tbuckley/cabot-search huggingface dataset:
Less stress, more success? Oncological implications of surgery-induced oxidative stress
Authors: D P O'Leary, J H Wang, T G Cotter, H P Redmond
Journal: Gut (2011)

Reactive oxygen species (ROS) possess important cell signalling properties. This contradicts traditional thought which associated ROS activity with cell death. Emerging evidence clearly demonstrates that ROS signalling acts as a key regulator in tumour cell survival and in the cellular processes required for tumour cells to successfully metastasise and proliferate. The discovery of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) family of enzymes in the last decade has unravelled much of the mystery surrounding how ROS are generated. Tumour cells are now known to express Nox enzymes which produce ROS required for cellular signalling. Activation of Nox enzymes occurs via interaction with proinflammatory cytokines and growth factors, all of which are released following surgical trauma. As our understanding of the signalling capabilities of ROS grows, the oncological implications of ROS activity are gradually being revealed. Nox-derived ROS are known to play a central role in each step of the metastatic cascade including invasion, adhesion, angiogenesis and proliferation. This article describes how surgery creates a ROS-rich environment, which facilitates redox signalling, and also examines the role played by Nox enzymes in this process. The authors then explore current knowledge of the oncological implications of surgery-induced redox signalling, and discuss current and future therapeutic strategies targeted at ROS and Nox enzymes in cancer patients.
ENZYMES OF THE GLYCOLYTIC PATHWAY IN SKIN..
Authors: P. D. MIER, D. W. K. COTTON
Journal: British Journal of Dermatology (1966)

Journal Article ENZYMES OF THE GLYCOLYTIC PATHWAY IN SKIN.: I. Hexokinase. Get access P. D. MIER, P. D. MIER The Institute of Dermatology, St. John's Hospital for Diseases of the Skin, Homerton Grove, London, E.9 Search for other works by this author on: Oxford Academic Google Scholar D. W. K. COTTON D. W. K. COTTON The Institute of Dermatology, St. John's Hospital for Diseases of the Skin, Homerton Grove, London, E.9 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 78, Issue 10, 1 October 1966, Pages 536–540, https://doi.org/10.1111/j.1365-2133.1966.tb12143.x Published: 01 October 1966
Physical Activity and Risk of All-Cause and Cardiovascular Disease Mortality in Diabetic Adults From Great Britain: Pooled Analysis of 10 Population-Based Cohorts
Authors: Kabir P. Sadarangani, Mark Hamer, Jenny S. Mindell, Ngaire A. Coombs, Emmanuel Stamatakis
Journal: Diabetes Care (2014)

OBJECTIVE To examine associations between specific types of physical activity and all-cause and cardiovascular disease (CVD) mortality in a large nationally representative sample of adults with diabetes from Great Britain. RESEARCH DESIGN AND METHODS There were a total of 3,038 participants (675 deaths) with diabetes in the Health Survey for England and the Scottish Health Surveys conducted between 1997 and 2008. Participants aged ≥50 years at baseline were followed up for an average of 75.2 months for all-cause and CVD mortality. Data were collected on self-reported frequency, duration, and intensity of participation in sports and exercise, walking, and domestic physical activity, from which the number of MET-hours/week were derived. Sex-specific medians of time spent in each type of physical activity (for those physically active) were calculated, and Cox proportional hazards regression conducted to examine type-specific associations between the level of physical activity and all-cause and CVD mortality risk. RESULTS Inverse associations with all-cause and CVD mortality were observed for overall physical activity in a dose-response manner after adjusting for covariates. Compared with those who individuals were inactive, participants who reported some activity, but below the recommended amount, or who met the physical activity recommendations had a 26% (95% CI 39–11) and 35% (95% CI 47–21) lower all-cause mortality, respectively. Similar results were found for below/above median physical activity levels. Sports and exercise participation was inversely associated with all-cause (but not CVD) mortality, as were above average levels of walking. Domestic physical activity was not associated with mortality. CONCLUSIONS Moderate physical activity levels were associated with better prognosis in diabetic adults.
Outcome of Children With Metastatic Medulloblastoma Treated With Carboplatin During Craniospinal Radiotherapy: A Children's Oncology Group Phase I/II Study
Authors: Regina I. Jakacki, Peter C. Burger, Tianni Zhou, Emiko J. Holmes, Mehmet Kocak, Arzu Onar, Joel Goldwein, Minesh Mehta, Roger J. Packer, Nancy Tarbell, Charles Fitz, Gilbert Vezina, Joanne Hilden, Ian F. Pollack
Journal: Journal of Clinical Oncology (2012)

