tbuckley/cabot-search huggingface dataset:
Antagonistic effect of 1-beta-D-arabinofuranosylcytosine and 5-aza—2′-deoxycytidine in human leukemic cells through regulation of DNA methylation
Authors: Taichun Qin, Emile M. Youssef, Allen S. Yang, Guillermo Garcia-Manero, Jean-Pierre J. Issa
Journal: Cancer Research (2004)

1601  1-beta-D-arabinofuranosylcytosine ( cytarabine; ara-C ) is the most active agent in myeloid leukemia. 5-aza-2′-deoxycytidine ( 5aza-dC) is a cytosine analog that inhibits DNA methylation and also has activity in myeloid leukemia. In order to investigate the possible therapeutic combination of these agents, we studied the interaction of ara-C and 5aza-dC on human Acute Myeloid Leukemia (HL-60, ML-1), and Acute Lymphoblastic Leukemia (RAJI) cell lines. We initially examined inhibition of cell growth. The combination of 5aza-dC 1uM + ara-C 0.01 uM, 0.1uM, or 1uM showed antagonism on day 3 or day 5 compared to either agent alone in HL60, ML-1 and RAJI. For example, 5aza-dC 1uM alone caused 43% growth inhibition at day 3 in HL60, ara-C 1uM alone caused 78% growth inhibition, while the combination showed 58% inhibition. Antagonism was also observed when 5aza-dC 1uM was given first followed by ara-C (0.1uM, 1uM) on day 3 or day 5 in HL60, ML-1 and RAJI. In searching for a possible mechanism for this antagonism, we initially examined reactivation of silenced genes. RIL and P57 were activated 5-fold or greater by 5aza-dC in HL60 and ML-1, but this activation was almost completely inhibited by the addition of ara-C to 5aza-dC. We next looked at DNA methylation of Alu repetitive elements in these cells as a surrogate for global methylation. In HL60, 5aza-dC induced Alu demethylation by 18% after 3 days and 30% after 5 days. With co-administration of ara-C at 0.1uM, Alu demethylation was reduced to 4.1% on day 3 and 5.0 % on day 5. Increasing ara-C to 1uM, 5aza-dC further reduced demethylation to 0.9% on day 3 or 3.9% on day 5. Similar results were seen in ML-1. These data show that ara-C administered with 5aza-dC or shortly after inhibits demethylation and gene reactivation, accounting for the observed antagonism. This is likely related to the fact that 5aza-dC and ara-C compete for deoxycytidine kinase for incorporation into DNA. Our results suggest that combination of 5aza-dC + ara-C must be designed with a large interval between the 2 drugs.
Idarucizumab for Dabigatran Reversal — Full Cohort Analysis
Authors: Charles V. Pollack, Paul A. Reilly, Joanne van Ryn, John W. Eikelboom, Stephan Glund, Richard A. Bernstein, Robert Dubiel, Menno V. Huisman, Elaine M. Hylek, Chak-Wah Kam, Pieter W. Kamphuisen, Jörg Kreuzer, Jerrold H. Levy, Gordon Royle, Frank W. Sellke, Joachim Stangier, Thorsten Steiner, Peter Verhamme, Bushi Wang, Laura Young, Jeffrey I. Weitz
Journal: New England Journal of Medicine (2017)

Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .).
Predictors of Hand-Foot Syndrome and Pyridoxine for Prevention of Capecitabine–Induced Hand-Foot Syndrome
Authors: Yoon-Sim Yap, Li-Lian Kwok, Nicholas Syn, Wen Yee Chay, John Whay Kuang Chia, Chee Kian Tham, Nan Soon Wong, Soo Kien Lo, Rebecca Alexandra Dent, Sili Tan, Zuan Yu Mok, King Xin Koh, Han Chong Toh, Wen Hsin Koo, Marie Loh, Raymond Chee Hui Ng, Su Pin Choo, Richie Chuan Teck Soong
Journal: JAMA Oncology (2017)

Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment.To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS.This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers.Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine.Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays.In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10-8), including a novel DPYD variant (rs75267292; P = 1.57 × 10-10), and variants in the MACF1 (rs183324967, P = 4.80 × 10-11; rs148221738, P = 5.73 × 10-10) and SPRY2 (rs117876855, P < 1.01 × 10-8; rs139544515, P = 1.30 × 10-8) genes involved in wound healing.Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS.clinicaltrials.gov Identifier: NCT00486213.
CCAAT/enhancer-binding protein delta promotes intracellular lipid accumulation in M1 macrophages of vascular lesions
Authors: Hong-Yue Lai, Ling-Wei Hsu, Hsin-Hwa Tsai, Yu-Chih Lo, Shang-Hsun Yang, Ping-Yen Liu, Ju-Ming Wang
Journal: Cardiovascular Research (2017)

Lipid homeostasis is reprogrammed in the presence of inflammation, which results in excessive lipid accumulation in macrophages, and leads to the formation of lipid-laden foam cells. We aimed to link an inflammation-responsive transcription factor CCAAT/enhancer-binding protein delta (CEBPD) with polarized macrophages and dissect its contribution to lipid accumulation.We found that CEBPD protein colocalized with macrophages in human and mouse (C57BL/6, Apoe-/-) atherosclerotic plaques and that Cebpd deficiency in bone marrow cells suppressed atherosclerotic lesions in hyperlipidemic Apoe-/- mice. CEBPD was responsive to modified low-density lipoprotein (LDL) via the p38MAPK/CREB pathway, and it promoted lipid accumulation in M1 macrophages but not in M2 macrophages. CEBPD up-regulated pentraxin 3 (PTX3), which promoted the macropinocytosis of LDL, and down-regulated ATP-binding cassette subfamily A member 1 (ABCA1), which impaired the intracellular cholesterol efflux in M1 macrophages. We further found that simvastatin (a HMG-CoA reductase inhibitor) could target CEBPD to block lipid accumulation in a manner not directly related to its cholesterol-lowering effect in M1 macrophages.This study underscores how CEBPD functions at the junction of inflammation and lipid accumulation in M1 macrophages. Therefore, CEBPD-mediated lipid accumulation in M1 macrophages could represent a new therapeutic target for the treatment of cardiovascular diseases.
NAM 2017 report: A national plan to eliminate hepatitis B and C in the United States by 2030 and the AASLD's response
Authors: Hugo R. Rosen, Marc G. Ghany, Raymond T. Chung, Anna S.F. Lok
Journal: Hepatology (2017)

Rosen, Hugo R. M.D.; Ghany, Marc G. M.D.; Chung, Raymond T. M.D.; Lok, Anna S.F. M.D. Author Information
Closed-loop interaction with the cerebral cortex: a review of wireless implant technology
Authors: Fabian Kohler, C. Alexis Gkogkidis, Christian Bentler, Xi Wang, Mortimer Gierthmuehlen, Joerg Fischer, Christian Stolle, Leonhard M. Reindl, Joern Rickert, Thomas Stieglitz, Tonio Ball, Martin Schuettler
Journal: Brain-Computer Interfaces (2017)

Wireless implants for interaction with the cortex have developed rapidly over the last decade and increasingly meet demands of clinical brain–computer interfaces. For such applications, well-established technologies are available, suitable for recording of neural activity at different spatial scales and adequate for modulating brain activity by cortical electrical stimulation. The incorporation of recording and stimulation into closed-loop systems is a major aim in active, fully implantable medical device design. To reduce clinical long-term implantation risk and to increase the spatial specificity of epicortical recordings and stimulation, micro-electrocorticography is a promising technology. However, currently there is a lack of implants suitable for chronic human clinical applications that utilize micro-electrocorticography and possess closed-loop functionality. Here, we describe the clinical importance of cortical stimulation, give an overview of existing implants that use mainly epicortical recording methods, and present results of a closed-loop micro-electrocorticography system developed for clinical application within a collaborative framework. Finally, we conclude with our vision of future design options in the field of neuroprosthetic devices.
Application of UGT1A1 Genetic Testing in Patients Treated with Irinotecan
Authors: Federico Innocenti
Journal: Clinical Cancer Research (2007)

