tbuckley/cabot-search huggingface dataset:
RasGRP3 regulates the activation of ras and rap1 and the migration of glioma cells
Authors: Hae Kyung Lee, Cunli Xiang, Simona Cazacu, Susan Finniss, Chaya Brodie
Journal: Cancer Research (2007)

LB-20  Gliomas are the most frequent primary brain tumors, accounting for more than 50% of all brain tumors. Glioblastomas, the most malignant form, are characterized by increased proliferationand invasion into the surrounding normal braintissue. Signaling pathways coupled to DAG production are highly active in glioma cells mainly downstream of the EGF and PDGF receptors. Similarly, Ras proteins are elevated in gliomas and play a role in their malignant phenotype. Although gliomas express high Ras activity and Ras proteins have been implicated in gliomagenesis, Ras activating mutations have not been identified in these tumors. RasGRP represents a new family of GEF proteins that belongs to the DAG/phorbol ester receptor family and that regulates the dissociation of GDPfrom Ras GTPases to enhance the formation of the active GTP-boundform. We previously found that RasGRP3 is expressed in gliomas and that stimulation with phorbol esters induces translocation of RasGRP3 to the peri-nuclear region and its interaction with PKCδ. We found that EGF also induced translocation of RasGRP3 to the peri-nuclear region, similar to the effect of phorbol esters. To examine the role of RasGRP3 in glioma cell function, we first overexpressed this protein in glioma cells. Overexpression of RasGRP3 increased the activation of both Ras and Rap1 and the phosphorylation of Erk1/2 and AKT. In addition, RasGRP3 significantly increased the migration and invasion of glioma cells and their anchorage-independent growth. The effect of RasGRP3 on cell migration was not dependent on the Erk1/2 pathway, since inhibition of Erk1/2 did not affect the migration of RasGRP3 over-expressing cells. In contrast, inhibition of AKT decreased the migration of both CV and RasGRP3 overexpressing cells. To explore the role of endogenous RasGRP3 in glioma cell functions, we employed siRNA duplexes directed against the RasGRP3 mRNA. Silencing of RasGRP3 in glioma cells that express high levels of this protein, decreased Ras activity, whereas it did not affect the activation of Rap1. In addition, silencing of RasGRP3 decreased the migration of the cells as compared to cells tranfected with control siRNA duplexes. The results of this study demonstrate that RasGRP3 plays a role in the regulation of Ras and Rap1 activation and in the migration of glioma cells. Thus, the RasGRP3 protein is an important link between the DAG and Ras signaling pathways and the astrocytic malignant transformation and may represent a novel therapeutic target in the treatment of gliomas.
SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B
Authors: Zhibin Yu, Yingnan Sun, Xiaoling She, Zeyou Wang, Shuai Chen, Zhiyong Deng, Yan Zhang, Qiang Liu, Qing Liu, Chunhua Zhao, Peiyao Li, Changhong Liu, Jianbo Feng, Haijuan Fu, Guiyuan Li, Minghua Wu
Journal: Journal of Hematology & Oncology (2017)

SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown.Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells.SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors.SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors.
Abstract NTOC-087: DYNAMIC REPROGRAMMING OF THE KINOME OVERCOMES BET PROTEIN INHIBITION IN OVARIAN CANCER
Authors: Alison M. Kurimchak, Claude Shelton, Kelly E. Duncan, Katherine J. Johnson, Jennifer Brown, Shane O'Brien, Rashid Gabbasov, Lauren S. Fink, Yuesheng Li, Nicole Lounsbury, Magid Abou-Gharbia, Wayne E. Childers, Denise C. Connolly, Jonathan Chernoff, Jeffrey R. Peterson, James S. Duncan
Journal: Clinical Cancer Research (2017)

