tbuckley/cabot-search huggingface dataset:
Redistribution of Nucleoside Transporters to the Cell Membrane Provides a Novel Approach for Imaging Thymidylate Synthase Inhibition by Positron Emission Tomography
Authors: Meg Perumal, Radhakrishna G. Pillai, Henryk Barthel, Julius Leyton, John R. Latigo, Martin Forster, Fraser Mitchell, Ann L. Jackman, Eric O. Aboagye
Journal: Cancer Research (2006)

Abstract Thymidylate synthase (EC 2.1.1.45) is a key enzyme for the de novo synthesis of DNA and as such a target for anticancer drug development. There is a need to develop noninvasive methods for assessing thymidylate synthase inhibition in tumors. The aim of this study was to assess the potential of 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) for early measurement of thymidylate synthase inhibition and to elucidate the cellular mechanisms involved. Radiation-induced fibrosarcoma-1 tumor-bearing mice were injected with a single i.p. dose of the thymidylate synthase inhibitor 5-fluorouracil (5-FU; 165 mg/kg) and imaged by [18F]FLT-PET at 1 to 2 hours after treatment. Deoxyuridine, thymidine kinase 1 (cytoplasmic thymidine kinase; EC2.7.1.21), and ATP levels in excised tumors were measured. Cellular assays for membrane transport were also done. There was a 1.8-fold increase in the 60-minute [18F]FLT tumor/heart radioactivity ratio in drug-treated mice compared with vehicle controls (P = 0.0016). Plasma and tumor deoxyuridine levels increased significantly but thymidine kinase and ATP levels were unchanged. Whole-cell assays implicated a (low level) functional role for the type-1 equilibrative nucleoside transporter (ENT). There was an increase in type-1 ENT-binding sites per cell from 49,110 in untreated cells to 73,142 (P = 0.03) in cells treated with 10 μg/mL 5-FU for 2 hours, without a change in transporter affinity (P = 0.41). We conclude that [18F]FLT-PET can be used to measure thymidylate synthase inhibition as early as 1 to 2 hours after treatment with 5-FU by a mechanism involving redistribution of nucleoside transporters to the plasma membrane. (Cancer Res 2006; 66(17): 8558-64)
Silent thyroiditis associated with etanercept in rheumatoid arthritis
Authors: E Andres
Journal: Annals of the Rheumatic Diseases (2002)

Blockade of tumour necrosis factor alpha (TNFα) using infliximab, a chimeric monoclonal antibody against TNFα, is an effective treatment in rheumatoid arthritis and Crohn's disease. 1 2 Sifikakis reported success using infliximab in sight threatening Behçet's disease. 3 A preliminary study has also reported clinical improvements in the primary systemic vasculitis, Wegener's granulomatosis, with the soluble TNFα receptor etanercept. 4 The benefit of lenercept, a soluble p55 TNFα receptor fusion protein, on digital vasculitis in rheumatoid arthritis has also been reported. 5 We report the compassionate treatment of six patients with refractory vasculitis using infliximab.Diagnoses were Wegener's granulomatosis in three and microscopic polyangiitis in three.Three patients were positive for proteinase-3 antineutrophil cytoplasmic antibodies (PR3-ANCA) and one for myeloperoxidase (MPO)-ANCA.Four were female, with a mean age of 58 years (range 23-77) and mean disease duration of 3.5 years.All had had at least three clinical relapses and had received prolonged treatment with corticosteroids and at least four immunosuppressive drugs.At the time of infliximab treatment the eyes were affected in four patients and the lung in three; in addition, five had profound constitutional symptoms.The mean prednisolone dose was 17 mg.Three intravenous doses of infliximab 200 mg were given at monthly intervals for three months.One patient complained of fatigue, myalgia, and blurred vision 24 hours after the first infusion, which did not recur on rechallenge.Infliximab was otherwise well tolerated.Five patients had remission of their disease, four within two weeks of treatment.This allowed steroid withdrawal in three and reduction by more than 50% in two.Disease activity assessed by the Birmingham Vasculitis Activity Scores (BVAS) improved from a mean of 6.3 to 0.8 at three months (fig 1). 6 One patient receiving continued infliximab for six months relapsed when the treatment interval was extended to two months.Mean falls in erythrocyte sedimentation rate and C reactive protein were 17 mm/1st h and 13 mg/l, respectively.The ANCA status was unchanged.Anti-TNFα treatment heralds a new wave of specifically targeted biological interventions of potential value in the treatment of vasculitis.It offers the hope of improved therapeutic efficacy over current agents and the possibility of reducing exposure to steroids and immunosuppressive drugs.Further studies are warranted to confirm these observations and explore the role of infliximab as a component of initial protocols.. . . . . .
The serine protease inhibitor serpinE2 is a novel target of ERK signaling involved in human colorectal tumorigenesis
Authors: Sébastien Bergeron, Etienne Lemieux, Véronique Durand, Sébastien Cagnol, Julie C Carrier, Jacques G Lussier, Marie-Josée Boucher, Nathalie Rivard
Journal: Molecular Cancer (2010)

