tbuckley/cabot-search huggingface dataset:
SLC1A5 Mediates Glutamine Transport Required for Lung Cancer Cell Growth and Survival
Authors: Mohamed Hassanein, Megan D. Hoeksema, Masakazu Shiota, Jun Qian, Bradford K. Harris, Heidi Chen, Jonathan E. Clark, William E. Alborn, Rosana Eisenberg, Pierre P. Massion
Journal: Clinical Cancer Research (2012)

We have previously identified solute-linked carrier family A1 member 5 (SLC1A5) as an overexpressed protein in a shotgun proteomic analysis of stage I non-small cell lung cancer (NSCLC) when compared with matched controls. We hypothesized that overexpression of SLC1A5 occurs to meet the metabolic demand for lung cancer cell growth and survival.To test our hypothesis, we first analyzed the protein expression of SLC1A5 in archival lung cancer tissues by immunohistochemistry and immunoblotting (N = 98) and in cell lines (N = 36). To examine SLC1A5 involvement in amino acid transportation, we conducted kinetic analysis of l-glutamine (Gln) uptake in lung cancer cell lines in the presence and absence of a pharmacologic inhibitor of SLC1A5, gamma-l-Glutamyl-p-Nitroanilide (GPNA). Finally, we examined the effect of Gln deprivation and uptake inhibition on cell growth, cell-cycle progression, and growth signaling pathways of five lung cancer cell lines.Our results show that (i) SLC1A5 protein is expressed in 95% of squamous cell carcinomas (SCC), 74% of adenocarcinomas (ADC), and 50% of neuroendocrine tumors; (ii) SLC1A5 is located at the cytoplasmic membrane and is significantly associated with SCC histology and male gender; (iii) 68% of Gln is transported in a Na(+)-dependent manner, 50% of which is attributed to SLC1A5 activity; and (iv) pharmacologic and genetic targeting of SLC1A5 decreased cell growth and viability in lung cancer cells, an effect mediated in part by mTOR signaling.These results suggest that SLC1A5 plays a key role in Gln transport controlling lung cancer cells' metabolism, growth, and survival.
Increased skeletal muscle-specific microRNA in the blood of patients with COPD
Authors: Anna Donaldson, Samantha A Natanek, Amy Lewis, William D-C Man, Nicholas S Hopkinson, Michael I Polkey, Paul R Kemp
Journal: Thorax (2013)

<h3>Background</h3> Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) carries a poor prognosis, therefore a non-invasive marker of this process could be useful. Reduced expression of muscle-specific microRNA (myomiRs) in quadriceps muscle in patients with COPD is associated with skeletal muscle weakness and changes in muscle fibre composition. Circulating exosomal miRNAs can be measured in blood, making them candidate biomarkers of biopsy phenotype. To determine whether plasma myomiR levels were associated with fibre size or fibre proportion, we measured myomiRs in plasma from patients with COPD and healthy controls. <h3>Methods and results</h3> 103 patients with COPD and 25 age-matched controls were studied. Muscle-specific miRNA was elevated in the plasma of patients with COPD and showed distinct patterns. Specifically, miR-1 was inversely associated with fat-free mass in the cohort, whereas levels of miR-499 were more directly associated with strength and quadriceps type I fibre proportion. Two miRs not restricted to muscle in origin (miR-16 and miR-122) did not differ between patients and controls. Plasma miR-499 was also associated with muscle nuclear factor κB p50 but not p65 in patients with early COPD whereas plasma inflammatory cytokines were associated with miR-206 in patients with more advanced disease. <h3>Conclusions</h3> Plasma levels of individual myomiRs are altered in patients with COPD but alone do not predict muscle fibre size or proportion. Our findings are consistent with an increase in muscle wasting and turnover associated with the development of skeletal muscle dysfunction and fibre-type shift in patients with stable COPD.
Effects of dilated cardiomyopathy on the diaphragm in the Syrian hamster
Authors: G Stassijns, G Gayan-Ramirez, P De Leyn, V de Bock, R Dom, R Lysens, M Decramer
Journal: European Respiratory Journal (1999)

