tbuckley/cabot-search huggingface dataset:
Serum Total Homocysteine and Cardiovascular Disease Occurrence in Chronic, Stable Renal Transplant Recipients
Authors: DIDIER DUCLOUX, GE[Combining Acute Accent]RARD MOTTE, BRUNO CHALLIER, ROGER GIBEY, JEAN-MARC CHALOPIN
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Renal transplant recipients have disproportionately high rates of arteriosclerotic outcomes, and recent studies provided controlled evidence that clinically stable renal transplant recipients have an excess prevalence of hyperhomocysteinemia. Few studies suggest that hyperhomocysteinemia may be a cardiovascular risk factor in renal transplant recipients. In the study presented here, the association between atherosclerotic events and homocysteine concentrations was examined in 207 stable renal transplant recipients. The role of hyperhomocysteinemia was analyzed with respect to other known cardio-vascular risk factors. The mean follow-up was 21.2 ± 1.9 mo (range, 14 to 26). Mean total homocysteine (tHcy) was 21.1 ± 9.5 μmol/L and median concentration was 19 μmol/L. Seventy percent of patients ( n = 153) were hyperhomocysteinemic (values &gt;15 μmol/L). tHcy correlated negatively with folate concentration ( r = -0.3; P &lt;0.01). tHcy was closely related to creatinine concentration ( r = 0.54; P &lt; 0.001). Cardiovascular disease events (CVE) including death were observed in 30 patients (14.5%; 7.34 events per 1000 person-months of follow-up). Fasting tHcy values were higher in patients who experienced CVE (31.5 ± 10.3 versus 17.8 ± 7.5; P &lt; 0.001). Cox regression analysis showed that tHcy was a risk factor for cardiovascular complications (relative risk [RR] 1.06; 95% confidence interval (95% CI), 1.04 to 1.09; P &lt; 0.0001). This corresponds to an increase in RR for CVE of 6% per μmol/L increase in tHcy concentration. Age (RR 1.55; 95% CI, 1.09 to 2.19; P &lt; 0.01) and creatinine concentration (RR 1.34; 95% CI, 1.08 to 1.66; P &lt; 0.01) were also independent predictor for CVE. This study demonstrates that elevated fasting tHcy is an independent risk factor for the development of CVE in chronic stable renal transplant recipients. Randomized, place-bo-controlled homocysteine studies of the effect of tHcy lowering on CVE rates are urgently required in this patient population.
Tumor-Infiltrating Lymphocytes Genetically Engineered with an Inducible Gene Encoding Interleukin-12 for the Immunotherapy of Metastatic Melanoma
Authors: Ling Zhang, Richard A. Morgan, Joal D. Beane, Zhili Zheng, Mark E. Dudley, Sadik H. Kassim, Azam V. Nahvi, Lien T. Ngo, Richard M. Sherry, Giao Q. Phan, Marybeth S. Hughes, Udai S. Kammula, Steven A. Feldman, Mary Ann Toomey, Sid P. Kerkar, Nicholas P. Restifo, James C. Yang, Steven A. Rosenberg
Journal: Clinical Cancer Research (2015)

Infusion of interleukin-12 (IL12) can mediate antitumor immunity in animal models, yet its systemic administration to patients with cancer results in minimal efficacy and severe toxicity. Here, we evaluated the antitumor activity of adoptively transferred human tumor-infiltrating lymphocytes (TILs) genetically engineered to secrete single-chain IL12 selectively at the tumor site.Thirty-three patients with metastatic melanoma were treated in a cell dose-escalation trial of autologous TILs transduced with a gene encoding a single-chain IL12 driven by a nuclear factor of the activated T cells promoter (NFAT.IL12). No IL2 was administered.The administration of 0.001 to 0.1 × 10(9) NFAT.IL12-transduced TILs to 17 patients resulted in a single, objective response (5.9%). However, at doses between 0.3 and 3 × 10(9) cells, 10 of 16 patients (63%) exhibited objective clinical responses. The responses tended to be short, and the administered IL12-producing cells rarely persisted at 1 month. Increasing cell doses were associated with high serum levels of IL12 and IFNγ as well as clinical toxicities, including liver dysfunction, high fevers, and sporadic life-threatening hemodynamic instability.In this first-in-man trial, administration of TILs transduced with an inducible IL12 gene mediated tumor responses in the absence of IL2 administration using cell doses 10- to 100-fold lower than conventional TILs. However, due to toxicities, likely attributable to the secreted IL12, further refinement will be necessary before this approach can be safely used in the treatment of cancer patients.
Effect of protriptyline, 10 mg daily, on chronic hypoxaemia in chronic obstructive pulmonary disease
Authors: K Strom, G Boman, K Pehrsson, M Alton, J Singer, PO Rydstrom, M Uddenfeldt, CH Ericsson, B Ostholm, C Morlin
Journal: European Respiratory Journal (1995)