We evaluated the feasibility of administering carboplatin as a radiosensitizer during craniospinal radiation therapy (CSRT) to patients with high-risk medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumors, and we report the outcome in the subset with metastatic (M+) MB.After surgery, patients received 36 Gy CSRT with boosts to sites of disease. During radiation, patients received 15 to 30 doses of carboplatin (30-45 mg/m(2)/dose), along with vincristine (VCR) once per week for 6 weeks. Patients on regimen A received 6 months of maintenance chemotherapy (MC) with cyclophosphamide and VCR. Once the recommended phase II dose (RP2D) of carboplatin was determined, cisplatin was added to the MC (regimen B).In all, 161 eligible patients (median age, 8.7 years; range, 3.1 to 21.6 years) were enrolled. Myelosuppression was dose limiting and 35 mg/m(2)/dose × 30 was determined to be the RP2D of carboplatin. Twenty-nine (36%) of 81 patients with M+ MB had diffuse anaplasia. Four patients were taken off study within 11 months of completing radiotherapy for presumed metastatic progression and are long-term survivors following palliative chemotherapy. Excluding these four patients, 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ± 11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36). There was no difference in survival by M stage. Anaplasia was a negative predictor of outcome.The use of carboplatin as a radiosensitizer is a promising strategy for patients with M+ MB. Early progression should be confirmed by biopsy.
Spatially and temporally distinct expression of fibroblast connexins after sheep ventricular infarction
Authors: P Camelliti
Journal: Cardiovascular Research (2004)

Myocardial infarction leads to extensive changes in the organization of cardiac myocytes and fibroblasts, and changes in gap junction protein expression. In the immediate period following ischemia, reperfusion causes hypercontraction, spreading the necrotic lesion. Further progressive infarction continues over several weeks. In reperfusion injury, the nonspecific gap junction channel uncoupler heptanol limits necrosis. We hypothesize that gap junction coupling and fibroblast invasion provide a substrate for progressive infarction via a gap junction mediated bystander effect.A sheep coronary occlusion infarct model was used with samples collected at 12, 24 and 48 h, and 6, 12 and 30 d (days) post-infarction. Immunohistochemical labelling of gap junction connexins Cx40, Cx43, and Cx45 was combined with cell-specific markers for fibroblasts (anti-vimentin) and myocytes (anti-myomesin). Double and triple immunolabelling and confocal microscopy were used to follow changes in cardiac myocyte morphology, fibroblast content and gap junction expression after myocardial infarction. Gap junction protein levels and fibroblast numbers were quantified.Within 12 h of ischemia, myocyte viability is impaired within small islands in the ischemic region. These islands spread and fuse into larger infarct zones until 12 d post-infarction. Thereafter, surviving myocytes within the infarct and in the border-zone appear to become stabilized. Distant from the infarct, continuing myocyte disruption is regularly observed, even after 30 d. Cx43 becomes redistributed from intercalated discs to the lateral surface of structurally compromised myocytes within 12 d. Cx45 expressing fibroblasts infiltrate the damaged region within 24 h, becoming most numerous at 6-12 d post-infarction, with peak Cx45 levels at 6 d. Later, Cx43 expressing fibroblasts are observed, and the related Cx43 label increases over the 30 d observation period, even though fibroblast numbers decline after 12 d. Cx40 was only seen in vascular endothelium.Progressive infarction, identified by myocyte sarcomere disruption and subsequent cell loss, occurs in parallel with fibroblast invasion and gap junction remodeling. Two fibroblast phenotypes occur within infarcts, expressing either Cx43 or Cx45. Coupled fibroblasts may play a number of roles in tissue remodeling following myocardial infarction, including provision of a possible substrate for progressive infarction via a gap junction mediated bystander effect.
Is Lanreotide and/or Interferon Alfa an Adequate Therapy for Neuroendocrine Tumors?
Authors: Verena Völter, Christian Peschel
Journal: Journal of Clinical Oncology (2004)

