tbuckley/cabot-search huggingface dataset:
Temporal Trends of Venous Thromboembolism Risk Before and After Diagnosis of Giant Cell Arteritis
Authors: Sebastian Unizony, Na Lu, Gunnar Tomasson, Yuqing Zhang, Peter A. Merkel, John H. Stone, J. Antonio Aviña‐Zubieta, Hyon K. Choi
Journal: Arthritis & Rheumatology (2016)

Objective Giant cell arteritis (GCA) and the use of glucocorticoids have both been associated with increased risk of venous thromboembolism (VTE). However, the possibility of confounding by indication has not been investigated. We undertook this study to examine the temporal risk of VTE in GCA patients before and after GCA diagnosis, accounting for confounders including glucocorticoid treatment. Methods We conducted a matched cohort study using an electronic medical record database representative of the UK population (1990–2013). We calculated age‐, sex‐, and entry time–matched and multivariate relative risks (RRs) of VTE, comparing 6,441 patients with new‐onset GCA (defined by corresponding diagnosis codes and prescribed glucocorticoid treatment) to 63,985 controls before and after GCA diagnosis. Analysis before GCA diagnosis was stratified by oral glucocorticoid use to account for confounding. Results There were 27 incident VTE events during the 12 months preceding GCA diagnosis and 195 afterward. Compared to controls, during the 12, 9, 6, and 3 months preceding GCA diagnosis, the age‐, sex‐, and entry time–matched RRs for VTE among patients with imminent GCA not treated with glucocorticoids were 1.8, 2.2, 2.4, and 3.6, respectively. In the first 3, 6, 12, 24, 48, and 96 months after GCA diagnosis, the corresponding RRs were 9.9, 7.7, 5.9, 4.4, 3.3, and 2.4. Multivariate analyses including several common VTE risk factors showed similar trends. Conclusion The risk of VTE increases shortly before GCA diagnosis, peaks at the time of diagnosis, and then progressively declines thereafter. This risk is apparent in patients with imminent GCA unexposed to oral glucocorticoids, suggesting a role for inflammation‐associated thrombosis that is independent of glucocorticoid use.
Abstract 598: Circulating peptides for predicting subsequent cardiotoxicity in cancer patients with chemotherapies
Authors: Jia Fan, Qing H. Meng, Christopher Bone, Stephen Igo, Ye Hu
Journal: Cancer Research (2015)

Abstract In recent years with the development of new anticancer therapies, cardiotoxicity has been a known adverse event resulting from direct myocyte damage, and leads to increased treatment-associated mortality. However, the effective approach of early diagnosis and monitoring treatment-induced cardiac dysfunction is not available because its underlying mechanism is still unclear. Traditional screening that relied on left ventricular ejection fraction (LVEF) is lack of sensitivity to early detect subclinical changes or predict the subsequent declines in cardiac functions with treatment. A more noninvasive approach to early diagnose and monitor treatment-induced cardiotoxicity is in an urgent need. Our group has developed nanoporous silica thin films (Nanotraps) for peptide enrichment prior to mass spectrometry (MS) analysis as a robust technology platform for accurate and reproducible peptide biomarkers detection. Cancer patients with chemotherapies were split into three groups, non-toxicity (NT, n = 36), slight cardiotoxicity (SCT, n = 26) and cardiotoxicity (CT, n = 23). After statistical analysis and sequencing by LC-MS/MS, two peptides candidates (a fragment from serum amyloid A-1525 (SAA-1525)) and Hepcidin-25) were identified with significant up-regulation in cardiotoxic groups (with the cut off ratio of 1.5-fold and p-value ≤ 0.01 among cohorts). The area under curve (AUC) values of SAA-1525 and hepcidin-25 are 0.929 and 0.844 for distinguishing CT from NT, respectively (95% CI = 0.839-1.000 and 0.696-0.993); if combining two peptides as a biomarker pattern, the AUC value can be increased to 0.942 (95% CI = 0.864-1.00). SCT patients could also be classified by this two-marker pattern (AUC = 0.771, 95%CI = 0.606-0.936). In addition, we investigated the proteolytic process analysis of cathepsin B, which was identified as the key protease to generate SAA-1525. SAA-1525 was detected in the mixture of recombinant SAA1 full protein and purified cathepsin B, and its expression level increased with reaction time and enzyme amount. Both cathepsin B inhibitors, E64 and ALLM, could stop the generation of SAA-1525. Our study provides strong evidence to support the application of circulating peptides as minimally invasive way for predicting/monitoring chemotherapy-induced cardiotoxicity. Citation Format: Jia Fan, Qing H. Meng, Christopher Bone, Stephen Igo, Ye Hu. Circulating peptides for predicting subsequent cardiotoxicity in cancer patients with chemotherapies. [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 598. doi:10.1158/1538-7445.AM2015-598
31. EncorStat®: A Human Donor Cornea Genetically Engineered To Resist Rejection in High Risk Patients
Authors: Laura McCloskey, Maria Parker, Vicky Kennedy, Trevor McFarland, Matt Hartzell, Binoy Appukuttan, Tim Stout, Khilan Shah, Frank Larkin, Simon Chandler, Kyriacos Mitrophanous, Scott Ellis
Journal: Molecular Therapy (2015)

