tbuckley/cabot-search huggingface dataset:
Abstract 10343: Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Peripheral Artery Disease and Non-valvular Atrial Fibrillation: Insights From the Aristotle Trial
Authors: Peter Hu, Renato D Lopes, Susanna Stevens, Lars Wallentin, Laine Thomas, John H Alexander, Michael Hanna, Basil S Lewis, Freek W Verheugt, Christopher B Granger, William S Jones
Journal: Circulation (2015)

Introduction: Vascular disease has been incorporated in the CHA2DS2-VASc risk tool to predict the risk of stroke/systemic embolism in patients with atrial fibrillation (AF). Hypothesis: This post hoc analysis of the ARISTOTLE trial aimed to determine the absolute rates of stroke/systemic embolism and bleeding associated with peripheral artery disease (PAD) as well as the efficacy and safety of apixaban vs warfarin in AF patients with and without PAD. Methods: ARISTOTLE randomized patients with AF and risk of stroke to apixaban and warfarin for the prevention of stroke/systemic embolism. Results: A total of 884 (4.9%) patients had PAD at baseline as defined by site investigators on the case report form. Patients with versus without PAD had non-significantly higher rates of stroke/systemic embolism [HR 1.32, 95% CI 0.93-1.88, p=0.12] and major or clinically relevant non-major (CRNM) bleeding [HR 1.12, 95% CI 0.90-1.39, p=0.31]. Those with PAD had an increased risk of all-cause death [HR 1.36, 95% CI 1.11-1.67, p=0.003] and CV death [HR 1.44, 95% CI 1.08-1.90, p=0.01] when compared with those without PAD. The effect of apixaban vs warfarin for the prevention of stroke/systemic embolism was similar in patients with PAD [HR 0.66, 95% CI 0.33- 1.31] and without PAD [HR 0.80, 95% CI 0.66-0.96, interaction p=0.61] [Table]. Patients with PAD appeared to have less reduction in major or CRNM bleeding with apixaban compared with warfarin [HR 1.04, 95% CI 0.69-1.57] versus those without PAD [HR 0.66, 95% CI 0.59-0.73, interaction p=0.03]. Conclusions: Patients with PAD in ARISTOTLE had non-significantly higher risk of stroke/systemic embolism when compared with patients without PAD. The benefits of apixaban versus warfarin on stroke and all-cause death are similar in patients with and without PAD. However, the reduction in bleeding with apixaban seemed to be greater in patients without PAD than in patients with PAD (interaction p=0.03).
Abstract 2987: Generation of a selectively cytotoxic fusion protein against p53 mutated cancers
Authors: Agamemnon A. Epenetos, Christina Kousparou, Aleksandra Filipovic
Journal: Cancer Research (2016)