Abstract High-grade serous ovarian carcinoma (HGS-OvCa) is the most common and deadly form of ovarian cancer, and currently lacks effective targeted therapies. Recently, proteins involved in chromatin remodeling such as the BET bromodomain protein BRD4 have emerged as an exciting new class of targets for the treatment of cancer. Targeted BRD4 inhibition has been shown to cause tumor regression and apoptosis in a number of cancers, including HGS-OvCa. Consequently, small molecule BET bromodomain inhibitors (BETi) are actively being pursued in clinical trials. In our preliminary studies, we discovered that the BET inhibitor JQ1 dramatically reduced MYC protein levels resulting in inhibited cell growth and survival in a panel of HGS-OvCa cell lines. Importantly, although JQ1 initially caused significant growth arrest and apoptosis, the majority of HGS-OvCa cell lines acquired drug resistance. Detailed molecular characterization of JQ1- resistant HGS-OvCa cells showed the return of MYC protein levels accompanied by elevated PI3K-AKT activity, suggesting the acquired resistance stems from activated kinase signaling. Our laboratory has designed a novel mass spectrometry approach that globally measures kinase activity to identify the kinase networks responsible for drug resistance. Using this technology, we analyzed global kinase activity in JQ1-resistant cells and observed the activation of several receptor-tyrosine kinases (RTKs), including EGFR, FGFRs and IGF1R known to strongly drive PI3K-AKT pro-survival signaling pathways. These findings suggest that BETi therapies may have limited success as single agent therapies due to “adaptive kinome reprogramming” and will likely require combination strategies involving inhibitors targeting protein kinases and BET bromodomain proteins. Citation Format: Alison M. Kurimchak, Claude Shelton, Kelly E. Duncan, Katherine J. Johnson, Jennifer Brown, Shane O'Brien, Rashid Gabbasov, Lauren S. Fink, Yuesheng Li, Nicole Lounsbury, Magid Abou-Gharbia, Wayne E. Childers, Denise C. Connolly, Jonathan Chernoff, Jeffrey R. Peterson, James S. Duncan. DYNAMIC REPROGRAMMING OF THE KINOME OVERCOMES BET PROTEIN INHIBITION IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-087.
Scientific Misconduct Hurts
Authors: George Henderson
Journal: Annals of Internal Medicine (2017)

Letters6 June 2017Scientific Misconduct HurtsGeorge HendersonGeorge HendersonFrom Auckland University of Technology, Auckland, New Zealand.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0147 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I read Laine's editorial (1) with interest. I work in the area of diet and risk for chronic diseases and would like to see this paper published. In fact, having read it without knowing that it was retracted, I could not at first understand why. However, its premise reminded me so much of Dansinger and colleagues' and Gardner and associates' studies that I easily understood the reason.I similarly do not understand why Dansinger and colleagues' manuscript was rejected in the first place. Either Finelli gave it such a bad review that the editors took his word ...Reference1. Laine C. Scientific misconduct hurts. Ann Intern Med. 2017;166:148-9. [PMID: 27951591]. doi:10.7326/M16-2550 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Auckland University of Technology, Auckland, New Zealand.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0147. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoScientific Misconduct Hurts Christine Laine Scientific Misconduct Hurts Christine Laine Metrics 6 June 2017Volume 166, Issue 11Page: 856KeywordsConflicts of interestCoronary heart diseaseDietDisclosureDrugsGenetic diseasesHigh density lipoprotein cholesterolLipidsLipoproteinsScientific misconduct ePublished: 6 June 2017 Issue Published: 6 June 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Significance of oliguria in critically ill patients with chronic liver disease
Authors: Roland Amathieu, Ali Al‐Khafaji, Florentina E. Sileanu, Emily Foldes, Rebecca DeSensi, Ibtesam Hilmi, John A. Kellum
Journal: Hepatology (2017)

