to 5. In spite of the restriction of lung function in water, all patients (even those with FEV1 &lt; 35% pred) performed the training in the pool well, without clinically relevant desaturation, arrhythmia or discomfort. No training session was discontinued due to dyspnoea. We conclude that a 15 min session of submaximal physical training in a pool with a water temperature of 32 degrees C is feasible and safe for nonhypoxaemic normotensive COPD patients without cardiac failure.
Celecoxib for the Prevention of Colorectal Adenomatous Polyps
Authors: Nadir Arber, Craig J. Eagle, Julius Spicak, István Rácz, Petr Dite, Jan Hajer, Miroslav Zavoral, Maria J. Lechuga, Paola Gerletti, Jie Tang, Rebecca B. Rosenstein, Katie Macdonald, Pritha Bhadra, Robert Fowler, Janet Wittes, Ann G. Zauber, Scott D. Solomon, Bernard Levin
Journal: New England Journal of Medicine (2006)

Overexpression of cyclooxygenase 2 (COX-2) has been associated with colorectal adenomatous polyps and cancer, prompting researchers to propose its inhibition as a chemopreventive intervention.The Prevention of Colorectal Sporadic Adenomatous Polyps trial was a randomized, placebo-controlled, double-blind study of the COX-2 inhibitor celecoxib given daily in a single 400-mg dose. At 107 centers in 32 countries, we randomly assigned 1561 subjects who had had adenomas removed before enrollment to receive celecoxib (933 subjects) or placebo (628 subjects) daily, after stratification according to the use or nonuse of low-dose aspirin. The primary outcome was detection of adenomas at either year 1 or year 3 by colonoscopy and was compared among the groups with the use of the Mantel-Cox test.Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P<0.001). The cumulative rate of advanced adenomas detected through year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). Adjudicated serious cardiovascular events occurred in 2.5 percent of subjects in the celecoxib group and 1.9 percent of those in the placebo group (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62).The use of 400 mg of celecoxib once daily significantly reduced the occurrence of colorectal adenomas within three years after polypectomy. (ClinicalTrials.gov number, NCT00141193 [ClinicalTrials.gov].).
Both Hepatic and Extrahepatic ABCA1 Have Discrete and Essential Functions in the Maintenance of Plasma High-Density Lipoprotein Cholesterol Levels In Vivo
Authors: Roshni R. Singaraja, Miranda Van Eck, Nagat Bissada, Francesca Zimetti, Heidi L. Collins, Reeni B. Hildebrand, Anna Hayden, Liam R. Brunham, Martin H. Kang, Jean-Charles Fruchart, Theo J.C. Van Berkel, John S. Parks, Bart Staels, George H. Rothblat, Catherine Fiévet, Michael R. Hayden
Journal: Circulation (2006)

Background— Extrahepatic tissues have long been considered critical contributors of cholesterol to nascent HDL particles in the reverse cholesterol transport pathway, in which ABCA1 plays the crucial role. Recent studies, however, including both overexpression and deletion of ABCA1 selectively in the liver, have highlighted the primary role of the liver in the maintenance of HDL levels in vivo. Methods and Results— The availability of mice with complete deletion of ABCA1 (total knockout [TKO]) and with liver-specific deletion of ABCA1 (LSKO) has enabled us to dissect the discrete roles of hepatic relative to extrahepatic ABCA1 in HDL biogenesis. Delivery of adenoviral ABCA1 resulted in selective expression of physiological levels of ABCA1 in the livers of both LSKO and TKO mice, resulting in increased HDL cholesterol (HDL-C). Expression of ABCA1 in the liver of LSKO mice resulted in plasma HDL-C levels that were similar to those in wild-type mice and significantly above those seen in similarly treated TKO mice. HDL particles from ABCA1-expressing LSKO mice were larger and contained significantly increased cholesterol compared with TKO mice. Infusion of human apolipoprotein A-I/phospholipid reconstituted HDL particles normalized plasma HDL-C levels in LSKO mice but had no effect on HDL-C levels in TKO mice. Conclusions— Although hepatic ABCA1 appears crucial for phospholipid transport, extrahepatic tissues play an important role in cholesterol transfer to nascent HDL particles. These data highlight the discrete and specific roles of both liver and extrahepatic ABCA1 in HDL biogenesis in vivo and indicate that ABCA1 shows lipid cargo selectivity depending on its site of expression.
Polyclonal B cell activation in ankylosing spondylitis.
Authors: P Barbieri, I Olivieri, G Benedettini, P Marelli, M L Ciompi, G Pasero, M Campa
Journal: Annals of the Rheumatic Diseases (1990)