Abstract The most common genetic alteration in human cancer involves the p53 tumor suppressor gene resulting in defective control of cell cycle arrest and death. The p53 protein induces a cyclin-dependent kinase (cdk) inhibitor, p21 which occupies a central position in cell cycle regulation. Cdk inhibition by p21 results in a lack of progression from the G1 to the S-phase due to the prevention of retinoblastoma (Rb) phosphorylation and subsequent inhibition of transcription factors that regulate the genes involved in DNA replication and cell-cycle progression. It is hypothesized that the re-introduction of p21 into tumor cells will regenerate the pathway to apoptosis (programmed cell death) and inhibit proliferation since it has been suggested that overexpression of p21 results in suppression of tumor growth in vitro and in vivo.Unfortunately, p21 protein alone is unable to be administered directly in vivo and progress to the cell nuclei of cancer cells since there is no active mechanism to transport the protein. However, a number of proteins are known which can translocate across the cytoplasmic membrane of mammalian cells and into the nuclei, carrying additional cargoes with them. One of these translocating proteins is a 60 amino acid peptide corresponding to the homeodomain of the Drosophilia protein Antennapedia [ANTP]. A fusion protein (TR1) has been developed where the full-length p21 protein is attached to the antennapedia protein with a view to delivering the p21 protein into cancer cells to restore cell cycle control. TR1 penetrated and killed cancer cells that do not express wild type p53 or p21. This included cells that were matched to cogenic parental cell lines. Antp-p21 killed cancer cells selectively that were malignant as a result of mutations or nuclear exclusion of the p53 and p21 genes and over-expression of MDM2.Non-specific toxicity was excluded by showing that TR1 penetrated but did not kill p53- or p21- wild-type cells. TR1 was not immunogenic in normal New Zealand White rabbits. Recombinant Antp peptide alone was not cytotoxic, showing that killing was due to the transduction of the p21 component of TR1. TR1was shown to penetrate cancer cells engrafted in vivo and resulted in tumour eradication when administered with chemotherapy. TR1 may represent a new and promising targeted therapy for patients with p53-associated cancers supporting the concept that rational design of therapies directed against specific cancer mutations will play a part in the future of cancer therapeutics. Citation Format: Agamemnon A. Epenetos, Christina Kousparou, Aleksandra Filipovic. Generation of a selectively cytotoxic fusion protein against p53 mutated cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2987.
Efficacy of Melflufen, a Peptidase Targeted Therapy, and Dexamethasone in an Ongoing Open-Label Phase 2a Study in Patients with Relapsed and Relapsed-Refractory Multiple Myeloma (RRMM) Including an Initial Report on Progression Free Survival
Authors: Peter M. Voorhees, Valeria Magarotto, Pieter Sonneveld, Torben Plesner, Ulf-Henrik Mellqvist, Claudia E. Paba-Prada, Catriona Byrne, Johan Harmenberg, Eva Nordstrom, Antonio Palumbo, Paul Richardson
Journal: Blood (2015)
Abstract 19275: Gender Differences in Cardiovascular- and Cancer Mortality During Long-term Follow-up After Acute Myocardial Infarction
Authors: Kristin M Kvakkestad, Morten W Fagerland, Jan Eritsland, Sigrun Halvorsen
Journal: Circulation (2015)

Background: The existence of gender differences in cause-specific mortality after acute myocardial infarction (AMI) is unknown. Aim: To study gender differences in all-cause and cause-specific mortality in women and men with AMI. Methods: Consecutive AMI patients were enrolled in a prospective cohort study during 2005-2011. Cardiovascular (CV) risk factors, treatment and in-hospital complications were registered. Date and cause of death were obtained from the Norwegian cause of death registry, with censoring date set to Dec 31, 2012. Patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) were analysed separately. We used Kaplan Meier- and cumulative incidence function-plots to assess gender differences in CV, cancer and all-cause mortality. Cox- and Fine-Gray regression models, adjusted for age, estimated the effect of female gender. Results: We included 5159 NSTEMI (34% women) and 4899 STEMI (25% women) patients. Women were older and had more complications compared to men. After a median follow-up time of 1043 and 1262 days for NSTEMI and STEMI, respectively, 1461 NSTEMI (28%) and 886 STEMI (18%) patients had died. After adjustment for age, NSTEMI women had lower (HR 0.89 [95% CI: 0.80-0.99]) and STEMI women similar (HR 1.05 [95% CI: 0.91-1.22]) risk of all-cause mortality compared to men. There were no gender differences in CV mortality. We observed a non-significant trend toward lower cancer mortality in women than men with NSTEMI (adjusted subhazard ratio 0.76 [95% CI:0.56-1.03]). In both genders, CV death was more prevalent (Figure) and occurred earlier than cancer death. Conclusion: After adjustment for age, there were no excess risks of all-cause or CV mortality in women versus men with AMI during long-term follow-up. Possible gender differences in risk of cancer mortality needs further investigation.
The Exposome: Embracing the Complexity for Discovery in Environmental Health
Authors: Yuxia Cui, David M. Balshaw, Richard K. Kwok, Claudia L. Thompson, Gwen W. Collman, Linda S. Birnbaum
Journal: Environmental Health Perspectives (2016)