Corneal transplantation is one of the most successful transplant procedures because of the relatively immune-privileged status of the eye and the avascularity of the cornea. However, normal corneal immune privilege can be eroded by neovascularization by providing a route of entry for immune-mediating cells, leading to subsequent irreversible immunological rejection of the corneal graft, the most common reason for graft failure. In high risk patients, which account for >20% of the 100,000 transplants carried out worldwide each year, the rejection rate can be very high (50-90%), particularly if there is pre-existing vascularization of the recipient corneal bed. In these patients the prognosis is extremely poor, with grafts failing at an accelerating rate to the point where patients are no longer considered suitable for further transplants and are left blind, despite an otherwise healthy eye. It is therefore not surprising that neovascularization (both pre- and post-grafting) is a significant risk factor for corneal graft failure. Neovascularization is thus an attractive target to prevent corneal graft failure due to rejection. EncorStat® is a human donor cornea modified prior to transplant by the ex vivo delivery of the genes encoding secretable forms of the angiostatic human proteins, endostatin and angiostatin, by a lentiviral vector, derived from the Equine Infectious Anaemia Virus (EIAV), which prevents subsequent rejection by suppressing neovascularization. Modified rabbit corneas have been evaluated in two different models of corneal graft rejection, a highly aggressive model in which rejection is driven by the retention of thick graft sutures, and a less aggressive model in which rejection is driven by pre-vascularizing the recipient corneal bed prior to surgery. In this latter model thin sutures are used to secure the graft that are removed two weeks following surgery, which is more analogous to the clinical setting. The process to generate EncorStat® corneas has been optimized to secrete substantial and persistent levels of angiostatic proteins with very little shedding of residual vector. These corneas substantially suppress corneal neovascularization, opacity and subsequent rejection in both rabbit models of cornea graft rejection. The non-clinical data to be presented support the evaluation of EncorStat® corneas in a First-in-Man trial. With support from the UK Technology Strategy Board (Innovate UK), this trial will be conducted in 2016, following completion of non-clinical safety studies and GMP vector manufacture this year. An outline of this clinical trial design will also be presented.
Safety and Efficacy of Subcutaneous (SC) Omacetaxine Mepesuccinate in Imatinib(IM)-Resistant Chronic Myeloid Leukemia (CML) Patients (pts) with the T315I Mutation – Results of An Ongoing Multicenter Phase II Study.
Authors: Jorge Cortes, H. Jean Khoury, Sélim Corm, Franck E Nicolini, Jeffrey H. Lipton, Dan Jones, Andreas Hochhaus, Adam R Craig, Annie-Claude Benichou, Eric Humphriss, Hagop Kantarjian
Journal: Blood (2008)
Chronic Myeloid Leukemia: Molecular Monitoring of Residual Disease by Genomic DNA Compared to Conventional mRNA Analysis in Follow-Ups up to 8 Years
Authors: Ilaria Stefania Pagani, Orietta Spinelli, Adelaide Bussini, Tamara Intermesoli, Francesco Pasquali, Francesco Lo Curto, Arnalda Lanfranchi, Fulvio Porta, Alessandro Rambaldi, Giovanni Porta
Journal: Blood (2011)
Targeting calcium signaling in cancer therapy
Authors: Chaochu Cui, Robert Merritt, Liwu Fu, Zui Pan
Journal: Acta Pharmaceutica Sinica B (2016)

