tbuckley/cabot-search huggingface dataset:
Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure
Authors: Maria D’Apolito, Xueliang Du, Haihong Zong, Alessandra Catucci, Luigi Maiuri, Tiziana Trivisano, Massimo Pettoello-Mantovani, Angelo Campanozzi, Valeria Raia, Jeffrey E. Pessin, Michael Brownlee, Ida Giardino
Journal: Journal of Clinical Investigation (2009)

Although supraphysiological concentrations of urea are known to increase oxidative stress in cultured cells, it is generally thought that the elevated levels of urea in chronic renal failure patients have negligible toxicity. We previously demonstrated that ROS increase intracellular protein modification by O-linked β-N-acetylglucosamine (O-GlcNAc), and others showed that increased modification of insulin signaling molecules by O-GlcNAc reduces insulin signal transduction. Because both oxidative stress and insulin resistance have been observed in patients with end-stage renal disease, we sought to determine the role of urea in these phenotypes. Treatment of 3T3-L1 adipocytes with urea at disease-relevant concentrations induced ROS production, caused insulin resistance, increased expression of adipokines retinol binding protein 4 (RBP4) and resistin, and increased O-GlcNAc–modified insulin signaling molecules. Investigation of a mouse model of surgically induced renal failure (uremic mice) revealed increased ROS production, modification of insulin signaling molecules by O-GlcNAc, and increased expression of RBP4 and resistin in visceral adipose tissue. Uremic mice also displayed insulin resistance and glucose intolerance, and treatment with an antioxidant SOD/catalase mimetic normalized these defects. The SOD/catalase mimetic treatment also prevented the development of insulin resistance in normal mice after urea infusion. These data suggest that therapeutic targeting of urea-induced ROS may help reduce the high morbidity and mortality caused by end-stage renal disease.
System B0,+ amino acid transport regulates the penetration stage of blastocyst implantation with possible long-term developmental consequences through adulthood
Authors: Lon J. Van Winkle, Julia K. Tesch, Anita Shah, Allan L. Campione
Journal: Human Reproduction Update (2005)

Amino acid transport system B0,+ was first characterized in detail in mouse blastocysts over two decades ago. Since then, this system has been shown to be involved in a wide array of developmental processes from blastocyst implantation in the uterus to adult obesity. Leucine uptake through system B0,+ in blastocysts triggers mammalian target of rapamycin (mTOR) signalling. This signalling pathway selectively regulates development of trophoblast motility and the onset of the penetration stage of blastocyst implantation about 20 h later. Meanwhile, system B0,+ becomes inactive in blastocysts a few hours before implantation in vivo. System B0,+ can, however, be activated in preimplantation blastocysts by physical stimuli. The onset of trophoblast motility should provide the physiological physical stimulus activating system B0,+ in blastocysts in vivo. Activation of system B0,+ when trophoblast cells begin to penetrate the uterine epithelium would cause it to accumulate its preferred substrates, which include tryptophan, from uterine secretions. A low tryptophan concentration in external secretions next to trophoblast cells inhibits T-cell proliferation and rejection of the conceptus. Suboptimal system B0,+ regulation of these developmental processes likely influences placentation and subsequent embryo nutrition, birth weight and risk of developing metabolic syndrome and obesity.
Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial
Authors: Yukito Shinohara, Yasuo Katayama, Shinichiro Uchiyama, Takenori Yamaguchi, Shunnosuke Handa, Kempei Matsuoka, Yasuo Ohashi, Norio Tanahashi, Hiroko Yamamoto, Chokoh Genka, Yasuhisa Kitagawa, Hideo Kusuoka, Katsuya Nishimaru, Motoo Tsushima, Yukihiro Koretsune, Tohru Sawada, Chikuma Hamada
Journal: The Lancet Neurology (2010)
Vascular COX-2 Modulates Blood Pressure and Thrombosis in Mice
Authors: Ying Yu, Emanuela Ricciotti, Rosario Scalia, Soon Yew Tang, Gregory Grant, Zhou Yu, Gavin Landesberg, Irene Crichton, Weichen Wu, Ellen Puré, Colin D. Funk, Garret A. FitzGerald
Journal: Science Translational Medicine (2012)

Deletion of vascular COX-2 predisposes mice to thrombosis and hypertension.
Longitudinal noninvasive PET-based cell mass estimates in a spontaneous diabetes rat model
Authors: Fabiola Souza, Norman Simpson, Anthony Raffo, Chitra Saxena, Antonella Maffei, Mark Hardy, Michael Kilbourn, Robin Goland, Rudolph Leibel, J. John Mann, Ronald Van Heertum, Paul E. Harris
Journal: Journal of Clinical Investigation (2006)