THE EDITOR: Faiss et al [1] report on a prospective, randomized trial investigating the antiproliferative effect of lanreotide and interferon alfa in 80 patients with metastatic neuroendocrine tumors.This is one of the largest prospective series ever reported.The authors assumed a 300% increase in 1-year progression-free survival when combining lanreotide and interferon alfa compared to interferon alfa alone.However, the study was prematurely closed after 80 patients instead of the calculated 105 patients.Furthermore, the authors do not provide the basis for their assumptions of a 15% progression-free survival at 1 year for interferon and 25% for lanreotide, respectively.Interpretation of some of the data presented has to be considered inaccurate and uncommon.Subgroups of eight to 12 patients each comparing symptom control cannot be analyzed statistically, and we doubt the clinical accuracy and relevance of one versus two or two versus three episodes of flush and/or diarrhea per day.Eleven patients crossed over, achieving a "clear reduction in tumor growth"-response criteria should be well defined and applied.Finally, the authors' point out their low disease stabilization (DS) rate compared with other reports, making four statements that are not supported by the literature.(1) The authors explain that the low DS rate is due to a large amount of foregut tumors.However, most other series do not specify the tumor localization and contain a high number of unknown primary sites [2,3].Some series report on a comparable high number of foregut tumors, but obtain a higher DS-rate [4].(2) Their study is not unique in having independent radiologic review [2][3][4].(3) The authors claim that lanreotide is inferior to octreotide, although it has been demonstrated that both somatostatin analogs are equiva-lent [4,5].(4) It is not clear why therapy-naïve patients should show a lower stable disease rate than patients who already received treatments.Unfortunately, the study presented shows some inconsistent results.In addition, although it is a large series of patients with this rare disease, the accrual could not be completed and thus did not reach statistical significance.
MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage
Authors: Marielle C. Gold, James E. McLaren, Joseph A. Reistetter, Sue Smyk-Pearson, Kristin Ladell, Gwendolyn M. Swarbrick, Yik Y.L. Yu, Ted H. Hansen, Ole Lund, Morten Nielsen, Bram Gerritsen, Can Kesmir, John J. Miles, Deborah A. Lewinsohn, David A. Price, David M. Lewinsohn
Journal: The Journal of Experimental Medicine (2014)

Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that detects microbial metabolites presented by the nonpolymorphic major histocompatibility complex (MHC)–like molecule MR1. The highly conserved nature of MR1 in conjunction with biased MAIT TCRα chain usage is widely thought to indicate limited ligand presentation and discrimination within a pattern-like recognition system. Here, we evaluated the TCR repertoire of MAIT cells responsive to three classes of microbes. Substantial diversity and heterogeneity were apparent across the functional MAIT cell repertoire as a whole, especially for TCRβ chain sequences. Moreover, different pathogen-specific responses were characterized by distinct TCR usage, both between and within individuals, suggesting that MAIT cell adaptation was a direct consequence of exposure to various exogenous MR1-restricted epitopes. In line with this interpretation, MAIT cell clones with distinct TCRs responded differentially to a riboflavin metabolite. These results suggest that MAIT cells can discriminate between pathogen-derived ligands in a clonotype-dependent manner, providing a basis for adaptive memory via recruitment of specific repertoires shaped by microbial exposure.
A 4-Gene Signature Associated with Clinical Outcome in High-Grade Gliomas
Authors: Marie de Tayrac, Marc Aubry, Stephan Saïkali, Amandine Etcheverry, Cyrille Surbled, Frédérique Guénot, Marie-Dominique Galibert, Abderrahmane Hamlat, Thierry Lesimple, Véronique Quillien, Philippe Menei, Jean Mosser
Journal: Clinical Cancer Research (2011)