The intracellular calcium ions (Ca2+) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca2+ homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Ca2+ signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca2+ channels, transporters and Ca2+-ATPases, which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca2+ channels/transporters or Ca2+-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research into the understanding of cellular mechanisms underlying the regulation of Ca2+ signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca2+ channels or transporters.
A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (<i>NLRP1-</i>associated autoinflammation with arthritis and dyskeratosis)
Authors: Sylvie Grandemange, Elodie Sanchez, Pascale Louis-Plence, Frédéric Tran Mau-Them, Didier Bessis, Christine Coubes, Eric Frouin, Marieke Seyger, Manon Girard, Jacques Puechberty, Valérie Costes, Michel Rodière, Aurélia Carbasse, Eric Jeziorski, Pierre Portales, Guillaume Sarrabay, Michel Mondain, Christian Jorgensen, Florence Apparailly, Esther Hoppenreijs, Isabelle Touitou, David Geneviève
Journal: Annals of the Rheumatic Diseases (2016)

Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined.To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients.We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome.We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity.NCT02067962; Results.
P0610 : Dynamic prediction of inactive chronic hepatitis B using repeated HBsAg and HBV DNA level measurements through long-term follow-up
Authors: W.P. Brouwer, H.L.-Y. Chan, M.R. Brunetto, M. Martinot-Peignoux, P. Arends, M. Cornberg, B. Cherubini, A.J. Thompson, Y.-F. Liaw, P. Marcellin, H.L Janssen, B.E. Hansen
Journal: Journal of Hepatology (2015)
Abstract A2-47: Informatics framework for clustering and deriving gene signatures for prognostic stratification of cancer patients
Authors: Segun Jung, Yingtao Bi, Ramana V. Davuluri
Journal: Cancer Research (2015)

Abstract Stratification of cancer patients into different molecular groups is essential for developing targeted therapies. High-throughput technologies, such as microarrays and next-generation sequencing, have been extensively used for generating multi-omics data. Indeed, The Cancer Genome Atlas (TCGA) consortium, one of the most comprehensive and popular databases of cancer, has been accumulating large volumes of invaluable data for more than 30 cancer types, offering unprecedented opportunity to attain new insights in cancer biology. Despite the technological advances, analyzing, integrating and translating the gene signatures across different platforms remains a computationally challenging task. Here, we developed a novel computational framework that integrates genomic and clinical data to stratify cancer patients into different molecular subgroups and predict clinically applicable phenotypes, such as survival. Application of this user-friendly framework derives platform-independent isoform-level gene signatures that can be translated from high-dimensional platforms (e.g., RNA-Seq) to clinically adaptable low-dimensional molecular assays (e.g., RT-PCR) for prognostic stratification. We applied the pipeline on two TCGA lung cancer datasets—Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LUSC). Using independent test data, we achieved about 93% (LUAD) and 98% (LUSC) classification accuracy using less than 70 isoform-level gene signature. The proposed informatics platform is applicable to other cancer types in TCGA data portal. Citation Format: Segun Jung, Yingtao Bi, Ramana V. Davuluri. Informatics framework for clustering and deriving gene signatures for prognostic stratification of cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-47.
Abstract 3905: DBNL is a pro-survival adaptor in ErbB2+ breast cancer
Authors: Josephine F. Wixted, Matthew K. Robinson
Journal: Cancer Research (2015)

