tbuckley/cabot-search huggingface dataset:
Anti–TNF-α therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β
Authors: Suchita Nadkarni, Claudia Mauri, Michael R. Ehrenstein
Journal: The Journal of Experimental Medicine (2007)

The induction of regulatory T (T reg) cells holds considerable potential as a treatment for autoimmune diseases. We have previously shown that CD4+CD25hi T reg cells isolated from patients with active rheumatoid arthritis (RA) have a defect in their ability to suppress proinflammatory cytokine production by CD4+CD25− T cells. This defect, however, was overcome after anti–tumor necrosis factor (TNF)-α antibody (infliximab) therapy. Here, we demonstrate that infliximab therapy gives rise to a CD4+CD25hiFoxP3+ T reg cell population, which mediates suppression via transforming growth factor (TGF)-β and interleukin 10, and lacks CD62L expression, thereby distinguishing this T reg cell subset from natural T reg cells present in healthy individuals and patients with active RA. In vitro, infliximab induced the differentiation of CD62L− T reg cells from CD4+CD25− T cells isolated from active RA patients, a process dependent on TGF-β. In spite of the potent suppressor capacity displayed by this CD62L− T reg cell population, the natural CD62L+ T reg cells remained defective in infliximab-treated patients. These results suggest that anti–TNF-α therapy in RA patients generates a newly differentiated population of T reg cells, which compensates for the defective natural T reg cells. Therefore, manipulation of a proinflammatory environment could represent a therapeutic strategy for the induction of T reg cells and the restoration of tolerance.
Elevated Galectin-3 Precedes the Development of CKD
Authors: Conall M. O’Seaghdha, Shih-Jen Hwang, Jennifer E. Ho, Ramachandran S. Vasan, Daniel Levy, Caroline S. Fox
Journal: Journal of the American Society of Nephrology (2013)

Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal models and inversely correlates with GFR in humans, but whether galectin-3 predicts incident kidney disease is unknown. Here, we assessed renal outcomes for 2450 Framingham Offspring participants who attended examination 6 (1995-1998) and had follow-up data at examination 8 (2005-2008). Renal outcomes of interest included rapid decline in renal function (≥3 ml/min per 1.73 m(2) per year decline in estimated GFR [eGFR]), CKD (eGFR < 60 ml/min per 1.73 m(2)), and albuminuria (albumin-to-creatinine ratio ≥17 mg/g in men or ≥25 mg/g in women). We used multivariable logistic regression models to evaluate associations between galectin-3 with incident renal outcomes at examination 8. During a mean follow-up of 10.1 years, GFR declined rapidly in 241 (9.2%) participants, incident CKD developed in 277 (11.3%), and albuminuria developed in 194 (10.1%). Higher plasma levels of galectin-3 were associated with rapid decline in eGFR (per 1-SD log-galectin-3; adjusted odds ratio [OR], 1.49; 95% confidence interval [CI], 1.28 to 1.73]) and a higher risk of incident CKD (OR, 1.47; 95% CI, 1.27 to 1.71), but not with the risk of incident albuminuria. The addition of galectin-3 to clinical predictors improved the C-statistic (0.837-0.845; P=0.02) but did not reach predefined thresholds for clinically significant improvements to risk prediction based on reclassification indices. In conclusion, elevated levels of plasma galectin-3 are associated with increased risks of rapid GFR decline and of incident CKD in the community, which calls for further study in higher-risk groups.
Dietary patterns in pregnancy and respiratory and atopic outcomes in childhood
Authors: S O Shaheen, K Northstone, R B Newson, P M Emmett, A Sherriff, A J Henderson
Journal: Thorax (2009)