A daily dose of 20 mg of protriptyline can improve daytime arterial blood gas tensions in chronic obstructive pulmonary disease (COPD). Its usefulness is limited by anticholinergic side-effects. This study examined whether a daily dose of 10 mg of protriptyline improved daytime arterial oxygen tension (PaO2) and quality of life in patients with stable mild or moderate hypoxaemia caused by COPD. Twenty six patients were randomized to receive protriptyline or placebo in a double-blind parallel-group trial for 12 weeks, following a run-in period of 4 weeks, in order to assess the stability of hypoxaemia. Patients with a change in PaO2 of &gt; 0.7 kPa during the run-in were excluded. Spirometry, quality of life and dyspnoea score were measured at randomization and after 12 weeks, whilst arterial blood gas tensions were also measured 2 and 6 weeks after randomization. No improvement in arterial blood gas tensions, spirometry values, dyspnoea score, or quality of life was found in either the protriptyline or the placebo group. The majority of patients receiving protriptyline experienced anticholinergic side-effects, which necessitated the withdrawal of the drug in one patient. We conclude that there was no evidence that a daily dose of 10 mg of protriptyline had a significant effect on daytime arterial oxygen tension in stable mild and moderate hypoxaemia caused by COPD. Despite the low dose, anticholinergic side-effects occurred in most patients.
Inhibition of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension
Authors: Abdul G. Hameed, Nadine D. Arnold, Janet Chamberlain, Josephine A. Pickworth, Claudia Paiva, Sarah Dawson, Simon Cross, Lu Long, Lan Zhao, Nicholas W. Morrell, David C. Crossman, Christopher M.H. Newman, David G. Kiely, Sheila E. Francis, Allan Lawrie
Journal: The Journal of Experimental Medicine (2012)

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies.
Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer
Authors: Anna Wojtalla, Barbara Fischer, Nataliya Kotelevets, Francesco A. Mauri, Jens Sobek, Hubert Rehrauer, Carlos Wotzkow, Mario P. Tschan, Michael J. Seckl, Uwe Zangemeister-Wittke, Alexandre Arcaro
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study, we investigated the potential of targeting the catalytic class IA PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types. Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or downregulation by siRNA. Results: Overexpression of the PI3K isoforms p110-α and p110-β and the antiapoptotic protein Bcl-2 was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110-α with RNA interference or selective pharmacologic inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, whereas targeting p110-β was less effective. Inhibition of p110-α also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mTOR pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1. A DNA microarray analysis revealed that p110-α inhibition profoundly affected the balance of pro- and antiapoptotic Bcl-2 family proteins. Finally, p110-α inhibition led to impaired SCLC tumor formation and vascularization in vivo. Conclusion: Together our data show the key involvement of the PI3K isoform p110-α in the regulation of multiple tumor-promoting processes in SCLC. Clin Cancer Res; 19(1); 96–105. ©2012 AACR.
TGF-?1 and angiotensin networking in cardiac remodeling
Authors: S ROSENKRANZ
Journal: Cardiovascular Research (2004)