PL07-03  Application of UGT1A1 genetic testing in patients treated with irinotecan  Federico Innocenti, MD, PhD  University of Chicago, Department of Medicine, Section of Hematology-Oncology, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637; business telephone: 773-834-2452; fax: 773-702-9698; email: finnocen@medicine.bsd.uchicago.edu  Abstract  Irinotecan is widely used in the treatment of metastatic colorectal cancer and extensive small-cell lung cancer. Its use is limited by severe toxicities, such as neutropenia and delayed-type diarrhea.  The pharmacology of irinotecan is quite complex. Irinotecan is converted to its active metabolite SN-38. SN-38 is further metabolized to SN-38G by various hepatic and extrahepatic UGT1A isozymes, mainly UGT1A1. Genetically impaired glucuronidation activity of the UGT1A1 enzyme has been linked with elevated levels of SN-38. UGT1A1*28 is the most studied functional UGT1A1 variant and involves an extra TA repeat in the UGT1A1 promoter region.  In several studies, homozygosity for the UGT1A1*28 allele has been associated with a higher risk of severe toxicity of irinotecan in cancer patients. This wealth of information led to the revision of the irinotecan label by the FDA. Recently, in addition to the UGT1A1*28 allele, the UGT1A1*6 variant seems to contribute to the risk of toxicity of irinotecan in Asian patients.  The pharmacogenetics of irinotecan (irinogenetics) is one of few promising examples of the application of pharmacogenetics to individualized drug therapy. This talk will discuss the use of UGT1A1 genetic testing for avoiding severe toxicity of irinotecan in predisposed patients. In addition, genotype-directed trials of irinotecan will be discussed, as an example of tailored dosing in oncology that could be obtained by knowing the genetic make up of patients.
Evidence in support of the call to ban the tackle and harmful contact in school rugby: a response to World Rugby
Authors: Allyson M Pollock, Adam John White, Graham Kirkwood
Journal: British Journal of Sports Medicine (2017)

In a paper published in BJSM (June 2016), World Rugby employees Ross Tucker and Martin Raftery and a third coauthor Evert Verhagen took issue with the recent call to ban tackling in school rugby in the UK and Ireland. That call (to ban tackling) was supported by a systematic review published in BJSM . Tucker et al claim that: (1) the mechanisms and risk factors for injury along with the incidence and severity of injury in youth rugby union have not been thoroughly identified or understood; (2) rugby players are at no greater risk of injury than other sports people, (3) this is particularly the case for children under 15 years and (4) removing the opportunity to learn the tackle from school pupils might increase rates of injuries. They conclude that a ban ‘may be unnecessary and may also lead to unintended consequences such as an increase in the risk of injury later in participation.’ Here we aim to rebut the case by Tucker et al . We share new research that extends the findings of our original systematic review and meta-analysis. A cautionary approach requires the removal of the tackle from school rugby as the quickest and most effective method of reducing high injury rates in youth rugby, a public health priority.
Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea
Authors: Jie Yu, Zien Zhou, R. Doug McEvoy, Craig S. Anderson, Anthony Rodgers, Vlado Perkovic, Bruce Neal
Journal: JAMA (2017)