Abstract DBNL, also known as mAbp1, Hip-55, or SH3P7, is a fairly novel, ubiquitously expressed, multidomain adapter protein consisting of an N-terminal F-actin binding domain, an internal proline-serine-and threonine-rich domain, and a C-terminal SH3-domain. The N-terminal and C-terminal domains of DBNL are highly conserved from mammal to yeast and are implicated in a multitude of cellular processes that include, endocytosis, migration, signaling, and viability. Recently, a proteomics analysis identified DBNL as a pro-survival signaling node in various cancers. Here we demonstrate that siRNA knockdown of DBNL reduces ErbB2+ breast cancer viability by arresting cell growth at the G1/S phase and by enhancing caspase-mediated apoptosis. Furthermore, knockdown of DBNL reduces cell surface levels of ErbB2 and decreases Akt phosphorylation. Elucidating the downstream signaling mechanisms that drive DBNL-mediated pro-survival will further aid in identifying new targets to ErbB2+ cancers as well as define additional roles of DBNL in cell biology. Citation Format: Josephine F. Wixted, Matthew K. Robinson. DBNL is a pro-survival adaptor in ErbB2+ breast cancer. [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 3905. doi:10.1158/1538-7445.AM2015-3905
Abstract 3749: Uses and update for CellMiner, a tool for access to and comparison of molecular data and pharmacological response for the NCI-60
Authors: William C. Reinhold, Margot Sunshine, Sudir Varma, Vinodh Rajapakse, James Doroshow, Joel Morris, Yves Pmmier
Journal: Cancer Research (2015)

Abstract Integration and understanding of genomic and proteomic data and their relationships with and influences on pharmacology have become key components of cancer research and its translation to therapeutics. Nonetheless, multiple significant obstacles need to be overcome for both their integration and understanding. The NCI-60 cancerous cell lines provide a premier opportunity in this area due to the scope and quality of the available data. CellMiner (http://discover.nci.nih.gov/cellminer) is a web-application that allows the user to rapidly access data for relative levels of transcript expression for 25,772 genes, genetic variants for 16,568 genes, transcript expression for 360 microRNAs, protein levels for 94 genes, and DNA copy number (from aCGH) for 23,413 genes. In addition, it provides concentration-response activities for 20,002 compounds including 114 Food and Drug Administration (FDA)-approved, 55 clinical trial, and 349 known mechanism-of-action drugs. Here we present our latest CellMiner update along with examples of data integration that provide enhanced understanding in the systems biological sense. Included in the tool updates are i) the upcoming “Protein mean value” cell line signature tool, ii) the recently introduced “Gene DNA copy number” tool, iii) introduction of the “Cross-correlations of transcripts, microRNAs, and drugs” tool, iv) the provision of additional forms of data in the standard output for the “Pattern comparisons” tool, and v) upgrades of the “Genetic variant versus drug visualization” tool allowing the user to query for all drugs significantly correlated to genomic variants for the whole human genome (or visa versa). Examples of data integration will include SLFN11 expression versus the activities of DNA-damaging drugs, RAS activation considering three forms of molecular data, and PTEN knockdown and pharmacological connection (also using three forms of molecular data). The data and tools are or shortly will be publicly available at CellMiner. Citation Format: William C. Reinhold, Margot Sunshine, Sudir Varma, Vinodh Rajapakse, James Doroshow, Joel Morris, Yves Pmmier. Uses and update for CellMiner, a tool for access to and comparison of molecular data and pharmacological response for the NCI-60. [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 3749. doi:10.1158/1538-7445.AM2015-3749
Abstract 17142: Increased Adherence to Patient Follow-up Visits within 7 dDys in Heart Failure Patients are Associated With Reduced Readmission Rates in MI and WI
Authors: Indermohan Thethi, Kathie Thomas, Lynn Mallas-Serdynski
Journal: Circulation (2015)