<h3>Background:</h3> Studies of the relation between maternal diet in pregnancy and respiratory and atopic outcomes in the offspring have focused on the effects of individual nutrients and foods rather than dietary patterns. A study was undertaken to determine whether dietary patterns in pregnancy are related to childhood asthma and related outcomes. <h3>Methods:</h3> In a population-based birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), dietary patterns in pregnancy previously identified using principal components analysis ("health conscious", "traditional", "processed", "vegetarian" and "confectionery") were related to early wheezing phenotypes and eczema; wheezing, hay fever, eczema, doctor-diagnosed asthma, atopy and total IgE at 7 years; lung function and bronchial responsiveness at 8–9 years. In regression models, confounders were controlled for using propensity scores. <h3>Results:</h3> Univariately, the "health conscious" pattern was positively associated with eczema, total IgE, forced expiratory volume in 1 s and forced expiratory flow and negatively associated with early wheezing and asthma (unadjusted odds ratios per standard deviation increase in pattern score for early persistent wheeze and asthma: 0.78 (95% CI 0.70 to 0.87), p = 7.3×10<sup>−6</sup>, N = 8886 and 0.90 (95% CI 0.84 to 0.97), p = 0.007, N = 7625, respectively). The "processed" pattern was positively associated with early wheezing and negatively associated with atopy and forced vital capacity. On controlling for confounders, the effects were substantially attenuated and became non-significant (adjusted odds ratios for the associations of the "health conscious" pattern with early persistent wheeze and asthma: 1.00 (0.86 to 1.16), p = 0.99 and 0.95 (0.86 to 1.04), p = 0.27, respectively). <h3>Conclusions:</h3> In this cohort, dietary patterns in pregnancy did not predict asthma and related outcomes in the offspring after controlling for confounders.
The Effect of Excess Weight Gain With Intensive Diabetes Mellitus Treatment on Cardiovascular Disease Risk Factors and Atherosclerosis in Type 1 Diabetes Mellitus
Authors: Jonathan Q. Purnell, Bernard Zinman, John D. Brunzell
Journal: Circulation (2012)

Background— Intensive diabetes mellitus therapy of type 1 diabetes mellitus reduces diabetes mellitus complications but can be associated with excess weight gain, central obesity, and dyslipidemia. The purpose of this study was to determine whether excessive weight gain with diabetes mellitus therapy of type 1 diabetes mellitus is prospectively associated with atherosclerotic disease. Methods and Results— Subjects with type 1 diabetes mellitus (97% white, 45% female, mean age 35 years) randomly assigned to intensive or conventional diabetes mellitus treatment during the Diabetes Control and Complications Trial (DCCT) underwent intima-media thickness (n = 1015) and coronary artery calcium score (n = 925) measurements during follow-up in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Intensive treatment subjects were classified by quartile of body mass index change during the DCCT. Excess gainers (4th quartile, including conventional treatment subjects meeting this threshold) maintained greater body mass index and waist circumference, needed more insulin, had greater intima-media thickness (+5%, P &lt; 0.001 EDIC year 1, P = 0.003 EDIC year 6), and trended toward greater coronary artery calcium scores (odds ratio, 1.55; confidence interval, 0.97 to 2.49; P = 0.07) than minimal gainers. DCCT subjects meeting metabolic syndrome criteria for waist circumference and blood pressure had greater intima-media thickness in both EDIC years ( P = 0.02 to &lt; 0.001); those meeting high-density lipoprotein criteria had greater coronary artery calcium scores (odds ratio, 1.6; confidence interval, 1.1 to 2.4; P = 0.01) during follow-up. Increasing frequency of a family history of diabetes mellitus, hypertension, and hyperlipidemia was associated with greater intima-media thickness with intensive but not conventional treatment. Conclusions— Excess weight gain in DCCT is associated with sustained increases in central obesity, insulin resistance, dyslipidemia and blood pressure, as well as more extensive atherosclerosis during EDIC. Clinical Trial Registration— URL for DCCT: http://clinicaltrials.gov ; Unique identifier: NCT00360815. URL for EDIC: http://clinicaltrials.gov ; Unique identifier: NCT00360893.
The vascular bed as the primary target in the destruction of skin grafts by antiserum. I. Resistance of freshly placed xenografts of skin to antiserum
Authors: SV Jooste, RB Colvin, WD Soper, HJ Winn
Journal: The Journal of Experimental Medicine (1981)