Gene expression studies provide molecular insights improving the classification of patients with high-grade gliomas. We have developed a risk estimation strategy based on a combined analysis of gene expression data to search for robust biomarkers associated with outcome in these tumors.We performed a meta-analysis using 3 publicly available malignant gliomas microarray data sets (267 patients) to define the genes related to both glioma malignancy and patient outcome. These biomarkers were used to construct a risk-score equation based on a Cox proportional hazards model on a subset of 144 patients. External validations were performed on microarray data (59 patients) and on RT-qPCR data (194 patients). The risk-score model performances (discrimination and calibration) were evaluated and compared with that of clinical risk factors, MGMT promoter methylation status, and IDH1 mutational status.This interstudy cross-validation approach allowed the identification of a 4-gene signature highly correlated to survival (CHAF1B, PDLIM4, EDNRB, and HJURP), from which an optimal survival model was built (P < 0.001 in training and validation sets). Multivariate analysis showed that the 4-gene risk score was strongly and independently associated with survival (hazard ratio = 0.46; 95% CI, 0.26-0.81; P = 0.007). Performance estimations indicated that this score added beyond standard clinical parameters and beyond both the MGMT methylation status and the IDH1 mutational status in terms of discrimination (C statistics, 0.827 versus 0.835; P < 0.001).The 4-gene signature provides an independent risk score strongly associated with outcome of patients with high-grade gliomas.
Management of Disseminated Nonseminomatous Germ Cell Tumors With Risk-Based Chemotherapy Followed by Response-Guided Postchemotherapy Surgery
Authors: Christian Kollmannsberger, Siamak Daneshmand, Alan So, Kim N. Chi, Nevin Murray, Christie Moore, Brandon Hayes-Lattin, Craig Nichols
Journal: Journal of Clinical Oncology (2009)

The management of patients with a radiographic complete response after chemotherapy remains controversial. The current study assesses the outcome for a modern, unselected patient population with disseminated testicular cancer with particular emphasis on those achieving a radiographic complete remission to combination chemotherapy.All patients with disseminated nonseminoma seen between 1999 and 2007 at the British Columbia Cancer Agency (BCCA) as well as through the Oregon Testis Cancer Program were retrospectively reviewed. A total of 276 patients treated with combination chemotherapy were identified. A radiographic complete remission (CR) was defined as disappearance of all metastatic lesions or minimal residual tissue <or= 1 cm.One hundred sixty-one patients achieved a CR. Results for the total population and CR subset were as follows: International Germ Cell Cancer Consensus Group stage good/intermediate/poor 84%/5%/11% (CR subset, 94%/3%/3%), presence of teratoma in the primary tumor 40% (CR subset, 55%), relapses 13%, death from disease 3% (CR subset, 6% and 0%, respectively). Two of the total 10 relapses in the CR group occurred beyond 2 years. Eight of the 10 relapses in the CR group were treated surgically for teratoma alone, whereas two required salvage chemotherapy. Disease-specific survival for the CR group was 100% after a median follow-up of 52 months (range, 3 to 135 months).Modern risk-adapted systemic chemotherapy with or without surgery for current populations of patients with disseminated testicular nonseminoma results in superb outcomes. Patients with disseminated germ cell tumors who obtain a complete serologic remission and no or minimal radiographic residual can be safely observed without adjunctive regional surgery.
ROCK1 and ROCK2 Are Required for Non-Small Cell Lung Cancer Anchorage-Independent Growth and Invasion
Authors: Dominico Vigil, Tai Young Kim, Ana Plachco, Andrew J. Garton, Linda Castaldo, Jonathan A. Pachter, Hanqing Dong, Xin Chen, Brianna Tokar, Sharon L. Campbell, Channing J. Der
Journal: Cancer Research (2012)

