tbuckley/cabot-search huggingface dataset:
Abstract 5452: Inhibition of sodium-independent and sodium-dependent nucleobase transport activities by tyrosine kinase inhibitors
Authors: Vijaya L. Damaraju, Michelle Kuzma, Carol E. Cass, Michael B. Sawyer
Journal: Cancer Research (2015)

Abstract Inhibition of nucleobase transport activities by tyrosine kinase inhibitors (TKIs) has not been studied to date. Since many targeted TKIs are often combined with either capecitabine or 5-fluorouracil (5-FU) in treatment of various advanced cancers, we examined TKI effects on both equilibrative nucleobase transport (ENBT) and sodium-dependent nucleobase transport (SNBT) activities. Our goal was to study effects of TKIs on human ENBT and SNBT activities to explore potential TKI interactions with nucleobase chemotherapy drugs. Effects of TKIs on ENBT activities were investigated in normal human renal proximal tubule epithelial cells (hRPTECs). TKI effects on SNBT activities were assessed in a pig kidney cell line (LLC-PK1). We showed that TKIs inhibited both ENBT and SNBT activities to different extents. Gefitinib inhibited ENBT activity with an IC50 value of 0.7 μM thus indicating high sensitivity of ENBT to inhibition by gefitinib in hRPTECs. Erlotinib &amp;gt; sorafenib &amp;gt; imatinib &amp;gt; sunitinib inhibited ENBT with IC50 values of 15, 40, 60, 78 μM, respectively whereas dasatinib, lapatinib and vandetanib were not inhibitory at concentrations &amp;gt;100 μM. Similar studies in LLC-PK1 cells, which exhibit SNBT activity, showed that vandetanib was the most potent inhibitor followed by sorafenib &amp;gt; erlotinib &amp;gt; gefitinib &amp;gt; sunitinib &amp;gt; imatinib with IC50 values of 14, 25, 28, 40, 47 and 94 μM, respectively whereas dasatinib and lapatinib were not inhibitory at concentrations &amp;gt;100 μM. These results indicate inhibition of both ENBT and SNBT activities by exposure of cells to TKIs. These effects on nucleobase transport activities, which could be direct or indirect, suggest why regimens combining gefitinib and 5-FU have failed. Further studies should test all TKI classes for such inhibitory activities to assess potential effects on combination regimens using TKIs with nucleobase drugs such as 5-FU in cancer treatment. Citation Format: Vijaya L. Damaraju, Michelle Kuzma, Carol E. Cass, Michael B. Sawyer. Inhibition of sodium-independent and sodium-dependent nucleobase transport activities by tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5452. doi:10.1158/1538-7445.AM2015-5452
Phase I/II study of Bortezomib Alone and Bortezomib with Dose-Adjusted EPOCH Chemotherapy in Relapsed or Refractory Aggressive B-Cell Lymphoma.
Authors: Kieron Dunleavy, John Janik, Juan Gea-Banacloche, Margaret Shovlin, Therese White, Neta Goldschmidt, Nicole Grant, Omer Koc, Stefania Pittaluga, Elaine Jaffe, Louis Staudt, Wyndham H. Wilson
Journal: Blood (2004)
Abstract 251: Circulating Mir-21, -378, and -940 Increase in Response to an Acute Exhaustive Exercise in Patients With Chronic Heart Failure
Authors: Tianzhao Xu, Qiulian Zhou, Lin Che, Guanghe Li, Junjie Xiao
Journal: Circulation Research (2015)