Diabetes results from an absolute or relative reduction in pancreatic beta cell mass (BCM) leading to insufficient insulin secretion and hyperglycemia. Measurement of insulin secretory capacity is currently used as a surrogate measure of BCM. However, serum insulin concentrations provide an imprecise index of BCM, and no reliable noninvasive measure of BCM is currently available. Type 2 vesicular monoamine transporters (VMAT2) are expressed in human islet beta cells, as well as in tissues of the CNS. [11C]Dihydrotetrabenazine ([11C]DTBZ) binds specifically to VMAT2 and is a radioligand currently used in clinical imaging of the brain. Here we report the use of [11C]DTBZ to estimate BCM in a rodent model of spontaneous type 1 diabetes (the BB-DP rat). In longitudinal PET studies of the BB-DP rat, we found a significant decline in pancreatic uptake of [11C]DTBZ that anticipated the loss of glycemic control. Based on comparison of standardized uptake values (SUVs) of [11C]DTBZ and blood glucose concentrations, loss of more than 65% of the original SUV correlated significantly with the development of persistent hyperglycemia. These studies suggest that PET-based quantitation of VMAT2 receptors provides a noninvasive measurement of BCM that could be used to study the pathogenesis of diabetes and to monitor therapeutic interventions.
Which patients stop working because of rheumatoid arthritis? Results of five years' follow up in 732 patients from the Early RA Study (ERAS)
Authors: A Young
Journal: Annals of the Rheumatic Diseases (2002)

Objectives: To assess the occurrence and prognostic factors for the ability to maintain paid work in patients with rheumatoid arthritis (RA). Setting: Inception cohort of patients with RA recruited from rheumatology departments in nine NHS Hospital Trusts in England. Patients: All consecutive patients with RA of less than two years9 duration, before any second line (disease modifying) drug treatment, and followed up for five years. Methods: Clinical, laboratory, and radiological assessments, and all treatments were recorded prospectively using a standardised format at presentation and yearly. Outcome measures: Changes in, and loss of paid work by five years9 follow up. Results: 732 patients completed the five year follow up. 353/721 (49%) were gainfully employed at the onset of RA, 211 (60%) were still working at five years, 104 (29%) stopped because of the disease, and 31 (9%) retired for reasons other than RA. Work disability at five years was more likely in manual workers (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.4 to 3.8) and worse baseline Health Assessment Questionnaire (HAQ&gt;1.5, OR 2.26, 95% CI 1.38 to 3.7). In combination with other baseline variables (erythrocyte sedimentation rate, sex, age of onset, and radiological erosions), employment outcome was predicted in 78% using multivariate analysis. Conclusions: Nearly half of the patients with RA were in paid employment at onset, work disability was an adverse outcome for a third of these patients by five years, and manual work and high baseline HAQ were important predictors for this. These details are likely to be useful to clinicians, health professionals, and patients in order to plan medical, orthopaedic, and remedial treatments in early RA. Future disease modifying treatments could be compared with this cohort of patients who were treated with conventional second line drugs.
Human Neural Stem Cells Target Experimental Intracranial Medulloblastoma and Deliver a Therapeutic Gene Leading to Tumor Regression
Authors: Seung-Ki Kim, Seung U. Kim, In Ho Park, Jung Hee Bang, Karen S. Aboody, Kyu-Chang Wang, Byung-Kyu Cho, Manho Kim, Lata G. Menon, Peter M. Black, Rona S. Carroll
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Medulloblastoma, a malignant pediatric brain tumor, is incurable in about one third of patients despite multimodal treatments. In addition, current therapies can lead to long-term disabilities. Based on studies of the extensive tropism of neural stem cells (NSC) toward malignant gliomas and the secretion of growth factors common to glioma and medulloblastoma, we hypothesized that NSCs could target medulloblastoma and be used as a cellular therapeutic delivery system. Experimental Design: The migratory ability of HB1.F3 cells (an immortalized, clonal human NSC line) to medulloblastoma was studied both in vitro and in vivo. As proof-of-concept, we used HB1.F3 cells engineered to secrete the prodrug activating enzyme cytosine deaminase. We investigated the potential of human NSCs to deliver a therapeutic gene and reduce tumor growth. Results: The migratory capacity of HB1.F3 cells was confirmed by an in vitro migration assay, and corroborated in vivo by injecting chloromethylbenzamido-Dil–labeled HB1.F3 cells into the hemisphere contralateral to established medulloblastoma in nude mice. In vitro studies showed the therapeutic efficacy of HB1.F3-CD on Daoy cells in coculture experiments. In vitro therapeutic studies were conducted in which animals bearing intracranial medulloblastoma were injected ipsilaterally with HB1.F3-CD cells followed by systemic 5-flourocytosine treatment. Histologic analyses showed that human NSCs migrate to the tumor bed and its boundary, resulting in a 76% reduction of tumor volume in the treatment group (P &amp;lt; 0.01). Conclusion: These studies show for the first time the potential of human NSCs as an effective delivery system to target and disseminate therapeutic agents to medulloblastoma.
IMPAIRMENT OF VASOMOTOR FUNCTION OF CONDUIT BUT NOT RESISTANCE ARTERIES AFTER LONG-TERM FEMORAL ARTERY OCCLUSION
Authors: Jin-Shen Li, Lakshmana K. Pendyala, Xinhua Yin, Jianing Yue, Jack P. Chen, Nicolas Chronos, Dongming Hou
Journal: Journal of the American College of Cardiology (2010)
Intrinsic bioactivity of thyrotropin in human serum is inversely correlated with thyroid hormone concentrations. Application of a new bioassay using the FRTL-5 rat thyroid cell strain.
Authors: P A Dahlberg, P A Petrick, M Nissim, M M Menezes-Ferreira, B D Weintraub
Journal: Journal of Clinical Investigation (1987)