The peripheral blood lymphocyte response of patients with ankylosing spondylitis (AS) to several polyclonal B cell activators was investigated. No differences were found in the reactivity to pokeweed mitogen and protein A between patients and controls; in contrast, the peripheral blood lymphocyte response to Staphylococcus aureus strain Cowan I (SAC) was significantly higher in patients with AS than in controls. This responsiveness was not influenced either by the presence of the HLA-B27 antigen or by environmental factors or associated diseases, and it was higher in patients with active AS than in those with inactive disease. The percentage of circulating B cells was normal. The responses to T cell mitogens and the percentages of T cell subpopulations were similar in patients and in controls. The peripheral blood lymphocyte hyperactivity of patients with AS to SAC was associated with an increased in vitro production of immunoglobulins.
Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells
Authors: Cristian Bellodi, Maria Rosa Lidonnici, Ashley Hamilton, G. Vignir Helgason, Angela Rachele Soliera, Mattia Ronchetti, Sara Galavotti, Kenneth W. Young, Tommaso Selmi, Rinat Yacobi, Richard A. Van Etten, Nick Donato, Ann Hunter, David Dinsdale, Elena Tirrò, Paolo Vigneri, Pierluigi Nicotera, Martin J. Dyer, Tessa Holyoake, Paolo Salomoni, Bruno Calabretta
Journal: Journal of Clinical Investigation (2009)

Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.
18F-Fluorodeoxyglucose Positron Emission Tomography to Evaluate Cervical Node Metastases in Patients With Head and Neck Squamous Cell Carcinoma: A Meta-analysis
Authors: Panayiotis A. Kyzas, Evangelos Evangelou, Despina Denaxa-Kyza, John P. A. Ioannidis
Journal: JNCI Journal of the National Cancer Institute (2008)

Positron emission tomography using 18F-fluorodeoxyglucose (18F-FDG PET) has been proposed to enhance preoperative assessment of cervical lymph node status in patients with head and neck squamous cell carcinoma (HNSCC). Management is most controversial for patients with a clinically negative (cN0) neck. We aimed to assess the diagnostic accuracy of 18F-FDG PET in detecting lymph node metastases in patients with HNSCC.We performed a meta-analysis of all available studies of the diagnostic performance of 18F-FDG PET in patients with HNSCC. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic curves using hierarchical regression models. We also compared the performance of 18F-FDG PET with that of conventional diagnostic methods (ie, computed tomography, magnetic resonance imaging, and ultrasound with fine-needle aspiration) by analyzing studies that had also used these diagnostic methods on the same patients.Across 32 studies (1236 patients), 18F-FDG PET sensitivity was 79% (95% confidence interval [CI] = 72% to 85%) and specificity was 86% (95% CI = 83% to 89%). For cN0 patients, sensitivity of 18F-FDG PET was only 50% (95% CI = 37% to 63%), whereas specificity was 87% (95% CI = 76% to 93%). Overall, LR+ was 5.84 (95% CI = 4.59 to 7.42) and LR- was 0.24 (95% CI = 0.17 to 0.33). In studies in which both 18F-FDG PET and conventional diagnostic tests were performed, sensitivity and specificity of 18F-FDG PET were 80% and 86%, respectively, and of conventional diagnostic tests were 75% and 79%, respectively.18F-FDG PET has good diagnostic performance in the overall pretreatment evaluation of patients with HNSCC but still does not detect disease in half of the patients with metastasis and cN0.
Determinants of the hyperdynamic circulation and central hypovolaemia in cirrhosis
Authors: S. Moller, L. Hobolth, C. Winkler, F. Bendtsen, E. Christensen
Journal: Gut (2011)

<h3>Background</h3> Patients with advanced cirrhosis often develop a hyperdynamic circulation with central hypovolaemia. The events that initiate the systemic haemodynamic abnormalities and the coupling of these factors to splanchnic haemodynamics are still unclear. <h3>Objective</h3> On the basis of a large population of patients with cirrhosis to identify splanchnic and clinical characteristics associated with the development of the hyperdynamic circulation and survival. <h3>Methods</h3> We included 410 patients with cirrhosis. In all patients, a full haemodynamic investigation was performed. The data were analysed using regression analyses, principal components analyses, and Cox proportional hazards analyses. <h3>Results</h3> Multivariate regression analyses showed that higher cardiac output was independently associated with higher hepatic venous pressure gradient (HVPG) and higher hepatic blood flow (HBF) (p&lt;0.00001). Higher heart rate was independently associated with presence of ascites and higher HVPG (p&lt;0.0001). Central blood volume and circulation time were independently associated with higher HBF and lower postsinusoidal resistance, respectively (p&lt;0.0001). Systemic vascular resistance was independently associated with lower HVPG (p&lt;0.0001). The final Cox proportional hazards model showed that decreased survival was independently associated with higher age (p=0.003), lower blood haemoglobin concentration (p=0.0006), higher plasma creatinine (p=0.01), higher plasma alkaline phosphatase (p=0.007), lower right atrial pressure (p=0.004), and higher heart rate (p=0.002). <h3>Conclusion</h3> The development of the hyperdynamic circulation and central hypovolaemia are mainly explained by changes in portal pressure and HBF. Together with indicators of liver dysfunction, central hypovolaemia is associated with poorer prognosis.