Background: Exercise training is recommended as a useful intervention in cardiac rehabilitation for patients with chronic heart failure. There has been emerging evidence indicating that circulating microRNA (miRNA, miR) could mediate the beneficial effects of exercise in both healthy persons and patients with cardiovascular diseases. The current study was aimed to investigate the regulation of circulating miRNAs in response to an acute exhaustive exercise in patients with chronic heart failure (CHF). Methods: Twenty-eight CHF patients (mean age=59.07±1.79 years, 14 in NYHA Class II and 14 in NYHA Class III) performed a symptom-limited incremental cardiopulmonary exercise test on a bicycle ergometer according to a standardized exercise protocol of revised Ramp10 programs (acute exercise). Serum samples were collected before and immediately after exercise session. The cardiac or muscle specific/enriched miRNAs including miR-1, miR-133a, miR-133b, miR-499, miR-208a, miR-208b, miR-378, miR-486, and miR-940 were determined. In addition, other miRNAs involved in angiogenesis (miR-20a, miR-328, miR-126, miR-221), inflammation (miR-21, miR-146a, miR-155), and ischemia adaptation (miR-210, miR-21, miR-146a) were also investigated. Moreover, inflammatory and muscle damage markers including creatine kinase (CK), creatine kinase MB isoenzyme (CK-MB), troponin T (Tn-T), N-terminal pro-brain natriuretic peptide (NT-ProBNP) and high sensitive C reactive protein (hs-CRP) were determined by enzyme linked immunosorbent assays (ELISA). Results: Serum miR-21, -378, and -940 were found to be significantly increased in response to acute exercise in CHF patients. In addition, no robust correlation was identified between changes of these miRNAs and muscle damage or inflammation, indicating a distinct adaptation by miRNAs. However, a linear correlation between the change of miR-21 and VO2max was observed (R=0.42, P=0.03). Conclusion: Our data suggest that circulating miR-21, miR-378, and miR-940 might be potential biomarkers for the improvement of exercise capacity in patients with chronic heart failure.
Physical activity, airway resistance and small airway dysfunction in severe asthma
Authors: Thomas Bahmer, Benjamin Waschki, Fee Schatz, Christian Herzmann, Peter Zabel, Anne-Marie Kirsten, Klaus F. Rabe, Henrik Watz
Journal: European Respiratory Journal (2016)

Asthma is a chronic airway disease with a heterogeneous clinical presentation [1], and a subset of ∼5–10% of patients suffer from severe disease [2]. Chronic obstructive pulmonary disease (COPD) is different from asthma with respect to underlying pathobiology but shares some clinical features with severe asthma, for instance fixed airway obstruction and small airway dysfunction [3, 4]. In COPD, the consequences of the disease for physical activity in daily life have been studied intensively [5–7]; in contrast, only few data are available on patients with asthma [8]. Measurements of physical activity in adult patients with stable asthma of different severity grades are lacking, and associations with airway physiology have not been evaluated. Physical activity is reduced in severe asthma; impulse oscillometry was a better predictor than spirometry <http://ow.ly/6WdN305D9aV> We thank Regine Wieland, Petra Hundack-Winter, Margret Gleiniger, Zaklina Hinz, Susann Prange, Corinna Derwort (LungClinic Grosshansdorf, Grosshansdorf, Germany), Christine Ballhausen, Johanna Döhling, Andrea Glaewe, Edda Horst, Lenka Krabbe, Birgit Kullmann, Monika Rennhack and Eva Wittmer (Research Center Borstel, Borstel, Germany) for their excellent support in study logistics. The members of the ERA Study Group are as follows: Thomas Bahmer, Benjamin Waschki and Klaus F. Rabe (LungClinic Grosshansdorf, Pulmonology, Grosshansdorf, Germany), Anne-Marie Kirsten, Frauke Pedersen and Henrik Watz (Pulmonary Research Institute at LungClinic Grosshansdorf), Christian Herzmann and Annika Opitz (Center for Clinical Studies, Research Center Borstel, Borstel, Germany), Peter Zabel (Medical Clinic, Research Center Borstel) and Karoline I. Gaede (Biobank, Research Center Borstel). The authors' contributions are as follows. Conception and design of the study: T. Bahmer, B. Waschki, P. Zabel, A-M. Kirsten, K.F. Rabe, H. Watz; acquisition, analysis and interpretation: T. Bahmer, B. Waschki, F. Schatz, C. Herzmann, A-M. Kirsten, H. Watz; drafting the manuscript: T. Bahmer, B. Waschki, F. Schatz, H. Watz; critically revising the manuscript: C. Herzmann, P. Zabel, A-M. Kirsten, K.F. Rabe. All authors read and approved the final version of the manuscript.
Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Authors: Anne Blanchard, Detlef Bockenhauer, Davide Bolignano, Lorenzo A. Calò, Etienne Cosyns, Olivier Devuyst, David H. Ellison, Fiona E. Karet Frankl, Nine V.A.M. Knoers, Martin Konrad, Shih-Hua Lin, Rosa Vargas-Poussou
Journal: Kidney International (2016)

Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.
Natriuretic Peptides, 6-Min Walk Test, and Quality-of-Life Questionnaires as Clinically Meaningful Endpoints in HF Trials
Authors: João Pedro Ferreira, Kevin Duarte, Todd L. Graves, Michael R. Zile, William T. Abraham, Fred A. Weaver, JoAnn Lindenfeld, Faiez Zannad
Journal: Journal of the American College of Cardiology (2016)
High Dose Therapy and Autologous Stem Cell Transplantation Still Improves Progression Free Survival in First Relapse for DLBCL in the Rituximab Era: A Study Using Patients as Their Own Controls.
Authors: Anna Sureda, Carme Canals, Nicolas Mounier, Roberto Foa, Eulogio Conde, Johan Maertens, Alessandro Rambaldi, Tamas Masszi, Charles Crawley, Gordon Cook, Michel Attal, Michael Pfreundschuh, Jean-Luc Harousseau, Christian Gisselbrecht
Journal: Blood (2008)
Outcome of Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) for Philadelphia Chromosome Acute Lymphoblastic Leukemia (Ph+ALL) in First Complete Remission (CR1) At the Era of Tyrosine Kinase Inhibitors (TKI): A Survey From the Acute Leukemia Working Party (ALWP) of EBMT,
Authors: Eolia Brissot, Myriam Labopin, Gérard Socié, Liisa Volin, Alessandro Rambaldi, Dietrich Beelen, Nicolaus Kroeger, Stig Lenhoff, Jurgen Finke, Jordi Esteve, Mohamad Mohty
Journal: Blood (2011)
499. Retinal Gene Therapy for Peroxisome Biogenesis Disorders
Authors: Joseph G. Hacia, Jeannette Bennicelli, Ning Huang, Nancy E. Braverman, Steven J. Steinberg, Jean Bennett
Journal: Molecular Therapy (2015)

Peroxisome biogenesis disorders (PBDs) are a group of autosomal recessive disorders most frequently caused by inherited defects in the PEX1 gene, which is required for normal peroxisome assembly and biochemical functions. Approximately 80% of patients fall within the category of Zellweger spectrum disorder (PBD-ZSD), which has an overall incidence of 1:50,000 births in the United States. The majority of patients have milder forms of disease compatible with survival through adulthood; however, they typically show mild to moderate developmental delays, and progressive vision and hearing loss. Thus, therapeutic interventions that prevent or slow down visual loss could have a profound impact on the lives of these individuals Here, we present a retinal gene therapy approach that addresses visual deterioration in patients with milder forms of disease. Optical coherence tomography (OCT) has demonstrated that the cone photoreceptor cells are most significantly affected by loss of peroxisome functions in such patients. These visual phenotypes are recapitulated in a new mouse model of disease that expresses the murine equivalent of most common PEX1 mutation found in patients (PEX1-p.G843D). Electroretinogram (ERG) analyses indicated severe impairment of the cone visual pathway in these homozygous Pex1-mutant mice by 4 months of age with the rod visual system being relatively preserved. Staining retinal sections with peanut agglutinin showed that some cone photoreceptors were retained in the homozygote murine Pex1 -mutant retina at 3 weeks, but were completely degenerated in the adult. Finally, genome-wide expression studies showed specific reduction of photoreceptor cone-specific genes with no differential expression of other cell lineage-specific genes or others that indicate cell death or stress responses. We have developed AAV vectors to deliver normal copies of the 3.85-kb human PEX1 gene to the mammalian retina. These vectors use the rhodopsin kinase 1 (RK1) or truncated cytomegalovirus (CMV) promoters, respectively. Subretinal injections of RK1.PEX1. rAAV9 in healthy mice resulted in robust expression of human PEX1 mRNA. Furthermore, transduction of cultured Pex1 -mutant murine skin fibroblasts with CMV.PEX1.rAAV9 results in the rescue of peroxisome assembly defects in these cells, as determine by the intracellular localization of a modified GFP reporter protein with a peroxisome targeting signal. This indicates that the human PEX1 transgene can complement the genetic defect in the murine Pex1 gene. We are currently testing the ability of the AAV9-PEX1 gene delivery system to complement the retinal gene defect in our Pex1 -mutant mouse model. If successful, this could provide the preliminary data required to begin initial planning for eventual clinical trials in patients.
Lesinurad combination therapy with allopurinol in gout: do CLEAR studies make the treatment of gout clearer?
Authors: Jasvinder A Singh
Journal: Annals of the Rheumatic Diseases (2016)