We have developed a new bioassay for thyrotropin (TSH) in human serum to evaluate bioactivity in normal individuals and patients with different degrees of primary hypothyroidism. Unpurified TSH in serum showed no stimulation of cyclic AMP production in cultured FRTL-5 rat thyroid cells, but after immunopurification showed potent stimulatory activity. Immunoaffinity purification permitted up to 400-fold concentration of serum TSH, allowing bioactivity measurements even in certain normal sera. The limit of detection in the FRTL-5 bioassay was 10 microU of human TSH per 0.5 ml incubate, and half-maximal responses for standard human TSH was 102 +/- 26 (+/- SE) microU/0.5 ml. Immunoaffinity-purified serum TSH varied in bioactivity-to-immunoactivity (B/I) ratios from less than 0.25 to 1.21 among four euthyroid subjects and eight primary hypothyroid patients. An inverse correlation was found between B/I ratios of immunopurified basal TSH and the serum-free T4 (r = -0.7237, P less than 0.01), T4 (r = -0.6650, P less than 0.05), and T3 (r = -0.6382, P less than 0.05). B/I ratios of immunopurified TSH from three hypothyroid patients before and after acute stimulation by thyrotropin-releasing hormone showed no significant change, despite major changes in serum TSH. In summary, the present study shows an inverse relationship between the metabolic status of an individual and the intrinsic bioactivity of TSH.
Dasatinib Plus Nutlin-3 Shows Synergistic Antileukemic Activity in Both p53wild-type and p53mutated B Chronic Lymphocytic Leukemias by Inhibiting the Akt Pathway
Authors: Giorgio Zauli, Rebecca Voltan, Raffaella Bosco, Elisabetta Melloni, Sandra Marmiroli, Gian Matteo Rigolin, Antonio Cuneo, Paola Secchiero
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To analyze the effect of the combination of Dasatinib, a multikinase inhibitor, plus Nutlin-3, a nongenotoxic activator of the p53 pathway, in primary B chronic lymphocytic leukemia (B-CLL) patient samples and B leukemic cell line models. Experimental Design: The induction of cytotoxicity was evaluated in both primary B-CLL cell samples (n = 20) and in p53wild-type (EHEB, JVM-2) and p53deleted/mutated (MEC-2, BJAB) B leukemic cell lines. The role of Akt in modulating leukemic cell survival/apoptosis in response to Dasatinib or Dasatinib + Nutlin-3 was documented by functional experiments carried out using specific pharmacological inhibitors and by overexpression of membrane-targeted constitutively active form of Akt. Results: The combination of Dasatinib + Nutlin-3 exhibited a synergistic cytotoxicity in the majority (19 out of 20) of B-CLL samples, including patients carrying 17p- (n = 4), and in both p53wild-type and p53deleted/mutated B leukemic cell lines. At the molecular level, Dasatinib significantly counteracted the Nutlin-3-mediated induction of the p53 transcriptional targets MDM2 and p21 observed in p53wild-type leukemic cells. Conversely, Nutlin-3 did not interfere with the ability of Dasatinib to decrease the phosphorylation levels of ERK1/2, p38/MAPK, and Akt in both p53wild-type and p53deleted/mutated B leukemic cell lines. A critical role of Akt downregulation in mediating the antileukemic activity of Dasatinib and Dasatinib + Nutlin-3 was demonstrated in experiments carried out by specifically modulating the Akt pathway. Conclusions: These findings suggest that Dasatinib + Nutlin-3 might represent an innovative therapeutic combination for both p53wild-type and p53deleted/mutated B-CLL. Clin Cancer Res; 17(4); 1–9. ©2010 AACR.
Combined Deficiency of p50 and cRel in CD4+ T Cells Reveals an Essential Requirement for Nuclear Factor κB in Regulating Mature T Cell Survival and In Vivo Function
Authors: Ye Zheng, Monika Vig, Jesse Lyons, Luk Van Parijs, Amer A. Beg
Journal: The Journal of Experimental Medicine (2003)