Background &amp; Objectives: Heart failure (HF) is the leading cause of hospitalization among adults aged 65 or older. Despite advancements in medical therapy, HF readmission rates remain high. The average cost of each HF readmission is about $13,000. High rates of readmissions can lead to penalties of up to 3% of Medicare reimbursement, the reduction of costs, &amp; the improvement of quality of care and patient outcomes, which makes reduction vital to hospitals. Having a follow up visit within 7 days of hospital discharge may help reduce HF readmissions. The objective of the abstract is to quantify the change in 7 day follow up visits and 30 day readmissions as part of the Get With The Guidelines (GWTG) HF quality improvement (QI) initiative. Methods: GWTG HF is an in-hospital quality initiative designed to improve care by promoting adherence to the latest scientific guidelines. A retrospective review was conducted of HF discharges from 19 hospitals using GWTG HF in Wisconsin and Michigan from 2011-2014. Readmission rates were determined from Centers for Medicare and Medicaid Services data. Results: 19 hospitals demonstrated improvement in the percentage of HF patients undergoing a follow-up visit within 7 days of hospital discharge when using GWTG HF as a QI program. As the percentage of HF patients receiving a follow-up visit within 7 days of hospital discharge increases, the number of readmissions decreases by 3% or 413 discharges over 4 years, which resulted in $5,369,000 cost savings. Conclusions: An in-hospital QI program, such as GWTG HF, improves the percentage of HF patients receiving a follow-up visit with 7 days of hospital discharge. Adherence to patient follow up visits for HF patients within 7 days of discharge leads to reduction in readmission rates. This translates into significant healthcare cost saving directly related to readmission in this patient category. Larger studies using a higher number of hospitals participating in quality programs is recommended.
A new side to an old coin: dynamin related protein-1 with benefits in the heart
Authors: Klitos Konstantinidis
Journal: Cardiovascular Research (2016)

This editorial refers to ‘A novel fission-independent role of dynamin-related protein 1 in cardiac mitochondrial respiration’ by Zhang et al ., pp. 160–170. 

Mitochondria are the powerhouse and a major constituent of cardiac myocytes with >40% of the cytoplasmic space occupied by mitochondria. The last few years, it has become evident that mitochondrial function and shape are closely interrelated.1 Mitochondrial shape is determined by two dynamic processes, fusion and fission. Mitochondrial fusion, mainly regulated by the outer mitochondrial membrane proteins mitofusin 1 and 2 (MFN1 and 2) and the inner mitochondrial membrane protein optic atrophy 1 (OPA1), leads to fused, elongated mitochondria. In contrast, fission results in fragmented, less filamentous mitochondria. The main regulator of fission is dynamin related protein-1 (DRP1), a member of the dynamin family of GTPases. DRP1 is a cytosolic protein which, upon post-translational modifications (phosphorylation, oxidation), translocates to the mitochondria where by oligomerization and constriction leads to mitochondrial fission. Non-cardiomyocyte cells with more filamentous mitochondrial networks exhibit a dynamic state of mitochondrial fusion and fission with remarkable changes in mitochondrial shape when the equilibrium is shifted towards the favour of either process. Adult cardiomyocytes, however, are inherently fragmented and exhibit far …
Donor Treatment with α1 Anti-Trypsin (AAT) Mitigates Gvhd and Increases Survival While Sparing GVL Effects
Authors: A. Mario Q. Marcondes, Ekapun Karoopongse, Marina Lesnikova, Sabina Janciauskiene, Charles A. Dinarello, H. Joachim Deeg
Journal: Blood (2012)