Abstract Background Among the most harmful of all genetic abnormalities that appear in colorectal cancer (CRC) development are mutations of KRAS and its downstream effector BRAF as they result in abnormal extracellular signal-related kinase (ERK) signaling. In a previous report, we had shown that expression of a constitutive active mutant of MEK1 (caMEK) in normal rat intestinal epithelial cells (IECs) induced morphological transformation associated with epithelial to mesenchymal transition, growth in soft agar, invasion and metastases in nude mice. Results from microarrays comparing control to caMEK-expressing IECs identified the gene encoding for serpinE2, a serine protease inhibitor, as a potential target of activated MEK1. Results 1- RT-PCR and western blot analyses confirmed the strong up-regulation of serpinE2 expression and secretion by IECs expressing oncogenic MEK, Ras or BRAF. 2- Interestingly, serpinE2 mRNA and protein were also markedly enhanced in human CRC cells exhibiting mutation in KRAS and BRAF . 3- RNAi directed against serpinE2 in caMEK-transformed rat IECs or in human CRC cell lines HCT116 and LoVo markedly decreased foci formation, anchorage-independent growth in soft agarose, cell migration and tumor formation in nude mice. 4- Treatment of CRC cell lines with U0126 markedly reduced serpinE2 mRNA levels, indicating that expression of serpinE2 is likely dependent of ERK activity. 5- Finally, Q-PCR analyses demonstrated that mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues and in colorectal tumors, regardless of tumor stage and grade. Conclusions Our data indicate that serpinE2 is up-regulated by oncogenic activation of Ras, BRAF and MEK1 and contributes to pro-neoplastic actions of ERK signaling in intestinal epithelial cells. Hence, serpinE2 may be a potential therapeutic target for colorectal cancer treatment.
Subcutaneous rupture of the Achilles tendon: basic science and some aspects of clinical practice.
Authors: S W Waterston, N Maffulli, S W Ewen
Journal: British Journal of Sports Medicine (1997)

<h3>Introduction</h3> The categorisation of NSCLC into squamous and non-squamous subtypes is an important requirement for the optimisation of patient care as this may modify chemotherapy regimens and direct molecular testing. The lung cancer national audit highlights the need to minimise the rate of NSCLC not otherwise specified (NSCLC-NOS).<sup>1</sup> The aim of our study was to determine whether samples obtained by endobronchial ultrasound guided-transbronchial needle aspiration (EBUS-TBNA) could be used to pathologically subtype NSCLC and provide sufficient material for molecular testing. <h3>Methods</h3> A prospectively maintained database of consecutive patients with suspected lung cancer referred to our unit, a UK regional thoracic oncology centre, was analysed. All patients diagnosed with NSCLC by EBUS-TBNA cytology at our centre between Sept 2013 and Sept 2014 were included in the study. <h3>Results</h3> A total of 89 patients were diagnosed with NSCLC using EBUS-TBNA. The pathological subtypes were: n = 46 (51.7%) squamous cell carcinoma, n = 41 (46%) adenocarcinoma and n = 2 (2.2%) NSCLC-NOS. All samples with a new diagnosis of non-squamous subtype were sent for EGFR mutation analysis, with sufficient material in 97% (n = 35/36) and one activating mutation was identified. ALK analysis was successfully performed in all 5 samples in which this was requested. Additional molecular testing was requested in 9 samples with sufficient material in 89% (n = 8/9). <h3>Conclusions</h3> EBUS-TBNA cytology can be used to successfully subtype NSCLC and provide adequate material for molecular testing in the majority of cases. The rate of NSCLC-NOS in our study (2.2%) compares favourably with local cancer network (13.5%) and national (12.9%) figures. <h3>Reference</h3> 1 National lung cancer audit report 2014 doi http://www.hscic.gov.uk/catalogue/PUB16019/clin-audi-supp-prog-lung-nlca-2014-rep.pdf
Mitogen stimulation of peripheral blood lymphocytes of duodenal ulcer patients during treatment with cimetidine or ranitidine.
Authors: N R Peden, A J Robertson, E J Boyd, R A Brown, J H Gibbs, R C Potts, K G Wormsley, J S Beck
Journal: Gut (1982)