Signaling pathways involved in regulating T cell proliferation and survival are not well understood. Here we have investigated a possible role of the nuclear factor (NF)-κB pathway in regulating mature T cell function by using CD4+ T cells from p50−/− cRel−/− mice, which exhibit virtually no inducible κB site binding activity. Studies with these mice indicate an essential role of T cell receptor (TCR)-induced NF-κB in regulating interleukin (IL)-2 expression, cell cycle entry, and survival of T cells. Our results further indicate that NF-κB regulates TCR-induced expression of antiapoptotic Bcl-2 family members. Strikingly, retroviral transduction of CD4+ T cells with the NF-κB–inducing IκB kinase β showed that NF-κB activation is not only necessary but also sufficient for T cell survival. In contrast, our results indicate a lack of involvement of NF-κB in both IL-2 and Akt-induced survival pathways. In vivo, p50−/− cRel−/− mice showed impaired superantigen-induced T cell responses as well as decreased numbers of effector/memory and regulatory CD4+ T cells. These findings provide the first demonstration of a role for NF-κB proteins in regulating T cell function in vivo and establish a critically important function of NF-κB in TCR-induced regulation of survival.
The Hemoglobin Glycation Index Identifies Subpopulations With Harms or Benefits From Intensive Treatment in the ACCORD Trial
Authors: James M. Hempe, Shuqian Liu, Leann Myers, Robert J. McCarter, John B. Buse, Vivian Fonseca
Journal: Diabetes Care (2015)

OBJECTIVE This study tested the hypothesis that intensive treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial disproportionately produced adverse outcomes in patients with diabetes with a high hemoglobin glycation index (HGI = observed HbA1c − predicted HbA1c). RESEARCH DESIGN AND METHODS ACCORD was a randomized controlled trial of 10,251 patients with type 2 diabetes assigned to standard or intensive treatment with HbA1c goals of 7.0% to 7.9% (53 to 63 mmol/mol) and less than 6% (42 mmol/mol), respectively. In this ancillary study, a linear regression equation (HbA1c = 0.009 × fasting plasma glucose [FPG] [mg/dL] + 6.8) was derived from 1,000 randomly extracted participants at baseline. Baseline FPG values were used to calculate predicted HbA1c and HGI for the remaining 9,125 participants. Kaplan-Meier and Cox regression were used to assess the effects of intensive treatment on outcomes in patients with a low, moderate, or high HGI. RESULTS Intensive treatment was associated with improved primary outcomes (composite of cardiovascular events) in the low (hazard ratio [HR] 0.75 [95% CI 0.59–0.95]) and moderate (HR 0.77 [95% CI 0.61–0.97]) HGI subgroups but not in the high HGI subgroup (HR 1.14 [95% CI 0.93–1.40]). Higher total mortality in intensively treated patients was confined to the high HGI subgroup (HR 1.41 [95% CI 1.10–1.80]). A high HGI was associated with a greater risk for hypoglycemia in the standard and intensive treatment groups. CONCLUSIONS HGI calculated at baseline identified subpopulations in ACCORD with harms or benefits from intensive glycemic control. HbA1c is not a one-size-fits-all indicator of blood glucose control, and taking this into account when making management decisions could improve diabetes care.
Renal haemodynamic characteristics in patients with lupus nephritis
Authors: M. Nakano, M. Ueno, H. Hasegawa, T. Watanabe, T. Kuroda, S. Ito, M. Arakawa
Journal: Annals of the Rheumatic Diseases (1998)