Gout is an often forgotten disease,1 despite being the most common inflammatory arthritis in adults in the Western world.2–4 Lesinurad, a new urate-lowering therapy (ULT), is now approved for the treatment of gout in the USA and the European Union,5 ,6 and is in phase III programmes as a combination therapy in many other countries. Lesinurad is a selective inhibitor of urate/anion exchanger 1 and organic acid transporter 4, two urate transporters responsible for the reabsorption of urate from the proximal renal tubule.7 Probenecid and benzbromarone are the other uricosurics available for use in gout as monotherapy or combination with allopurinol in case of an inadequate response to allopurinol. In the current issue of the journal, Bardin et al present the results of a 12-month, randomised, phase III trial efficacy and safety of oral lesinurad (200 or 400 mg) in combination with allopurinol.8 Combining Lesinurad with Allopurinol in Inadequate Responders (CLEAR) were two replicate studies, one in the USA (CLEAR-1)9 and one in Europe (CLEAR-2), published in the current issue of this journal.8 CLEAR-2 compared daily lesinurad (200 or 400 mg orally) with placebo when added to allopurinol in 610 patients with gout with serum uric acid (sUA) above target (<6 mg/dL or <0.36 mmol/L) and frequent gout flares (≥2 gout flares in the prior year).

The primary trial endpoint of sUA <6 mg/dL (ie, <0.36 mmol/L) at 6 months was achieved by a significantly greater proportion of patients, 55% and 66% in the lesinurad 200 mg+allopurinol and lesinurad 400 mg+allopurinol groups versus 23% in the allopurinol alone group (p<0.0001 vs either lesinurad group).8 These rates were similar to the achievement of target sUA <6 mg/dL (ie, <0.36 mmol/L) in CLEAR-1.9 To my knowledge, CLEAR-28 and the replicate study, CLEAR-1,9 are the two largest randomised control trials …
Hypothalamic inflammation in obesity and metabolic disease
Authors: Alexander Jais, Jens C. Brüning
Journal: Journal of Clinical Investigation (2017)

Over the last years, hypothalamic inflammation has been linked to the development and progression of obesity and its sequelae. There is accumulating evidence that this inflammation not only impairs energy balance but also contributes to obesity-associated insulin resistance. Elevated activation of key inflammatory mediators such as JNK and IκB kinase (IKK) occurs rapidly upon consumption of a high-fat diet, even prior to significant weight gain. This activation of hypothalamic inflammatory pathways results in the uncoupling of caloric intake and energy expenditure, fostering overeating and further weight gain. In addition, these inflammatory processes contribute to obesity-associated insulin resistance and deterioration of glucose metabolism via altered neurocircuit functions. An understanding of the contributions of different neuronal and non-neuronal cell types to hypothalamic inflammatory processes, and delineation of the differences and similarities between acute and chronic activation of these inflammatory pathways, will be critical for the development of novel therapeutic strategies for the treatment of obesity and metabolic syndrome.
CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D
Authors: H Bruns, M Böttcher, M Qorraj, M Fabri, S Jitschin, J Dindorf, L Busch, R Jitschin, A Mackensen, D Mougiakakos
Journal: Leukemia (2016)
Novel Role of Histone Deacetylase 11 (HDAC11) in Hematopoiesis
Authors: Eva Sahakian, John Powers, Pedro Horna, Jennifer Rock-Klotz, Susan Deng, David M Woods, Michael Nguyen, Karrune V. Woan, Fengdong Cheng, Alejandro Villagra, Dmitry Gabrilovich, Eduardo M. Sotomayor, Javier Pinilla-Ibarz
Journal: Blood (2012)
Mortality in Type 1 Diabetes in the DCCT/EDIC Versus the General Population
Journal: Diabetes Care (2016)