This study aimed to elucidate changes in respiratory muscles and their mechanism in cardiomyopathy. The contractile properties and histology of the diaphragm, as well as serum levels of insulin-like growth factor (IGF)-1, were examined in 10 hamsters with idiopathic dilated cardiomyopathy (CM) and 10 controls. At 28 weeks, body weight in CM was reduced compared with controls (114+/-10 versus 144+/-14 g, p&lt;0.0001). The ratio of diaphragm to body weight was significantly higher in CM than in controls (0.228+/-0.015 versus 0.182+/-0.017, p&lt;0.0001). In vitro, maximal diaphragmatic twitch (303+/-63 versus 455+/-119 g x cm(-2)) and tetanic tensions (1,555+/-369 versus 2,204+/-506 g x cm(-2)) were significantly lower in CM than in controls (p&lt;0.005). The half-relaxation time was significantly shorter in CM (19+/-1 ms) than in controls (24+/-3 ms, p&lt;0.0005). Fatiguability at 25 Hz was significantly less in CM (28%) than in controls (42%, p&lt;0.0001). Diaphragm and gastrocnemius adenosine triphosphatase staining showed type I fibre atrophy in CM, associated with an increase in the number of type I fibres in the diaphragm. Histological examination of both muscles revealed an abnormal muscular pattern. Finally, serum levels of IGF-1 were 47% lower in the CM group than in controls (p&lt;0.0001) and were clearly related to the changes in the contractile properties and histology of the diaphragm. In conclusion, cardiomyopathy in hamsters: 1) depressed the force-generating capacity and shortened the relaxation of the hamster diaphragm; 2) induced type I fibre atrophy in combination with a myopathic pattern; and 3) was associated with a significant reduction in serum levels of insulin-like growth factor-1, related to the diaphragmatic changes. Whether these changes are primary myopathic or secondary to heart failure remains to be elucidated.
Antibiotic Treatment of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue: An Uncontrolled Trial
Authors: Gideon Steinbach, Richard Ford, Gary Glober, Dory Sample, Frederick B. Hagemeister, Patrick M. Lynch, Peter W. McLaughlin, Maria A. Rodriguez, Jorge E. Romaguera, Andreas H. Sarris, Anas Younes, Rajyalakshmi Luthra, John T. Manning, Constance M. Johnson, Sandeep Lahoti, Yu Shen, Jeffrey E. Lee, Rodger J. Winn, Robert M. Genta, David Y. Graham, Fernando F. Cabanillas
Journal: Annals of Internal Medicine (1999)

Background: Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is related to Helicobacter pylori infection and may depend on this infection for growth. Objective: To determine the response of gastric MALT lymphoma to antibiotic treatment. Design: Prospective, uncontrolled treatment trial. Setting: University hospital referral center and three collaborating university and community hospitals. Patients: 34 patients with stage I or stage II N1 gastric MALT lymphoma. Intervention: Two of three oral antibiotic regimens—1] amoxicillin, 750 mg three times daily, and clarithromycin, 500 mg three times daily; 2) tetracycline, 500 mg four times daily, and clarithromycin, 500 mg three times daily; or 3) tetracycline, 500 mg four times daily, and metronidazole, 500 mg three times daily—were administered sequentially (usually in the order written) for 21 days at baseline and at 8 weeks, along with a proton-pump inhibitor (lansoprazole or omeprazole) and bismuth subsalicylate. Measurements: Complete remission was defined as the absence of histopathologic evidence of lymphoma on endoscopic biopsy. Partial remission was defined as a reduction in endoscopic tumor stage or 50% reduction in the size of large tumors. Results: 34 patients were followed for a mean (±SD) of 41 ± 16 months (range, 18 to 70 months) after antibiotic treatment. Of 28 H. pylori-positive patients, 14 (50% [95% CI, 31% to 69%]) achieved complete remission, 8 (29%) achieved partial remission (treatment eventually failed in 4 of the 8), and 10 (36% [CI, 19% to 56%]) did not respond to treatment. Treatment failed in all 6 (100% [CI, 54% to 100%]) H. pylori-negative patients. Patients with endoscopic appearance of gastritis (stage I T1 disease) were most likely to achieve complete remission within 18 months. Tumors in the distal stomach were associated with more favorable response than tumors in the proximal stomach. Conclusions: A subset of H. pylori-positive gastric MALT lymphomas, including infiltrative tumors, may respond to antibiotics. The likelihood of early complete remission seems to be greatest for superficial and distal tumors.
Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma-In-Situ: Ten-Year Results of European Organisation for Research and Treatment of Cancer Randomized Phase III Trial 10853—A Study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group
Authors: Nina Bijker, Philip Meijnen, Johannes L. Peterse, Jan Bogaerts, Irène Van Hoorebeeck, Jean-Pierre Julien, Massimiliano Gennaro, Philippe Rouanet, Antoine Avril, Ian S. Fentiman, Harry Bartelink, Emiel J. Th. Rutgers
Journal: Journal of Clinical Oncology (2006)