Rat skin grafted onto immunosuppressed mice is resistant to mouse anti-rat serum during the first 7-10 d after transplantation. It gradually acquires susceptibility, reaching a peak of sensitivity at 14-16 d after grafting. The grafts remain sensitive to antiserum, though at decreasing levels for an additional 3 wk, and grafts that persist beyond that time are resistant to antiserum for as long as they survive. In the study reported here, it is shown that the initial period of resistance to antiserum is due to factors acting locally within the graft and is entirely uninfluenced by the regimen of immunosuppression or the protective dressings that are used. After administration of antiserum, deposits of the injected immunoglobulin and of endogenous C3 are found on the luminal surfaces of graft vessels, although no significant tissue damage is observed. Rat skin that has become highly sensitive to antiserum 14-16 d after transplantation loses that sensitivity if it is regrafted to a new recipient, and then regains it 8-10 d later. Thus, the resistance of freshly grafted skin to antisera is associated with the process of healing into place, a conclusion that is supported by the observation that the intracutaneous administration of antisera to rats causes intense local inflammation and necrosis. The skin is therefore sensitive just before it is removed for grafting, but temporarily loses sensitivity thereafter. Resistance to antiserum during the first 3 or 4 d after transplantation is probably attributable to the fact that at that time grafts are vascularized poorly if at all. The state of resistance extends for several days after vascularization of the graft takes place and is then only gradually lost, a phenomenon that seems to be associated with the resistance of newly formed and regenerating blood vessels to vasoactive substances. This view is in accord with and, indeed, supports the idea that the induction of vascular injury is an essential step in antisera-mediated damage to tissue grafts.
Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment
Authors: Vivian Barry-Hamilton, Rhyannon Spangler, Derek Marshall, Scott McCauley, Hector M Rodriguez, Miho Oyasu, Amanda Mikels, Maria Vaysberg, Haben Ghermazien, Carol Wai, Carlos A Garcia, Arleene C Velayo, Brett Jorgensen, Donna Biermann, Daniel Tsai, Jennifer Green, Shelly Zaffryar-Eilot, Alison Holzer, Scott Ogg, Dung Thai, Gera Neufeld, Peter Van Vlasselaer, Victoria Smith
Journal: Nature Medicine (2010)
Immunohistochemical Analysis of Renin Activity in Chronic Cyclosporine Nephropathy in Childhood Nephrotic Syndrome
Authors: KAZUMOTO IIJIMA, KIYOSHI HAMAHIRA, AKIKO KOBAYASHI, HAJIME NAKAMURA, NORISHIGE YOSHIKAWA
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Although the pivotal role of activation of the intrarenal renin-angiotensin system (RAS) has been demonstrated in the rat model of chronic cyclosporine (CyA) nephropathy, it is still unclear whether intrarenal RAS activation is responsible for chronic CyA nephropathy in humans. Therefore, the distribution of renin in formalin-fixed, paraffin-embedded renal biopsy specimens obtained from 26 children who had idiopathic nephrotic syndrome (NS) and who were treated with long-term moderate-dose CyA was examined with the use of immunohistochemistry with rabbit polyclonal anti-human renin antibody. Nineteen patients had steroid-dependent NS, and 7 had steroid-resistant NS. However, CyA treatment led all of the latter patients into complete remission. All of the patients underwent renal biopsies at the start and the end of CyA treatment. In the pre-CyA specimens, immunoreactivity to renin was detected mainly in those parts of arterioles within the anatomically well-defined juxtaglomerular apparatus. In the post-CyA specimens, it was also detected in those parts of the vessels upstream from the juxtaglomerular apparatus. Moreover, the ratio of the number of renin-positive cells to the number of glomeruli (histologic renin index) increased significantly with long-term CyA treatment (from 1.26 ± 0.24 to 4.30 ± 0.40, P < 0.0001). Eleven of the post-CyA specimens showed mild or moderate CyA-associated arteriolopathy (CAA), whereas 15 showed no CAA. The histologic renin index was significantly higher in specimens with CAA than in those without CAA (5.16 ± 0.59 versus 3.67 ± 0.48, P = 0.031). Seven CAA-positive patients underwent repeat biopsies 6 to 12 mo after discontinuing the CyA. Their specimens showed an improvement in the CAA and significantly lower histologic renin index compared with the post-CyA (from 4.18 ± 0.69 to 2.10 ± 0.25, P = 0.018). Eleven of the post-CyA specimens showed mild to moderate interstitial fibrosis, and 15 showed no fibrosis. There was no significant difference in immunoreactivity to renin between the specimens with interstitial fibrosis and those without. However, patients with interstitial fibrosis had significantly longer periods of heavy proteinuria during CyA therapy, because of either steroid-resistant NS or frequent relapses of NS (83 ± 18 versus 35 ± 12 d, P = 0.030). These findings indicate that long-term CyA treatment for idiopathic NS in children may stimulate renin production in arterioles. They also suggest that CyA-stimulated intrarenal RAS activation is responsible for the development of CAA and that CyA-induced interstitial fibrosis is potentiated by long-term heavy proteinuria and is at least partly independent of CyA-stimulated intrarenal RAS activation.
Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma
Authors: Elizabeth Fox, Brigitte C. Widemann, Meredith K. Chuk, Leigh Marcus, Alberta Aikin, Patricia O. Whitcomb, Maria J. Merino, Maya Lodish, Eva Dombi, Seth M. Steinberg, Samuel A. Wells, Frank M. Balis
Journal: Clinical Cancer Research (2013)

Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit.Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects.Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.
Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years.
Authors: J E Lennard-Jones, D M Melville, B C Morson, J K Ritchie, C B Williams
Journal: Gut (1990)

Patients with extensive ulcerative colitis who do not need early surgery have been offered regular examination with the aim of detecting precancerous change (dysplasia) or early colorectal carcinoma. Outpatient visits with clinical examination, sigmoidoscopy, and biopsy were supplemented by two-yearly colonoscopy after the disease course reached 10 years. During the 22 year period from the beginning of 1966 to the end of 1987, 401 patients entered the programme and together contributed 4048 patient-years of observation. Apart from nine patients who left the country, follow up is complete until 1986 or 1987. Colorectal carcinoma developed in 22 patients and, in a further 12, biopsy evidence of precancer, described as severe/high grade dysplasia, was confirmed in a colectomy specimen. The cumulative probability of developing carcinoma was 3% at 15 years, 5% at 20 years, and 9% at 25 years; corresponding figures for precancer or carcinoma, or both were 4%, 7%, and 13%. Five patients died of colorectal carcinoma, two while under regular observation and three after developing carcinoma four to six years after their last attendance. Among the 17 patients who developed carcinoma while under observation, the Dukes stage was A or B in 12. Patients with extensive colitis whose disability does not warrant early surgery have a clinically important cancer risk after the disease has been present for 10 years. Our results suggest that follow up in the manner described reduces the mortality from this complication. Further work is needed to define the optimum method of surveillance and show if it is cost effective.
Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumours
Authors: M. De las Heras, S.H. Barsky, P. Hasleton, M. Wagner, E. Larson, J. Egan, A. Ortin, J.A. Gimenez-Mas, M Palmarini, J.M Sharp
Journal: European Respiratory Journal (2000)

Human bronchioloalveolar carcinoma (BAC) is a lung cancer, morphologically similar to an endemic contagious lung neoplasm of sheep called sheep pulmonary adenomatosis (SPA) or jaagsiekte. SPA is caused by an exogenous type B/D retrovirus (jaagsiekte sheep retrovirus (JSRV)), which prompted the present study to obtain evidence of a retrovirus in BAC. A panel of 249 human lung tumours, 21 nontumour lung lesions, four normal lung tissues, 23 adenocarcinomas from other organs and a cell line expressing a human endogenous retrovirus protein was examined immunohistochemically using a rabbit antiserum directed against the JSRV capsid protein. Specific staining was detected only in the cytoplasm of recognizably neoplastic cells in the pulmonary alveoli of 39 of 129 (30%) BACs, 17 of 65 (26%) lung adenocarcinomas and two of seven large cell carcinomas. The remaining samples were negative. These results support the hypothesis that some human pulmonary tumours may be associated with a jaagsiekte sheep retrovirus-related retrovirus, warranting further studies.
Increased ABCA1 activity protects against atherosclerosis
Authors: Roshni R. Singaraja, Catherine Fievet, Graciela Castro, Erick R. James, Nathalie Hennuyer, Susanne M. Clee, Nagat Bissada, Jonathan C. Choy, Jean-Charles Fruchart, Bruce M. McManus, Bart Staels, Michael R. Hayden
Journal: Journal of Clinical Investigation (2002)