OBJECTIVE Historically, mortality in type 1 diabetes has exceeded that in the general population. We compared mortality in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study cohort to that of the current general U.S. population. RESEARCH DESIGN AND METHODS The DCCT (1983–1993) compared intensive versus conventional therapy, with HbA1c levels of ∼7 vs. 9%, respectively, over an average of 6.5 years of treatment. EDIC is the observational follow-up study of the DCCT (1994 to the present). Vital status was ascertained for 97.5% of the original DCCT cohort (n = 1,441) after a mean of 27 years follow-up. Expected mortality during DCCT/EDIC was estimated using the current age-, sex-, and race-specific risks in the general U.S. population, and the observed versus expected mortality compared using standardized mortality ratios (SMRs) and Poisson regression models. RESULTS Mortality in the DCCT intensive therapy group was nonsignificantly lower than that in the general U.S. population (SMR = 0.88 [95% CI 0.67, 1.16]), whereas mortality in the DCCT conventional therapy group was significantly greater than that in the general population (SMR = 1.31 [95% CI 1.05, 1.65]). The SMR increased with increasing mean HbA1c, and above an HbA1c of 9%, the rate of increase in SMR among females was greater than that among males. CONCLUSIONS Overall mortality in the combined DCCT/EDIC cohort was similar to that of the general population but was higher in the DCCT conventional therapy group. Mortality increased significantly with increasing mean HbA1c, more so among females than males, especially for HbA1c &amp;gt;9%.
A Phase II Trial Comparison of Once Versus Twice Weekly Bortezomib in CYBORD Chemotherapy for Newly Diagnosed Myeloma: Identical High Response Rates and Less Toxicity.
Authors: Craig B. Reeder, Donna E. Reece, Vishal Kukreti, Joseph R. Mikhael, Christine Chen, Suzanne Trudel, Kristina Laumann, Joseph Hentz, Nick Pirooz, Jg Piza, Victor J Jimenez Zepeda, Rafael Fonseca, P. Leif Bergsagel, Jose Leis, Rodger E. Tiedemann, A. Keith Stewart
Journal: Blood (2009)
Abstract 812: Processing of core protein by signal peptide peptidase participates in propagation and pathogenesis of hepatitis C virus
Authors: Toru Okamoto, Sayaka Aizawa, Takahisa Kouwaki, Tatsuya Suzuki, Takasuke Fukuhara, Kohji Moriishi, Kazuhiko Koike, Yoshiharu Matsuura
Journal: Cancer Research (2015)

Abstract Hepatitis C virus (HCV) is a major causative agent of chronic liver diseases including steatosis, cirrhosis and hepatocellular carcinoma (HCC). The HCV core protein is cleaved off from a precursor polyprotein by a signal peptidase and then further processed by signal peptide peptidase (SPP) within the transmembrane region. However, the biological significance of the processing of HCV core protein by SPP remains largely unknown. Transgenic mice expressing HCV core protein exhibit insulin-resistance, steatosis and finally develop HCC, suggesting that core protein plays crucial roles in pathogenesis of HCV. In this study we have established SPP-knockout (KO) mice and cell lines to examine the roles of SPP on the propagation and pathogenesis of HCV. SPP KO mice were embryonic lethal at around E13.5, therefore we prepared SPP-KO mouse embryonic fibroblast cells (MEFs). In SPP-KO cells, HCV core protein was quickly degraded by proteasome and propagation of HCV was severely impaired. Treatment of cells with LY-411575, an inhibitor for SPP, also induced degradation of HCV core protein and suppressed the production of infectious HCV particles. PA28γ or E6AP, which had been reported to degrade core protein, were not involved in SPP-mediated degradation, suggesting the other mechanisms were involved in SPP-induced core protein degradation. Furthermore, oral administration of LY-411575 into HCV core transgenic mice reduced expression of core protein and cured insulin-resistance. The deletion of one allele of SPP gene in core transgenic mice led to impair the expression of core protein and cure insulin-resistance. These results suggest that SPP is a novel drug target for chronic hepatitis C through suppression of viral propagation and liver failures. Citation Format: Toru Okamoto, Sayaka Aizawa, Takahisa Kouwaki, Tatsuya Suzuki, Takasuke Fukuhara, Kohji Moriishi, Kazuhiko Koike, Yoshiharu Matsuura. Processing of core protein by signal peptide peptidase participates in propagation and pathogenesis of hepatitis C virus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 812. doi:10.1158/1538-7445.AM2015-812