The European Organisation for Research and Treatment of Cancer conducted a randomized trial investigating the role of radiotherapy (RT) after local excision (LE) of ductal carcinoma-in-situ (DCIS) of the breast. We analyzed the efficacy of RT with 10 years follow-up on both the overall risk of local recurrence (LR) and related to clinical, histologic, and treatment factors.After complete LE, women with DCIS were randomly assigned to no further treatment or RT (50 Gy). One thousand ten women with mostly (71%) mammographically detected DCIS were included. The median follow-up was 10.5 years.The 10-year LR-free rate was 74% in the group treated with LE alone compared with 85% in the women treated by LE plus RT (log-rank P < .0001; hazard ratio [HR] = 0.53). The risk of DCIS and invasive LR was reduced by 48% (P = .0011) and 42% (P = .0065) respectively. Both groups had similar low risks of metastases and death. At multivariate analysis, factors significantly associated with an increased LR risk were young age (< or = 40 years; HR = 1.89), symptomatic detection (HR = 1.55), intermediately or poorly differentiated DCIS (as opposed to well-differentiated DCIS; HR = 1.85 and HR = 1.61 respectively), cribriform or solid growth pattern (as opposed to clinging/micropapillary subtypes; HR = 2.39 and HR = 2.25 respectively), doubtful margins (HR = 1.84), and treatment by LE alone (HR = 1.82). The effect of RT was homogeneous across all assessed risk factors.With long-term follow-up, RT after LE for DCIS continued to reduce the risk of LR, with a 47% reduction at 10 years. All patient subgroups benefited from RT.
Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage
Authors: P V Sivakumar
Journal: Gut (2002)

Persistent inflammation observed in inflammatory bowel disease may be the consequence of an increased or aberrant immune response to normal gut constituents or an overall immune dysregulation and imbalance. Cytokines play an important role in immune regulation and interleukin 18 (IL-18) is one such cytokine that has emerged as being instrumental in driving CD4+ T cell responses towards a Th1-type. IL-18 can also directly mediate inflammation, moderate interleukin 1 activity, and can act on cell types other than T cells. It has been reported recently that IL-18 mRNA and protein are upregulated in gut tissue from IBD patients. The aim of this study was to understand more about the role of IL-18 in contributing to the pathology of IBD and to assess whether blocking IL-18 activity may be of therapeutic benefit as a treatment regimen for IBD.Mice with dextran sulphate sodium (DSS) induced colitis were treated with recombinant IL-18 binding protein (IL-18bp.Fc), a soluble protein that blocks IL-18 bioactivity. Histopathological analysis was performed and RNA from the large intestine was analysed using the RNase protection assay and gene arrays.IL-18 RNA levels increased very early in the colon during DSS colitis. Treatment of mice with IL-18bp.Fc inhibited IBD associated weight loss and significantly inhibited the intestinal inflammation induced by DSS. IL-18bp.Fc treatment also attenuated mRNA upregulation of multiple proinflammatory cytokine genes, chemokine genes, and matrix metalloprotease genes in the large intestine that are commonly elevated during IBD.IL-18bp treatment attenuated inflammation during DSS induced colitis in mice. Neutralising IL-18 activity may therefore be of benefit for ameliorating the inflammation associated with human intestinal diseases.
The Association of Early Adolescent Problem Behavior With Adult Psychopathology
Authors: Matt McGue, William G. Iacono
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The authors investigated whether the association between adolescent problem behavior and adult substance use and mental health disorders was general, such that adolescent problem behavior elevates the risk for a variety of adult disorders, or outcome-specific, such that each problem behavior is associated specifically with an increased risk for disorders clinically linked to that behavior (e.g., early alcohol use with adult alcohol abuse). METHOD: A population-based group of 578 male and 674 female twins reported whether they had ever engaged in, and the age of initiation of, five adolescent problem behaviors: smoking, alcohol use, illicit drug use, police trouble, and sexual intercourse. Participants also completed a structured clinical interview at both ages 17 and 20 covering substance use disorders, major depressive disorder, and antisocial personality disorder. Data were analyzed with simple bivariate methods, survival analysis, and structural equation analysis. RESULTS: Each problem behavior was significantly related with each clinical diagnosis. The association was especially marked for those who had engaged in multiple problem behaviors before age 15. Among those with four or more problem behaviors before age 15, the lifetime rates of substance use disorders, antisocial personality disorder, and major depressive disorder exceeded 90%, 90%, and 30% in males and 60%, 35%, and 55% in females, respectively. The association between the clinical diagnoses and adolescent problem behavior was largely accounted for by two highly correlated factors. CONCLUSIONS: Early adolescent problem behavior identifies a subset of youth who are at an especially high and generalized risk for developing adult psychopathology.
miR-181b negatively regulates activation-induced cytidine deaminase in B cells
Authors: Virginia G. de Yébenes, Laura Belver, David G. Pisano, Susana González, Aranzazu Villasante, Carlo Croce, Lin He, Almudena R. Ramiro
Journal: The Journal of Experimental Medicine (2008)