Summary:Environmental exposures are ubiquitous and play a fundamental role in the development of complex human diseases. The exposome, which is defined as the totality of environmental exposures over the life course, allows for systematic evaluation of the relationship between exposures and associated biological consequences, and represents a powerful approach for discovery in environmental health research. However, implementing the exposome concept is challenged by the ability to accurately assess multiple exposures and the ability to integrate information across the exposure–disease continuum. On 14–15 January 2015, the National Institute of Environmental Health Sciences (NIEHS) held the Exposome Workshop where a group of international and U.S. scientists from different disciplines gathered to review the state of the science in research areas related to the exposome and to provide recommendations for incorporating the exposome concept into each research area. To move the field forward, the NIEHS is establishing a Children's Health Exposure Analysis Resource (CHEAR) to provide infrastructure support for access to laboratory and statistical analyses to children's health studies. It is recognized that incorporating the exposome concept into exposure and environmental health research will be a long journey and will require significant collaborative efforts from different scientific disciplines, nations, and stakeholders.
Classification of Advanced Human Cancers Based on Tumor Immunity in the MicroEnvironment (TIME) for Cancer Immunotherapy
Authors: Yu Zhang, Lieping Chen
Journal: JAMA Oncology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease
Authors: Vivian Zhou, Kimberle Agle, Xiao Chen, Amy Beres, Richard Komorowski, Ludovic Belle, Carolyn Taylor, Fenlu Zhu, Dipica Haribhai, Calvin B. Williams, James Verbsky, Wendy Blumenschein, Svetlana Sadekova, Eddie Bowman, Christie Ballantyne, Casey Weaver, David A. Serody, Benjamin Vincent, Jonathan Serody, Daniel J. Cua, William R. Drobyski
Journal: Journal of Clinical Investigation (2016)

Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell–mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the β2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules α4β7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of β2 integrin–expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non–Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10–regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers.
Abstract 2761: Cellular consequences of human tyrosyl-DNA phosphodiesterase I dysregulation
Authors: Selma M. Cuya, Kellie M. Regal, Robert C.A.M. Van Waardenburg.
Journal: Cancer Research (2016)

Abstract Tyrosyl-DNA phosphodiesterase I (Tdp1) is a highly conserved eukaryotic DNA repair enzyme that catalyzes the resolution of 3’ and 5’ phospho-DNA adducts. Tdp1 has been implicated in the repair of DNA topoisomerase I (Topo1)-DNA covalent complexes reversibly stabilized by camptothecins (CPTs) such as the FDA approved CPT derivatives topotecan and irinotecan. Tdp1 utilizes a two-step catalytic cycle that centers on the formation of an obligatory Tdp1-DNA covalent complex (Tdp1-cc) through its nucleophilic histidine (Hisnuc), resulting in dissociation of the adduct, while its general acid/base histidine (Hisgab) mediates Tdp1 dissociation. A Tdp1Hisgab to Arg (H493R) mutant stabilizes the Tdp1-cc and is associated with autosomal recessive ataxia SCAN1. Alternative substitutions of Hisgab or substitutions of the Hisnuc transforms yeast Tdp1 into a potent toxin via stabilization of Tdp1-cc. We propose that stabilization of this Tdp1-DNA covalent complex is a potential novel therapeutic anti-cancer strategy. As proof-of-concept, we analyzed two catalytic Hisgab (H493R or H493N) mutants and one Hisnuc (H263A) mutant of hTdp1 in HEK293 cells. Doxycycline-induced expression of Tdp1H263A, Tdp1H493R, and Tdp1H493N mutant enzymes induced Tdp1-dependent cytotoxicity without additional genotoxic stress. Utilizing two different immuno-assays, we validated that the observed Tdp1-dependent toxicity correlates with stabilization of their enzyme-DNA covalent complex. Moreover, all of these Tdp1 catalytic mutants show reduced catalytic activity compared to wild type hTdp1, but they do not all show a stabilized Tdp1-cc in this in vitro assay. This indicates a significant difference between in vitro Tdp1 activity and cellular Tdp1 activity, which is most likely due to the difference in substrate; a small oligonucleotide with a 3’phospho-tyrosyl modification versus covalent complex of full length Topo1 with genomic DNA. However, these results confirm our previous yeast studies: Stabilization of the Tdp1-cc converts a DNA repair enzyme into a cellular toxin, which constitutes a potential novel therapeutic strategy to treat cancer. In addition, we are comparing schedule dependent ‘drug’-combinations of our toxic Tdp1 mutant expression with topotecan, etoposide (targets Topo2-cc) and cisplatin to evaluate the potential therapeutic value of this novel Tdp1 targeted strategy. This work is in part supported by the ADDA, UAB ACS-IRG, and DOD OCRP WX81WH-15-1-0198. Citation Format: Selma M. Cuya, Kellie M. Regal, Robert C.A.M. Van Waardenburg. Cellular consequences of human tyrosyl-DNA phosphodiesterase I dysregulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2761.
Abstract 22: Transient Receptor Potential M2 is Involved in Secondary Myocardial Injury Induced by Nonlethal Mechanical Trauma in Rats
Authors: Shuzhuang Li, Tingting Cao, Shuo Ma, Xiujie Li, Yue Bi, Jicheng Zhou, Liang Zhu, Deqin Yu, Guofeng Lv
Journal: Circulation Research (2015)