The renin-angiotensin system (RAS) and transforming growth factor-beta1 (TGF-beta1) play a pivotal role in the development of cardiac hypertrophy and heart failure. Recent studies indicate that angiotensin II (Ang II) and TGF-beta1 do not act independently from one another but rather act as part of a signalling network in order to promote cardiac remodeling, which is a key determinant of clinical outcome in heart disease. This review focuses on recent advances in the understanding, how Ang II and TGF-beta1 are connected in the pathogenesis of cardiac hypertrophy and dysfunction. Increasing evidence suggests that at least some of the Ang II-induced effects on cardiac structure are mediated via indirect actions. Ang II upregulates TGF-beta1 expression via activation of the angiotensin type 1 (AT1) receptor in cardiac myocytes and fibroblasts, and induction of this cytokine is absolutely required for Ang II-induced cardiac hypertrophy in vivo. TGF-beta induces the proliferation of cardiac fibroblasts and their phenotypic conversion to myofibroblasts, the deposition of extracellular matrix (ECM) proteins such as collagen, fibronectin, and proteoglycans, and hypertrophic growth of cardiomyocytes, and thereby mediates Ang II-induced structural remodeling of the ventricular wall in an auto-/paracrine manner. Downstream mediators of cardiac Ang II/TGF-beta1 networking include Smad proteins, TGFbeta-activated kinase-1 (TAK1), and induction of hypertrophic responsiveness to beta-adrenergic stimulation in cardiac myocytes.
Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer
Authors: Kristen N. Stevens, Celine M. Vachon, Adam M. Lee, Susan Slager, Timothy Lesnick, Curtis Olswold, Peter A. Fasching, Penelope Miron, Diana Eccles, Jane E. Carpenter, Andrew K. Godwin, Christine Ambrosone, Robert Winqvist, Hiltrud Brauch, Marjanka K. Schmidt, Angela Cox, Simon S. Cross, Elinor Sawyer, Arndt Hartmann, Matthias W. Beckmann, Rüdiger Schulz-Wendtland, Arif B. Ekici, William J. Tapper, Susan M. Gerty, Lorraine Durcan, Nikki Graham, Rebecca Hein, Stephan Nickels, Dieter Flesch-Janys, Judith Heinz, Hans-Peter Sinn, Irene Konstantopoulou, Florentia Fostira, Dimitrios Pectasides, Athanasios M. Dimopoulos, George Fountzilas, Christine L. Clarke, Rosemary Balleine, Janet E. Olson, Zachary Fredericksen, Robert B. Diasio, Harsh Pathak, Eric Ross, JoEllen Weaver, Thomas Rüdiger, Asta Försti, Thomas Dünnebier, Foluso Ademuyiwa, Swati Kulkarni, Katri Pylkäs, Arja Jukkola-Vuorinen, Yon-Dschun Ko, Erik Van Limbergen, Hilde Janssen, Julian Peto, Olivia Fletcher, Graham G. Giles, Laura Baglietto, Senno Verhoef, Ian Tomlinson, Veli-Matti Kosma, Jonathan Beesley, Dario Greco, Carl Blomqvist, Astrid Irwanto, Jianjun Liu, Fiona M. Blows, Sarah-Jane Dawson, Sara Margolin, Arto Mannermaa, Nicholas G. Martin, Grant W. Montgomery, Diether Lambrechts, Isabel dos Santos Silva, Gianluca Severi, Ute Hamann, Paul Pharoah, Douglas F. Easton, Jenny Chang-Claude, Drakoulis Yannoukakos, Heli Nevanlinna, Xianshu Wang, Fergus J. Couch
Journal: Cancer Research (2011)

Abstract Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer. Cancer Res; 71(19); 6240–9. ©2011 AACR.
Reduced bone formation in non-steroid treated patients with rheumatoid arthritis.
Authors: J E Compston, S Vedi, R W Mellish, P Croucher, M M O'Sullivan
Journal: Annals of the Rheumatic Diseases (1989)

The cellular basis of trabecular bone loss in rheumatoid arthritis was investigated in 45 non-steroid treated patients. Mean wall thickness, an indicator of the amount of bone formed per remodelling unit, mean interstitial bone thickness, which is related to resorption depth, and the extent of trabecular surface covered by osteoid, which reflects the number of remodelling units, were assessed in iliac crest biopsy specimens. The mean wall thickness was significantly reduced in the patient group when compared with controls matched for age and sex (mean (SD) 39.8 (5.4) v 51.6 (9.7) microns). There was no significant difference between patients and controls in the mean interstitial bone thickness (51.0 (26.4) v 61.4 (31.9) microns) or osteoid surface (16.7 (11.4) v 21.0 (10.5)%). These results show that reduced bone formation at the remodelling unit level is the predominant mechanism of bone loss in rheumatoid arthritis.
Reply to M.J. Molina-Garrido et al
Authors: Andrea Luciani, Paolo Foa
Journal: Journal of Clinical Oncology (2011)