<h3>Importance</h3> Sleep apnea (obstructive and central) is associated with adverse cardiovascular risk factors and increased risks of cardiovascular disease. Positive airway pressure (PAP) provides symptomatic relief, whether delivered continuously (CPAP) or as adaptive servo-ventilation (ASV), but the associations with cardiovascular outcomes and death are unclear. <h3>Objective</h3> To assess the association of PAP vs control with cardiovascular events and death in patients with sleep apnea. <h3>Data Sources and Study Selection</h3> MEDLINE, EMBASE, and the Cochrane Library were systematically searched from inception date to March 2017 for randomized clinical trials that included reporting of major adverse cardiovascular events or deaths. <h3>Data Extraction and Synthesis</h3> Two authors independently extracted data using standardized forms. Summary relative risks (RRs), risk differences (RDs) and 95% CIs were obtained using random-effects meta-analysis. <h3>Main Outcomes and Measures</h3> The main outcomes were a composite of acute coronary syndrome (ACS) events, stroke, or vascular death (major adverse cardiovascular events); cause-specific vascular events; and death. <h3>Results</h3> The analyses included data from 10 trials (9 CPAP; 1 ASV) of patients with sleep apnea (N = 7266; mean age, 60.9 [range, 51.5 to 71.1] years; 5847 [80.5%] men; mean [SD] body mass index, 30.0 [5.2]. Among 356 major adverse cardiovascular events and 613 deaths recorded, there was no significant association of PAP with major adverse cardiovascular events (RR, 0.77 [95% CI, 0.53 to 1.13];<i>P</i> = .19 and RD, −0.01 [95% CI, −0.03 to 0.01];<i>P</i> = .23), cardiovascular death (RR, 1.15 [95% CI, 0.88 to 1.50];<i>P</i> = .30 and RD −0.00 [95% CI, −0.02 to 0.02];<i>P</i> = .87), or all-cause death (RR, 1.13 [95% CI, 0.99 to 1.29];<i>P</i> = .08 and RD, 0.00 [95% CI, −0.01 to 0.01];<i>P</i> = .51). The same was true for ACS, stroke, and heart failure. There was no evidence of different associations for CPAP vs ASV (all<i>P</i>value homogeneity &gt;.24), and meta-regressions identified no associations of PAP with outcomes for different levels of apnea severity, follow-up duration, or adherence to PAP (all<i>P</i>values &gt; .13). <h3>Conclusions and Relevance</h3> The use of PAP, compared with no treatment or sham, was not associated with reduced risks of cardiovascular outcomes or death for patients with sleep apnea. Although there are other benefits of treatment with PAP for sleep apnea, these findings do not support treatment with PAP with a goal of prevention of these outcomes.
C5 nephritic factors drive the biological phenotype of C3 glomerulopathies
Authors: Maria-Chiara Marinozzi, Sophie Chauvet, Moglie Le Quintrec, Morgane Mignotet, Florent Petitprez, Christophe Legendre, Mathilde Cailliez, Georges Deschenes, Michel Fischbach, Alexandre Karras, Francois Nobili, Christine Pietrement, Marie-Agnes Dragon-Durey, Fadi Fakhouri, Lubka T. Roumenina, Veronique Fremeaux-Bacchi
Journal: Kidney International (2017)
Synthesis and antitumor studies of N4-substituted thiosemicarbazones derived from acyl diazines
Authors: Johnny Easmon, Gotffried Heinisch, Gerhard Pürstinger, Ivan King, Li-Mou Li-Mou Zheng, Pui-Kwong Chan, Johann Hofmann
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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Very recently we described the synthesis and antitumor properties of N4-azabicyclo[3.2.2]nonane thiosemicarbazones (TSCs) derived from acyl diazines (Easmon, J, et. al. J . Med . Chem . 2001, 44 , 2164-2171). Although the compounds were potent antiproliferative agents, only a moderate inhibition of tumor growth (40%) was observed accompanied by high in vivo toxicity. In a continued effort to obtain more efficacious compounds, we have synthesized TSC-derivatives bearing N4-methyl and cycloaliphatic moieties. The cytotoxic activities of the TSCs were evaluated in a panel of human tumor cell lines by the MTT assay. TSCs bearing terminal cycloaliphatic amines and especially a pyrrolidine moiety exhibited potent cytotoxic activity against Burkitt's lymphoma Ca 46 (IC50 = 0.002-0.59 μM), HeLa cervical (IC50 = 0.0003-0.057 μM), and Colon HT-29 (IC50 = 0.0005-0.47 μM) cells. Several of the highly active TSCs were tested in viv o in CD1 nude mice bearing various tumor xenografts. The compound Hexahydro-1 H -azepine-1-thiocarboxylic acid 2-[1-(3-methyl-2-pyrazinyl)ethylidene}hydrazide (EPH 280) applied at doses of 20-25 mg/kg in mice bearing H460 human lung carcinoma xenograft resulted in a 70% reduction in tumor burden. Treatment of DLD1 colon adenocarcinoma cells with 40 nM of EPH 280 resulted in the increase of the phosphorylation of HSP 27 which was determined to occur at the ser-82 site. Financial support by the Austrian Science Foundation (FWF) is generally acknowledged (project no. P 09879-MED).
Evidence supports the use of multidisciplinary team meetings
Authors: Lara C. Pullen
Journal: CA A Cancer Journal for Clinicians (2017)