Background: It is an imperative task to identify the mechanisms responsible for post-traumatic secondary myocardial injury. Our previous experiments showed that mechanical trauma (MT) could induce secondary myocardial injury via oxidative stress. The transient potential receptor M2 (TRPM2) channel has emerged as an important Ca 2+ signaling mechanism in a variety of cells, contributing to cellular functions that include cytokine production, cell motility and cell death. However, the role of TRPM2 channel in nonlethal mechanical traumatic cardiac damage remains unclear. The aim of the present study was to investigate whether TRPM2 channel is involved in myocardial injury in rats subjected to nonlethal MT. Methods and results: Western blot was used to quantify TRPM2 protein levels in Ventricular myocytes of adult male Sprague Dawley rats. Up-regulation of TRPM2 channel protein was observed in the following 12h after MT. It was observed that plasma harvested from MT rats increased cytosolic Ca 2+ concentration dose-dependently in H9c2 cells. To verify the role of TRPM2 further, we administered TRPM2 blockers flufenamic acid (FFA, 100uM) and clotrimazole (CLZ, 30uM) respectively to inhibit Ca 2+ influx, which leads to attenuated intracelluar Ca 2+ overload and apoptosis induced by MT plasma in H9c2 cells. Those two TRPM2 blockers also improved cardiac dysfunction induced MT in rats. When we used TMB-8 (inhibitor of sarcoplasmic reticulum Ca 2+ store) to inhibit calcium store mobilization, intracellular Ca 2+ level, apoptosis and cardiac dysfunction were also ameliorated. However, the administration of KBR-7943 (inhibitor of Na/Ca exchanger) did not reverse the pathological process following MT. Conclusion: These results demonstrate that post-trauma pathological phenomena is associated with TRPM2 closely via a redox-sensitive signal transduction pathway (mainly via MT-initiated Ca 2+ influx, even calcium overload pathway) .We propose that treatments like blockage of TRPM2 channel-associated Ca 2+ influx and mobilization, may shed light on the novel therapeutic strategy in reducing cardiac injury and post-trauma multiple organ failure.
Interferon Alpha Alone Is Able to Cure Chronic Myeloid Leukemia In a Small Subset of Patients Despite the Persistence of Leukemic Cells: Experience of Long Follow up After Treatment Discontinuation
Authors: Francois-Xavier Mahon, Marie-Pierre Fort, Gabriel Etienne, Gerald Marit, Noel Milpied, Arnaud Pigneux, Pascale Cony-Makhoul, Josy Reiffers
Journal: Blood (2010)
Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: Survival analysis of 6,908 cases from the National Cancer Data Base.
Authors: Shailender Bhatia, Jayasri G Iyer, Barry Storer, Ata Moshiri, Upendra Parvathaneni, David R. Byrd, Vernon K. Sondak, Jeffrey E. Gershenwald, Arthur Sober, Paul Nghiem
Journal: Journal of Clinical Oncology (2014)