We would like to thank Molina-Garrido and Guille ´n-Ponce 1 for their comments on our article, and appreciate this opportunity to clarify some of the points they discussed.The vulnerable elders survey-13 (VES-13) is a geriatric instrument that has been validated as a means of indentifying elderly people with functional decline. 2 Patients are considered vulnerable if their score is 3 or higher, and an age older than 85 years is considered a criterion of vulnerability by itself.These criteria were established in a cohort of nononcologic elderly patients.The aim of our clinical trial was to compare the accuracy of VES-13 with the Comprehensive Geriatric Assessment (CGA) in detecting disabilities in elderly patients with cancer.We made an intrapatient analysis, and both scales were administered to every patient, thus reducing the possible biases arising from the type of population.Our patient series is larger than those of previously published studies, and unlike a previous study of patients with prostate cancer 3 in which the comparison involved the CGA as a whole (including the evaluation of cognitive and depressive status, which are not assessed by the VES-13 items), we only compared homogeneous items (ie, we only analyzed CGA functional status scores corrected for an age older than 85 years or younger than 85 years.The conclusions of our study underline the usefulness and accuracy of VES-13 when diagnosing impaired functional status in everyday clinical practice.The National Comprehensive Cancer Network and the International Society of Geriatric Oncology guidelines 3a recommend assessing elderly patients with cancer by using any form of geriatric evaluation regardless of the length of the instrument or how long it takes to complete.There is no answer to the question as to which instrument is the best.We believe that research should concentrate on identifying new screening tools for assessing the impact of geriatric impairments on oncologic outcomes (such as survival or toxicity) rather than on finding new cutoff points for classic geriatric scales, given that this should promote the wider use of geriatric assessments in oncologic clinics.Multicenter and international validations are the most appropriate methodologic means of avoiding selection biases.
Quantitative analysis of peroxisome proliferator‐activated receptor gamma (PPARγ) expression in arteries and hearts of patients with ischaemic or dilated cardiomyopathy
Authors: Mohammad R. Mehrabi, Petra Haslmayer, Susanne Humpeler, Gerhard Strauss‐Blasche, Wolfgang Marktl, Forouzan Tamaddon, Nermin Serbecic, Georg Wieselthaler, Theresia Thalhammer, Helmut D. Glogar, Cem Ekmekcioglu
Journal: European Journal of Heart Failure (2003)
Interleukin 12–mediated Prevention of Spontaneous Mammary Adenocarcinomas in Two Lines of Her-2/<i>neu</i> Transgenic Mice
Authors: Katia Boggio, Giordano Nicoletti, Emma Di Carlo, Federica Cavallo, Lorena Landuzzi, Cecilia Melani, Mirella Giovarelli, Ilaria Rossi, Patrizia Nanni, Carla De Giovanni, Page Bouchard, Stanley Wolf, Andrea Modesti, Piero Musiani, Pier Luigi Lollini, Mario P. Colombo, Guido Forni
Journal: The Journal of Experimental Medicine (1998)

The ability of interleukin (IL)-12 to prevent tumors when administered to individuals with a genetic risk of cancer was studied in two lines of transgenic mice expressing rat HER-2/neu oncogene in the mammary gland. Female BALB/c (H-2d) mice carrying the activated HER-2/ neu oncogene show no morphological abnormalities of the mammary gland until 3 wk of age. They then progress through atypical hyperplasia to in situ lobular carcinoma and at 33 wk of age all 10 mammary glands display invasive carcinomas. Adult FVB mice (H-2q) carrying the HER-2/neu protooncogene develop mammary carcinomas with a longer latency (38-49 wk) and a lower multiplicity (mean of 2.6 tumors/mice). Treatment with IL-12 (5 daily intraperitoneal injections, 1 wk on, 3 wk off; the first course with 50 ng IL-12/day, the second with 100 ng IL-12/day) begun at 2 wk of age in BALB/c mice and at 21 wk of age in FVB mice markedly delayed tumor onset and reduced tumor multiplicity. Analogous results were obtained in immunocompetent and permanently CD8+ T lymphocyte–depleted mice. In both transgenic lines, tumor inhibition was associated with mammary infiltration of reactive cells, production of cytokines and inducible nitric oxide synthase, and reduction in microvessel number, in combination with a high degree of hemorrhagic necrosis.
A Double-Blind, Randomized, Placebo-Controlled Clinical Trial on Benfotiamine Treatment in Patients With Diabetic Nephropathy
Authors: Alaa Alkhalaf, Astrid Klooster, Willem van Oeveren, Ulrike Achenbach, Nanne Kleefstra, Robbert J. Slingerland, G. Sophie Mijnhout, Henk J.G. Bilo, Reinold O.B. Gans, Gerjan J. Navis, Stephan J.L. Bakker
Journal: Diabetes Care (2010)

OBJECTIVE To investigate the effect of benfotiamine on urinary albumin excretion (UAE) and the tubular damage marker kidney injury molecule-1 (KIM-1) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes and UAE equivalent to 15–300 mg/24 h, despite ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), were randomly assigned to 12 weeks of benfotiamine (900 mg/day) (n = 39) or placebo (n = 43). RESULTS Compared with placebo, benfotiamine treatment resulted in significant improvement of thiamine status (P &amp;lt; 0.001). Benfotiamine treatment did not significantly decrease 24-h UAE or 24-h KIM-1 excretion. CONCLUSIONS In patients with type 2 diabetes and nephropathy, high-dose benfotiamine treatment for 12 weeks in addition to ACE-Is or ARBs did not reduce UAE or KIM-1 excretion, despite improvement of thiamine status.