Activated B cells reshape their primary antibody repertoire after antigen encounter by two molecular mechanisms: somatic hypermutation (SHM) and class switch recombination (CSR). SHM and CSR are initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues on the immunoglobulin loci, which leads to the generation of DNA mutations or double-strand break intermediates. As a bystander effect, endogenous AID levels can also promote the generation of chromosome translocations, suggesting that the fine tuning of AID expression may be critical to restrict B cell lymphomagenesis. To determine whether microRNAs (miRNAs) play a role in the regulation of AID expression, we performed a functional screening of an miRNA library and identified miRNAs that regulate CSR. One such miRNA, miR-181b, impairs CSR when expressed in activated B cells, and results in the down-regulation of AID mRNA and protein levels. We found that the AID 3′ untranslated region contains multiple putative binding sequences for miR-181b and that these sequences can be directly targeted by miR-181b. Overall, our results provide evidence for a new regulatory mechanism that restricts AID activity and can therefore be relevant to prevent B cell malignant transformation.
Penicillin-binding protein inactivation by human neutrophil myeloperoxidase.
Authors: R M Rakita, H Rosen
Journal: Journal of Clinical Investigation (1991)

Myeloperoxidase (MPO), H2O2, and chloride comprise a potent antimicrobial system believed to contribute to the antimicrobial functions of neutrophils and monocytes. The mechanisms of microbicidal action are complex and not fully defined. This report describes the MPO-mediated inactivation, in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, of a class of cytoplasmic membrane enzymes (penicillin-binding proteins, PBPs) found in all eubacteria, that covalently bind beta-lactam antibiotics to their active sites with loss of enzymatic activity. Inactivation of "essential" PBPs, including PBP1-PBP3 of E. coli, leads to unbalanced bacterial growth and cell death. MPO treatment of bacteria was associated with loss of penicillin binding by PBPs, strongly suggesting PBP inactivation. In E. coli, PBP inactivation was most rapid with PBP3, where the rate of decline in binding activity approximated but did not equal loss of viability. Changes in E. coli morphology (elongation), observed just before bacteriolysis, were consistent with early predominant inactivation of PBP3. We conclude that inactivation of essential PBPs is sufficient to account for an important fraction of MPO-mediated bacterial action. This feature of MPO action interestingly recapitulates an antibacterial strategy evolved by beta-lactam-producing molds that must compete with bacteria for limited ecologic niches.
Abnormal subendocardial blood flow in pressure overload hypertrophy is associated with pacing-induced subendocardial dysfunction.
Authors: K Nakano, W J Corin, J F Spann, R W Biederman, S Denslow, B A Carabello
Journal: Circulation Research (1989)

To detect the functional significance of subendocardial hypoperfusion in the pressure-overloaded left ventricle, we studied subendocardial and subepicardial function and subendocardial and subepicardial blood flow simultaneously in seven dogs with left ventricular hypertrophy (left ventricle/body weight ratio, 7.2 g/kg) produced by chronic aortic banding. Seven normal dogs served as controls. Subendocardial and subepicardial segment lengths were measured by ultrasonic dimension gauges, and myocardial blood flow was measured with radioactive microspheres. Atrial pacing (180-200 beats/min for 5 minutes) was used to produce a chronotropic stress. In dogs with left ventricular hypertrophy, the subendocardial blood flow failed to increase during pacing compared with the baseline state (1.21 +/- 0.17 vs. 1.22 +/- 0.17 ml/min/g). Subendocardial shortening fraction deteriorated with pacing stress (before pacing, 30.6 +/- 3.9%; after pacing, 24.2 +/- 3.7%; p less than 0.001). In controls, subendocardial blood flow increased from 1.32 +/- 0.19 to 1.80 +/- 0.19 ml/min/g during pacing, and shortening fraction was preserved (before pacing, 25.5 +/- 3.9%; after pacing, 25.9 +/- 3.3%). Subepicardial blood flow in dogs with hypertrophy increased from 1.54 +/- 0.24 to 2.32 +/- 0.34 ml/min/g, and subepicardial shortening fraction was maintained (before pacing, 10.4 +/- 1.0%; after pacing, 10.5 +/- 1.2%) as it was in controls (subepicardial blood flow, from 1.27 +/- 0.18 to 2.12 +/- 0.17 ml/min/g; shortening fraction, from 16.6 +/- 2.5% to 15.5 +/- 2.2%). We conclude that, with pacing stress in pressure-overload hypertrophy, subendocardial blood flow failed to increase. This abnormality corresponded with a deterioration in subendocardial contractile function.
Expression of basic and acidic fibroblast growth factors and their receptor in normal and atherosclerotic human arteries
Authors: S. E Hughes, D. Crossman, P. A Hall
Journal: Cardiovascular Research (1993)