The ABC transporter ABCA1 plays a key role in the first steps of the reverse cholesterol transport pathway by mediating lipid efflux from macrophages. Previously, it was demonstrated that human ABCA1 overexpression in vivo in transgenic mice results in a mild elevation of plasma HDL levels and increased efflux of cholesterol from macrophages. In this study, we determined the effect of overexpression of ABCA1 on atherosclerosis development. Human ABCA1 transgenic mice (BAC+) were crossed with ApoE–/– mice, a strain that spontaneously develop atherosclerotic lesions. BAC+ApoE–/– mice developed dramatically smaller, less-complex lesions as compared with their ApoE–/– counterparts. In addition, there was increased efflux of cholesterol from macrophages isolated from the BAC+ApoE–/– mice. Although the increase in plasma HDL cholesterol levels was small, HDL particles from BAC+ApoE–/– mice were significantly better acceptors of cholesterol. Lipid analysis of HDL particles from BAC+ApoE–/– mice revealed an increase in phospholipid levels, which was correlated significantly with their ability to enhance cholesterol efflux.
THE USE OF RETINOIC ACID IN CONGENITAL ICHTHYOSIFORM ERYTHRODERMA *
Authors: J. THOMSON, J. A. MILNE
Journal: British Journal of Dermatology (1969)

Journal Article THE USE OF RETINOIC ACID IN CONGENITAL ICHTHYOSIFORM ERYTHRODERMA Get access J. THOMSON, J. THOMSON Department of Dermatology, University of Glasgow Search for other works by this author on: Oxford Academic Google Scholar J. A. MILNE J. A. MILNE Department of Dermatology, University of Glasgow Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 81, Issue 6, 1 June 1969, Pages 452–455, https://doi.org/10.1111/j.1365-2133.1969.tb14017.x Published: 01 June 1969 Article history Accepted: 18 October 1968 Published: 01 June 1969
Behavioral Profiling of Human Transitional Cell Carcinoma <i>Ex vivo</i>
Authors: Carlos R. Estrada, Matthew Salanga, Diane R. Bielenberg, W. Bruce Harrell, David Zurakowski, Xuping Zhu, Matthew R. Palmer, Michael R. Freeman, Rosalyn M. Adam
Journal: Cancer Research (2006)

Abstract Outcome studies of many types of cancer have revealed that tumors of indistinguishable histologic appearance may differ significantly in aggressiveness and in their response to therapy. A strategy that would enable early identification of patients at high risk for disease progression and allow screening of multiple therapeutic agents simultaneously for efficacy would improve clinical management. We have developed an orthotopic organ culture model of bladder cancer in which quantum dot–based fluorescent imaging approaches are used to obtain quantitative measurements of tumor cell behavior. Human transitional cell carcinoma (TCC) cells are labeled with quantum dot nanoparticles, and the cells instilled into the rat bladder in vivo, after which the bladder is excised and cultured ex vivo. Cell implantation, proliferation, and invasion into the organ wall are monitored using epifluorescence imaging and two-photon laser scanning confocal microscopy. Using this approach, we were able to assign distinct phenotypes to two metastatic bladder cancer cell lines based on different patterns of invasiveness into the bladder wall. We also showed that established tumor cell masses regressed following intravesical administration of the chemotherapeutic drug thiotepa. Collectively, these findings suggest that this assay system, which we have named EViTAS (for ex vivo tumor assay system), can recapitulate salient aspects of tumor growth in the host and is amenable to behavioral profiling of human cancer. (Cancer Res 2006; 66(6): 3078-86)