To clarify the characteristics of renal haemodynamics in patients with lupus nephritis (LN).The glomerular filtration rate (GFR) and renal plasma flow (RPF) of 37 patients with active LN were studied longitudinally over an interval of 8 to 144 weeks during treatment with corticosteroids or cytotoxic drugs, or both. All patients had clinical renal disorders and underwent renal biopsies.Analysis of renal biopsy specimens showed that 31 patients had class IV LN. Class II, III, and VLN were present in two patients each. The average GFR increased significantly from 65.4 (SD 33.0) in the pretreatment stage to 86.6 (31.6) ml/min in the post-treatment stage, accompanied by an improvement in urinary or immunological abnormalities, or both. On the other hand, RPF decreased significantly from 625.2 (243.0) to 519.8 (179.0) ml/min. Therefore, the filtration fraction (FF) increased significantly from 10.7 (4.3)% to 16.8 (3.7)%. Low FF was recognised predominantly in patients with class IV LN, but was also observed in patients with other classes. The FF returned towards normal irrespective of the degree of GFR recovery. No significant changes were observed in the levels of blood pressure.A reduction in GFR out of proportion to the reduction in RPF as demonstrated by the low FF values was related to the severity of LN or disease activity, or both. Therefore, relative evaluation of GFR and RPF, namely the determination of FF, may be a useful clinical parameter to determine the status of LN.
Inadequate reporting of research ethics review and informed consent in cluster randomised trials: review of random sample of published trials
Authors: M. Taljaard, A. D. McRae, C. Weijer, C. Bennett, S. Dixon, J. Taleban, Z. Skea, M. P. Eccles, J. C. Brehaut, A. Donner, R. Saginur, R. F. Boruch, J. M. Grimshaw
Journal: BMJ (2011)

<b>Objectives</b> To investigate the extent to which authors of cluster randomised trials adhered to two basic requirements of the World Medical Association's Declaration of Helsinki and the International Committee of Medical Journal Editors' uniform requirements for manuscripts (namely, reporting of research ethics review and informed consent), to determine whether the adequacy of reporting has improved over time, and to identify characteristics of cluster randomised trials associated with reporting of ethics practices. <b>Design</b> Review of a random sample of published cluster randomised trials from an electronic search in Medline. <b>Setting</b> Cluster randomised trials in health research published in English language journals from 2000 to 2008. <b>Study sample</b> 300 cluster randomised trials published in 150 journals. <b>Results</b> 77 (26%, 95% confidence interval 21% to 31%) trials failed to report ethics review. The proportion reporting ethics review increased significantly over time (P&lt;0.001). Trials with data collection interventions at the individual level were more likely to report ethics review than were trials that used routine data sources only (79% (n=151) <i>v</i> 55% (23); P=0.008). Trials that accounted for clustering in the design and analysis were more likely to report ethics review. The median impact factor of the journal of publication was higher for trials that reported ethics review (3.4 <i>v</i> 2.3; P&lt;0.001). 93 (31%, 26% to 36%) trials failed to report consent. Reporting of consent increased significantly over time (P&lt;0.001). Trials with interventions targeting participants at the individual level were more likely to report consent than were trials with interventions targeting the cluster level (87% (90) <i>v</i> 48% (41); P&lt;0.001). Trials with data collection interventions at the individual level were more likely to report consent than were those that used routine data sources only (78% (146) <i>v</i> 29% (11); P&lt;0.001). <b>Conclusions</b> Reporting of research ethics protections in cluster randomised trials is inadequate. In addition to research ethics approval, authors should report whether informed consent was sought, from whom consent was sought, and what consent was for.
Mining yeast in silico unearths a golden nugget for mitochondrial biology
Authors: R. L. Nussbaum
Journal: Journal of Clinical Investigation (2005)

NADH:ubiquinone oxidoreductase (complex I) of the electron transport chain is a multimeric mitochondrial enzyme of approximately 1000 kDa consisting of 46 different proteins encoded by both the mitochondrial and nuclear genomes. Little is known about the cellular mechanisms and protein chaperones that guide its assembly. In this issue of the JCI, Ogilvie et al. use genomic sequence data to compare the proteins produced by yeasts with and without complex I in order to generate a list of proteins whose human orthologs might serve as complex I assembly proteins. The gene encoding one of these candidate proteins, B17.2L, was found to harbor a nonsense mutation in one of 28 patients with a deficiency of complex I. B17.2L associated with subcomplexes that are seen when complex I assembly is incomplete. The research described here combines clever model organism genomics and bioinformatics with sophisticated human molecular and biochemical genetics to identify the first mammalian protein required for the normal assembly of complex I.