Objective: Acidic and basic fibroblast growth factors (FGF) are potent mitogens for vascular endothelial and smooth muscle cells and also promote angiogenesis. Given that atheroma is associated with the proliferation of a range of cell types, including smooth muscle cells, it has been proposed that these growth factors may play a part in the genesis and/or maintenance of atheromatous lesions. The aim of our study was to examine the distribution of acidic and basic FGF and their known receptor, fibroblast growth factor receptor 1 (FGFR-1), in normal and atherosclerotic arteries. Methods: Formalin fixed wax embedded archival material from a wide range of vessels was examined using a three stage avidin-biotin immunoperoxidase technique and specific polyclonal antibodies to acidic and basic FGF and FGFR-1. Results: In normal arteries basic FGF immunoreactivity was found in medial smooth muscle cells and adventitial blood vessels, the luminal endothelium being non-reactive. Acidic FGF expression was observed predominantly in adventitial fibroblasts, while FGFR-1 expression was confined to the adventitial microvasculature. In early, simple, and advanced lesions acidic and basic FGF were expressed in macrophages and smooth muscle cells, the principal cell types involved in atherosclerotic lesion formation. Increased expression of basic FGF and FGFR-1 was particularly associated with neovascularisation of the atheromatous lesions. Conclusions: Acidic and basic FGF are expressed in early, simple and advanced atherosclerotic plaques. This suggests that in vivo these growth factors may have a role in the genesis of this disease. Basic FGF and FGFR-1 may potentially be involved in plaque neovascularisation. Such FGF driven angiogenic events may be central to the life threatening complications of atheroma and provide new options for therapeutic intervention. Cardiovascular Research 1993;27:1214-1219
Impact of EGFR expression on colorectal cancer patient prognosis and survival
Authors: J.-P. Spano, C. Lagorce, D. Atlan, G. Milano, J. Domont, R. Benamouzig, A. Attar, J. Benichou, A. Martin, J.-F. Morere, M. Raphael, F. Penault-Llorca, J.-L. Breau, R. Fagard, D. Khayat, P. Wind
Journal: Annals of Oncology (2004)
Analysis of the expression pattern of the BCL11B gene and its relatives in patients with T-cell acute lymphoblastic leukemia
Authors: Xin Huang, Shaohua Chen, Qi Shen, Lijian Yang, Bo Li, Liye Zhong, Suxia Geng, Xin Du, Yangqiu Li
Journal: Journal of Hematology & Oncology (2010)

Abstract Background In a human T-cell acute lymphoblastic leukemia (T-ALL) cell line (Molt-4), siRNA-mediated suppression of BCL11B expression was shown to inhibit proliferation and induce apoptosis, functions which may be related to genes involved in apoptosis (such as TNFSF10 and BCL2L1 ) and TGF-β pathways (such as SPP1 and CREBBP ). Methods The expression levels of the above mentioned genes and their correlation with the BCL11B gene were analyzed in patients with T-ALL using the TaqMan and SYBR Green I real-time polymerase chain reaction technique. Results Expression levels of BCL11B, BCL2L1 , and CREBBP mRNA in T-ALL patients were significantly higher than those from healthy controls ( P &lt; 0.05). In T-ALL patients, the BCL11B expression level was negatively correlated with the BCL2L1 expression level ( r s = -0.700; P &lt; 0.05), and positively correlated with the SPP1 expression level ( r s = 0.683; P &lt; 0.05). In healthy controls, the BCL11B expression level did not correlate with the TNFSF10 , BCL2L1 , SPP1 , or CREBBP expression levels. Conclusions Over-expression of BCL11B might play a role in anti-apoptosis in T-ALL cells through up-regulation of its downstream genes BCL2L1 and CREBBP .