Abstract Evidence is emerging that the closely related ROCK1 and ROCK2 serine/threonine kinases support the invasive and metastatic growth of a spectrum of human cancer types. Therefore, inhibitors of ROCK are under preclinical development. However, a key step in their development involves the identification of genetic biomarkers that will predict ROCK inhibitor antitumor activity. One identified mechanism for ROCK activation in cancer involves the loss of function of the DLC1 tumor suppressor gene, which encodes a GTPase activating protein (RhoGAP) for the RhoA and RhoC small GTPases. DLC-1 loss may lead to hyperactivation of RhoA/C and its downstream effectors, the ROCK kinases. We therefore determined whether loss of DLC-1 protein expression identifies non-small cell lung carcinoma (NSCLC) cell lines whose growth and invasion phenotypes are sensitive to ROCK inhibition. We identified and characterized a novel small molecule pharmacologic inhibitor of ROCK and additionally applied genetic approaches to impair ROCK1 and/or ROCK2 activity, and we determined that although NSCLC anchorage-dependent growth was ROCK-independent, both anchorage-independent growth and Matrigel invasion were ROCK-dependent. However, loss of DLC-1 expression did not correlate with ROCK activation or with OXA-06 sensitivity. Unexpectedly, suppression of ROCK1 or ROCK2 expression alone was sufficient to impair anchorage-independent growth, supporting their nonoverlapping roles in oncogenesis. Mechanistically, the block in anchorage-independent growth was associated with accumulation of cells in the G0–G1 phase of the cell cycle, but not increased anoikis. We conclude that ROCK may be a useful therapeutic target for NSCLC. Cancer Res; 72(20); 5338–47. ©2012 AACR.
<i>POLE</i> Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer
Authors: Inge C. van Gool, Florine A. Eggink, Luke Freeman-Mills, Ellen Stelloo, Emanuele Marchi, Marco de Bruyn, Claire Palles, Remi A. Nout, Cor D. de Kroon, Elisabeth M. Osse, Paul Klenerman, Carien L. Creutzberg, Ian P.M. Tomlinson, Vincent T.H.B.M. Smit, Hans W. Nijman, Tjalling Bosse, David N. Church
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity. Experimental Design: We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers. Results: Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8+ tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings. Conclusions: Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers. Clin Cancer Res; 21(14); 3347–55. ©2015 AACR.
Enzymatic degradation of uric acid by uricase-loaded human erythrocytes.
Authors: G Ihler, A Lantzy, J Purpura, R H Glew
Journal: Journal of Clinical Investigation (1975)

Erythrocytes containing pig liver uricase have been prepared by hypotonic hemolysis in the presence of the enzyme. Uricase is shown to be active within the erythrocytes and to degrade uric acid as rapidly as it enters the cells when high intracellular enzyme concentrations are employed. The kinetics and characteristics of uric acid entry are shown to be the same for hemolysed and normal erythrocytes. At physiological concentrations of uric acid, loaded erythrocytes can degrade a maximum of about 21 mumol uric acid/liter erythrocytes per min. The possible application of enzyme-loaded erythrocytes to medicine is discussed.
Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease
Authors: Koji Tamada, Hideto Tamura, Dallas Flies, Yang-Xin Fu, Esteban Celis, Larry R. Pease, Bruce R. Blazar, Lieping Chen
Journal: Journal of Clinical Investigation (2002)

Previous studies have shown that blockade of LIGHT, a T cell costimulatory molecule belonging to the TNF superfamily, by soluble lymphotoxin β receptor–Ig (LTβR-Ig) inhibits the cytotoxic T lymphocyte (CTL) response to host antigenic disparities and ameliorates lethal graft-versus-host disease (GVHD) in a B6 to BDF1 mouse model. Here, we demonstrate that infusion of an mAb against CD40 ligand (CD40L) further increases the efficacy of LTβR-Ig, leading to complete prevention of GVHD. We further demonstrate that alloantigen-specific CTLs become anergic upon rapid expansion, and persist in the tolerized mice as a result of costimulatory blockade. Transfer of anergic CTLs to secondary F1 mice fails to induce GVHD despite the fact that anergic CTLs can be stimulated to proliferate in vitro by antigens and cytokines. Our study provides a potential new approach for the prevention of lethal GVHD.