9014 Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer with high risk of recurrence after surgery. Adjuvant radiation therapy (RT) and/or chemotherapy are commonly used, but with limited data regarding their effectiveness. To assess the impact of adjuvant RT and chemotherapy on MCC survival, we performed a retrospective analysis of the National Cancer Data Base (NCDB) that has the largest known cohort of MCC patients (pts). NCDB also collects data on adjuvant chemotherapy and comorbidity status (Charlson/Deyo score) that were missing in a prior study of outcomes with adjuvant RT in 1,487 pts in the Surveillance, Epidemiology, and End Results (SEER) database. Methods: 6,908 MCC pts with stage, treatment and survival data available were included in this analysis. Multiple covariate analyses were conducted for overall survival outcomes with various treatment modalities while adjusting for age, sex, comorbidity score, and other therapies. Results: In pts with localized MCC (AJCC stage I N=3,369; stage II N=1,474), surgery plus RT was associated with significantly better survival than seen with surgery alone (Stage I HR 0.75 [95% CI 0.67–0.83], p<0.0001; Stage II HR 0.77 [95% CI 0.67–0.90], p=0.0006). In pts with nodal involvement (stage III N=2,065), adjuvant chemotherapy was not associated with improved or worsened survival versus no chemotherapy (HR 1.07 [95% CI 0.93–1.22], p=0.37). Even among a subgroup of stage III pts aged < 65 and with comorbidity score=0, adjuvant chemotherapy was not associated with improved survival. Conclusions: This retrospective study analyzed the largest MCC dataset to date for outcomes with adjuvant therapy. These results suggest improved survival with the use of adjuvant RT in stage I-II MCC pts. Adjuvant RT or chemotherapy were not associated with improved survival in stage III MCC pts. Despite the ability to assess comorbidity scores, treatment biases that could have accounted for some of the observed effects cannot be directly addressed, and prospective multicenter evaluations of adjuvant RT and chemotherapy remain warranted. Until then, multidisciplinary evaluation and individualized care is appropriate for all pts with MCC.
NIMG-53A FUZZY-BASED MODEL TO PREDICT THE SURVIVAL RATE OF PATIENTS WITH GIOBLASTOMA MLTIFORME TUMOR
Authors: Azimeh N.V. Dehkordi, Alireza Kamali-Asl, Hamed Moradi, Brent Griffith, Tom Mikkelsen, Ali S. Arbab, Lisa Scarpace, Hamid Soltanian-Zadeh, Milan V. Pantelic, David S. Nathanson, Hassan Bagher-Ebadian
Journal: Neuro-Oncology (2015)

Prediction of patient survival with brain tumor can play an important role in treatment planning and quality of a patient's life. This study investigates the effect of permeability and perfusion parameters on survival rate. This study identifies the most effective parameters on the survival time and then combines these parameters with experts' knowledge to construct a fuzzy-based model for predicting the survival rate of patients with Glioblastoma Multiforme (GBM). 25 treatment-naive GBM patients were studied using Dynamic Contrast Enhanced Magnetic Resonance Imaging. Using the standard Toft-model combined with Model Selection technique and Maximum-Likelihood algorithm, for each patient, the following permeability parameters were estimated: plasma volume (vp), outward and inward transfer constants (ktrans and kep). The estimated parameters were averaged across the tumor volume for each patient. Histogram of each parameter in whole volume of tumor was calculated and a Normal distribution was assigned to each histogram. Mean and standard deviation of each normal distribution were used to calculate the probability of each parameter being effective on survival rate. All the estimated parameters along with age, gender and hemodynamic parameters (relative Cerebral Blood Volume, rCBV and Cerebral Blood Flow, rCBF) were used as independent features for Cox-proportional-hazard regression model and Wald-test for survival analysis and to identify the parameters with most predictive power of survival. This pilot study revealed that the following physiological parameters are the best candidates to construct the fuzzy-based model for prediction of GBM patient survival: Mean and standard deviation of kep and extra-vascular extra-cellular volume (ve = ktrans/kep), vp, patient age, and rCBV. Compared to the other conventional predictors, the proposed model in this study showed a superior predictive power (∼ 93%) which is due to the fact that it can benefit from experimental data and a set of rules that can be constructed based on the knowledge of experts.
2009 ACCF/AHA Focused Update on Perioperative Beta Blockade
Authors: Kirsten E. Fleischmann, Joshua A. Beckman, Christopher E. Buller, Hugh Calkins, Lee A. Fleisher, William K. Freeman, James B. Froehlich, Edward K. Kasper, Judy R. Kersten, John F. Robb, R. James Valentine
Journal: Journal of the American College of Cardiology (2009)