During a double-blind randomised clinical trial of cimetidine and ranitidine in the management of duodenal ulcer, the response of patients9 peripheral blood lymphocytes to optimal mitogenic stimulation in vitro has been measured. Treatment with cimetidine, but not ranitidine, was associated with a significant increase in the proportion of peripheral blood lymphocytes responding to this optimal mitogenic stimulation. We conclude that these effects of cimetidine may not be mediated at classical histamine H2-receptors.
Effect of a novel palatinose-based liquid balanced formula (MHN-01) on glucose and lipid metabolism in male Sprague-Dawley rats after short- and long-term ingestion
Authors: Hidekazu Arai, Akira Mizuno, Kaoru Matsuo, Makiko Fukaya, Hajime Sasaki, Hirofumi Arima, Motoi Matsuura, Yutaka Taketani, Toshio Doi, Eiji Takeda
Journal: Metabolism (2004)
Minimal and Null Predictive Effects for the Most Popular Blood Biomarkers of Cardiovascular Disease
Authors: John P.A. Ioannidis, Ioanna Tzoulaki
Journal: Circulation Research (2012)

At least 10 cardiovascular biomarkers that can be measured in blood have accrued more than 6000 published related papers each.A systematic evaluation of the evidence suggests that they have limited or no predictive ability for cardiovascular disease and suggests the need for a paradigm shift in testing and qualifying biomarkers and in the expectations surrounding them.
Serum ferritin and transferrin levels as serologic markers of methylene diphenyl diisocyanate–induced occupational asthma
Authors: Gyu-Young Hur, Gil-Soon Choi, Seung-Soo Sheen, Hyun-Young Lee, Han-Jung Park, Sung-Jin Choi, Young-Min Ye, Hae-Sim Park
Journal: Journal of Allergy and Clinical Immunology (2008)
The Tumor-Suppressive Function of <i>UNC5D</i> and Its Repressed Expression in Renal Cell Carcinoma
Authors: Dan Lu, Dong Dong, Yu Zhou, Min Lu, Xue-Wen Pang, Yan Li, Xiao-Jun Tian, Yu Zhang, Jun Zhang
Journal: Clinical Cancer Research (2013)

Abstract Purpose: As a newly added member of the UNC5H receptors, the function of UNC5D/H4 in tumorigenesis remains poorly defined. The aim of this study was to examine the expression of UNC5D in primary renal cell carcinomas (RCC), analyze the mechanisms responsible for its downregulation in RCC, and assess its functional relevance to tumor growth and migration. Experimental Design: Forty-four paired primary RCCs and corresponding adjacent noncancerous tissues were collected. The mRNA and protein expression level of UNC5D was assessed by reverse transcriptase-PCR, real-time PCR, or immunohistochemistry. Epigenetic alterations in UNC5D promoter and LOH in the UNC5D locus were also analyzed. Ectopic expression of UNC5D in renal cancer cells with silenced expression of UNC5D was used for analysis of the biologic functions of UNC5D. Results: UNC5D expression was attenuated in multiple carcinoma cell lines including renal cancer cells. Similar reduction was also observed in primary RCC tissues as compared with paired adjacent noncancerous tissues. Methylation-specific PCR showed hypermethylation in UNC5D promoter in a significant proportion (18 of 44) of tumor tissue (40.9%). LOH of UNC5D was observed in 13 of 44 patients with RCCs (29.5%). Restoration of UNC5D expression in renal cancer cells significantly inhibited cell proliferation, anchorage-dependent and -independent growth, as well as migration and invasion, whereas knockdown of UNC5D promoted cell growth. Furthermore, ectopic expression of UNC5D induced G2–M cell-cycle arrest. Conclusions: UNC5D is a functional tumor suppressor that is frequently downregulated in RCCs due to promoter hypermethylation and LOH. Clin Cancer Res; 19(11); 2883–92. ©2013 AACR.
The Dark Side of Mast Cell–Targeted Therapy in Prostate Cancer
Authors: Paola Pittoni, Mario Paolo Colombo
Journal: Cancer Research (2012)