Key Points A recent systematic review of MDTMs for patients with GI cancers confirmed their value in improving quality of care. According to the 9 published articles identified by the researchers that included data regarding discussions of treatment plans during MDTMs, changes in treatment were discussed by the meeting participants in 23.0% to 41.7% of evaluated cases. The systematic review also determined that treatment plans formulated during MDTMs are implemented in 90% to 100% of discussed patients, according to the 4 articles that reported this outcome.
Event-free survival and overall survival in 2,253 patients with osteosarcoma registered to EURAMOS-1.
Authors: Sigbjorn Smeland, Jeremy Whelan, Stefan S. Bielack, Neyssa Marina, Gordana Jovic, Trude Butterfass-Bahloul, Gabriele Calaminus, Mikael Eriksson, Hans Gelderblom, Richard Greg Gorlick, Pancras C. W. Hogendoorn, Jane Hook, Leo Kager, Mark D. Krailo, Thomas Kühne, R. Lor Randall, Kirsten Sundby Hall, Lisa A. Teot, Matthew Robert Sydes, Mark L. Bernstein
Journal: Journal of Clinical Oncology (2015)

10512 Background: EURAMOS-1 (NCT00134030) is an international study in osteosarcoma including two Phase III randomized controlled trials that investigated postoperative treatment optimization on the basis of histological response to preoperative chemotherapy (CT). One study aim was to report outcomes from diagnosis for all registered patients in this large, intergroup study. Methods: Patients (pts) were eligible for registration if: < 30 days from diagnostic biopsy; age ≤ 40yrs; with localized or primary metastatic, high-grade extremity or axial osteosarcoma; resectable disease; fit for treatment and follow-up. Treatment was preop CT with methotrexate, doxorubicin, cisplatin (MAP), surgery and then post-op MAP-based CT according to response and optional randomization. The primary outcome measure was event-free survival (EFS), defined as time from diagnostic biopsy until the earliest of: death, local recurrence, new metastatic disease, progression of metastatic disease or secondary malignancy, or date of last contact; a secondary outcome measure was overall survival (OS). Standard statistical methods were used. Results: 2260 pts from 17 countries & > 300 centres were registered from 2005 to 2011; this analysis excludes 7 ineligible pts. The site was 13% proximal femur or humerus, 82% other limb site, 5% axial skeletal; 16% had definitive metastases. 92% had conventional osteosarcoma. Median age was 14yrs (quartiles 11, 17). 1334 (59%) were randomized; 919 (41%) were not, mostly for non-consent. Median follow-up was 5.2 yrs. 1000 EFS events and 634 deaths were reported. From biopsy, 5-yr EFS = 54% (95%CI 52%, 57%), and 5-yr OS = 71% (95%CI 69%, 73%). In 1881 pts with localized disease, 5-yr EFS = 59% (95%CI 57%, 62%) and 5-yr OS = 75% (95%CI 73%, 77%); in 357 pts with metastases 5-yr EFS = 29% (95%CI 24%, 34%) and 5-yr OS = 46% (95%CI 41%, 52%); metastases were unreported for 15 pts. Prognostic models will be presented. Conclusions: EFS and OS rates in this multinational study were comparable to centres' reported series. We used broader eligibility criteria than most osteosarcoma studies, by including patients with axial or metastatic disease. However, this extends recruitment and relevance of our findings. Clinical trial information: 67613327.