Tumor development requires accomplices among white blood cells. Other than macrophages, mast cells have been observed to support the outgrowth of certain neoplasias because of their proangiogenic properties. In some tumor settings, however, mast cells may have a protective role, exerted by their proinflammatory mediators. In prostate cancer, no conclusive data on mast cell function were available. Here, we discuss recent work on the role of mast cells in mouse and human prostate cancer, showing that mast cells can behave alternatively as dangerous promoters, innocent bystanders, or essential guardians of tumors, according to the stage and origin of transformed cells. In particular, mast cells are essential for the outgrowth of early-stage tumors due to their matrix metalloproteinase-9 production, become dispensable in advanced-stage, post-epithelial-to-mesenchymal transition, and are protective against neuroendocrine prostate tumor variants. The common expression of c-Kit by mast cells and neuroendocrine clones suggests a possible competition for the ligand Stem cell factor and offers the chance of curing early-stage disease while preventing neuroendocrine tumors using c-Kit-targeted therapy. This review discusses the implications of these findings on the advocated mast cell-targeted cancer therapy and considers future directions in the study of mast cells and their interactions with other c-Kit-expressing cells.
<i>Schnurri-3</i> (KRC) Interacts with c-Jun to Regulate the IL-2 Gene in T Cells
Authors: Mohamed Oukka, Marc N. Wein, Laurie H. Glimcher
Journal: The Journal of Experimental Medicine (2004)

The activator protein 1 (AP-1) transcription factor is a key participant in the control of T cell proliferation, cytokine production, and effector function. In the immune system, AP-1 activity is highest in T cells, suggesting that a subset of T cell–specific coactivator proteins exist to selectively potentiate AP-1 function. Here, we describe that the expression of Schnurri-3, also known as κ recognition component (KRC), is induced upon T cell receptor signaling in T cells and functions to regulate the expression of the interleukin 2 (IL-2) gene. Overexpression of KRC in transformed and primary T cells leads to increased IL-2 production, whereas dominant-negative KRC, or loss of KRC protein in KRC-null mice, results in diminished IL-2 production. KRC physically associates with the c-Jun transcription factor and serves as a coactivator to augment AP-1–dependent IL-2 gene transcription.
The Role of Platelet-Activating Factor in Pathogenesis of Type 1 Diabetes
Authors: Betül Ersoy, Afig Hüseyinov, Şükran Darcan
Journal: Diabetes Care (2005)

Platelet-activating factor (PAF) is a phospholipid mediator that exhibits diverse and potent effects on many cell types (1). PAF is a potent mediator of hypersensitivity and inflammatory reactions (2). Type 1 diabetes is caused by autoimmune destruction of the β-cells in the pancreas, which is initiated years before the clinical presentation of disease (3). In recent-onset type 1 diabetes and in animal models of autoimmune diabetes, a characteristic pathological finding in the islets of Langerhans is the accumulation of mononuclear cells and β-cell death (insulitis) (4,5). In this study, we investigated the role of PAF as an inflammatory mediator in pathogenesis of type 1 diabetes, …
Randomized controlled study of the efficacy and immunologic effects of a short course of prednisone followed by alpha-interferon versus alpha-interferon alone in the treatment of chronic hepatitis B: Preliminary results
Authors: C Garcia-Monzon, R Moreno-Otero, L Garcia-Buey, M Lopez-Botet, MO de Landazuri, F Sanchez-Madrid
Journal: Journal of Hepatology (1990)
Differential effects of chlorpromazine on the in vitro generation and effector function of cytotoxic lymphocytes.
Authors: R M Ferguson, J R Schmidtke, R L Simmons
Journal: The Journal of Experimental Medicine (1976)

Allograft rejection represents a cytotoxic response mediated to a large degree by thymus-derived T lymphocytes (1). The study of such cell-mediated cytotoxic phenomena has been greatly facilitated by the discovery first noted by Hayry and Defendi (2) and Wunderlich and Cany (3), that a natural consequence of allogeneic stimulation in an unidirectional mixed lymphocyte culture (MLC) was the appearance of cytotoxic lymphocytes specific for antigens present on the stimulator cells. Subsequent studies have shown that such in vitro generation of cytotoxic lymphocytes was dependent on the proliferative response in an MLC (4), was genetically determined (5), and possibly required the interaction of several subpopulations of T cells (6). We now report that the surface active agent chlorpromazine: (a) inhibits allogeneic stimulation of the proliferative response in an MLC; (b) inhibits the MLC generation of cytotoxic lymphocytes, (c) has no effect on the recognition, binding, or lysis of target cells by already sensitized lymphocytes; and (d) blocks a postproliferative membrane-mediated event, independent of proliferation, and necessary for the MLC generation of cytotoxic lymphocytes.
Alkylaniline-Hemoglobin Adducts and Risk of Non-Smoking-Related Bladder Cancer
Authors: J. Gan, P. L. Skipper, M. Gago-Dominguez, K. Arakawa, R. K. Ross, M. C. Yu, S. R. Tannenbaum
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Some members of the arylamine family of compounds, specifically 4-aminobiphenyl (ABP), 2-naphthylamine, and benzidine, are established human bladder carcinogens. Cigarette smoking and use of permanent hair dye contribute substantially to current arylamine exposure. Low levels of 4-ABP exposure have been associated with non–smoking-related bladder cancer. Other arylamine compounds coming from as yet unidentified environmental sources may also be human bladder carcinogens. Methods: We conducted a population-based case–control study in Los Angeles County, California, involving 298 case subjects with bladder cancer and 308 control subjects, who were matched on age, sex, race/ethnicity, and neighborhood of residence. In-person interviews provided information on tobacco smoking and other potential risk factors for bladder cancer. To assess arylamine exposure, levels of arylamine–hemoglobin adducts of nine selected alkylanilines (2,3-dimethylaniline [2,3-DMA], 2,4-DMA, 2,5-DMA, 2,6-DMA, 3,4-DMA, 3,5-DMA, 2-ethylaniline [2-EA], 3-EA, 4-EA) were measured in peripheral blood collected from study subjects. Analysis of covariance and conditional logistic regression methods were used to analyze the relationship between arylamine–hemoglobin adducts and bladder cancer risk. All statistical tests were two-sided. Results: Levels of all arylamine–hemoglobin adducts, with the exception of 2,6-DMA, were higher in smokers than in nonsmokers, and levels of all arylamine–hemoglobin adducts were higher in case subjects than in control subjects. Arylamine–hemoglobin adducts of 2,6-DMA, 3,5-DMA, and 3-EA were all independently, statistically significantly (all P<.001) associated with bladder cancer risk after adjusting for cigarette smoking at the time of blood collection, lifetime smoking history, and other potential risk factors. These adducts were also independently associated with bladder cancer risk when only nonsmokers at time of blood draw were considered (highest quartile versus lowest quartile: 2,6-DMA, relative risk [RR] of bladder cancer = 8.1, 95% confidence interval [CI] = 3.6 to 18.0; 3,5-DMA, RR = 2.7, 95% CI = 1.2 to 6.0; 3-EA, RR = 4.3, 95% CI = 1.6 to 11.6). Conclusions: Diverse arylamine exposures are strongly associated with bladder cancer risk among nonsmokers. Because arylamines may account for a substantial proportion of bladder cancers among the general population, identification of environmental sources of these compounds is needed.
A Selective Retinoid X Receptor Agonist Bexarotene (Targretin) Prevents and Overcomes Acquired Paclitaxel (Taxol) Resistance in Human Non–Small Cell Lung Cancer
Authors: Wan-Ching Yen, Manny R. Corpuz, Rene Y. Prudente, Tracy A. Cooke, Reid P. Bissonnette, Andrés Negro-Vilar, William W. Lamph
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Paclitaxel is an important anticancer agent for the treatment of non–small cell lung cancer (NSCLC). However, its use in cancer therapy is limited by development of acquired drug resistance. The goal of this study was to determine the effect of bexarotene on development of acquired paclitaxel resistance in NSCLC. Experimental Design: Human NSCLC Calu3 cells were repeatedly treated in culture with intermittent paclitaxel alone or in combination with continuous bexarotene for 3 months. Thereafter, cells were isolated and characterized for their drug sensitivity in vitro and in vivo. Results: Repeat exposure to paclitaxel alone resulted in development of paclitaxel resistance with cross-resistance to multidrug resistance P-glycoprotein substrates, whereas the bexarotene/paclitaxel combination prevented the development of drug resistance and the cells remained chemosensitive. Furthermore, paclitaxel resistance could be overcome when the resistant cells were treated with the combination regimen. Fluctuation analysis showed that treatment with bexarotene decreased the rate of spontaneous development of paclitaxel resistance. In vivo, the bexarotene/paclitaxel combination regimen produced a statistically significant decrease in tumor growth in a Calu3 NSCLC xenograft model compared with the single agents (two-tailed, P &amp;lt; 0.05). In addition, paclitaxel-resistant Calu3 tumors treated with the bexarotene/paclitaxel combination showed greater delay in tumor growth compared with those treated with paclitaxel alone. Conclusions: Our results suggest that bexarotene may offer a novel approach to prevent and overcome paclitaxel resistance in patients with NSCLC.