Clinical guidelines recommend using Kidney Disease Improving Global Outcomes (KDIGO) criteria for the diagnosis and classification of acute kidney injury (AKI) in patients with chronic liver disease (CLD). Concerns have been raised about the use of urine output (UO) criteria in CLD. We examined the significance of oliguria meeting the urine output criteria for AKI (AKI‐UO) and examined its association with clinical outcomes in CLD patients. Using an 8‐year clinical database from a large university medical center, 3458 patients with CLD were identified. AKI occurred in 2854 (82.5%) patients when they fulfilled any KDIGO criteria. When serum creatinine (SC) and UO criteria were used, 604 patients (17.5%) had no evidence of AKI and had the lowest hospital mortality rate (5%). Using AKI‐UO criteria alone, 2103 patients (60.8%) were classified as stage 2‐3 AKI. When only SC criteria were applied, 1281 (61%) of those patients with stage 2‐3 AKI‐UO were misclassified as either no AKI or AKI stage 1. Patients reclassified with AKI according to UO criteria (AKI‐UO) had nearly a 3‐fold increased rate of hospital mortality compared with patients without any AKI (14.6% versus 5%; P &lt; 0.001) and more than a 50% increased mortality compared with stage 1 AKI‐SC (14.6% versus 9%; P &lt; 0.001). Patients with transient oliguria (AKI‐UO stage 1) had increased mortality rates compared with patients without oliguria (14.9% versus 6.9%; P &lt; 0.001). Conclusion : CLD patients have a high incidence of AKI. Compared with creatinine criteria alone, incorporating UO into the diagnostic criteria increased the measured incidence of AKI. Stage 2‐3 AKI‐UO has a high negative impact on hospital mortality. (H epatology 2017;66:1592–1600)
Mutations in the proapoptotic BAX gene are associated with defective DNA mismatch repair and altered tumor growth rates in human colon cancers
Authors: F. Sinicrope, R. L. Rego, A. J. French, N. R. Foster, D. J. Sargent, H. Windschitl, M. J. O'Connell, S. N. Thibodeau
Journal: Journal of Clinical Oncology (2007)

10529 Background: BAX mutations are associated with defective DNA mismatch repair (MMR) in human colon cancers. However, the impact of BAX inactivation upon tumor cell apoptosis and proliferation in vivo remain unknown. We analyzed and compared caspase-3 and Ki-67 expression in tumors with and without BAX mutations. Methods: TNM stage II and III (n= 377) colon carcinomas were studied from participants in a 5-FU-based adjuvant therapy trial. Archival tumors were analyzed for instability at the BAT26 mononucleotide locus using polymerase chain reaction and hMLH1, hMSH2 and hMSH6 by immunohistochemistry (IHC). Frameshift mutations in a tract of eight deoxyguanosines within BAX were analyzed. Expression of caspase-3 and Ki-67 proteins were analyzed by IHC. Results: Thirty-nine of 377 (10%) tumors showed defective MMR defined as instability at BAT26 and loss of either hMLH1, hMSH2 and/or hMSH6 proteins. BAX mutations were found in 20 of 37 (54%) MMR deficient tumors and in 1 of 50 (2%) tumors with intact MMR. Mean and median number of caspase-3-positive cells were increased in tumors with defective MMR (p= 0.04), but did not differ based upon BAX status [ Table ]. However, tumors with BAX mutations showed higher Ki-67 labeling indices compared to those with wild type BAX (p= 0.01)[ Table ]. Neither BAX mutations nor caspase-3- positive cells were prognostic in a univariate analysis. Tumors with lower Ki-67 extent had improved overall survival (p=0.06), but not DFS (p=0.24). Defective MMR (vs intact) was associated with better DFS in a multivariate analysis (p= 0.03). Conclusion: MMR deficient colon cancers show frequent BAX inactivation, yet have increased apoptotic rates as indicated by increased caspase-3 expressing tumor cells. BAX mutation was associated with hyperproliferation suggesting a growth advantage compared to wild type tumors. [Table: see text] No significant financial relationships to disclose.
Does the Type and Dose of Palliative Care Services Received by Patients With Advanced Heart Failure Impact Symptom Burden
Authors: Lorraine S Evangelista, Jennifer Ballard-Hernandez, Dawn Lombardo, Shaista Malik, Marjan Motle, Solomon Liao
Journal: Circulation (2013)

CORE 2. EPIDEMIOLOGY AND PREVENTION OF CV DISEASE: PHYSIOLOGY, PHARMACOLOGY AND LIFESTYLE SESSION TITLE: HEART FAILURE DISEASE MANAGEMENT Abstract 10131 : Does the Type and Dose of Palliative Care Services Received by Patients With Advanced Heart Failure Impact Symptom Burden? Lorraine S Evangelista, Jennifer Ballard-Hernandez, Dawn Lombardo, Shaista Malik, Marjan Motie and Solomon Liao Published: November 26, 2013 Article Info & Metrics eletters ..- Jump to Abstract Introduction: Outpatient palliative care (PC) for patients with symptomatic heart failure (HF) is a relatively new practice and few data exist that describe the nature of these clinical encounters. HYPOTHESIS: We hypothesized that the nature of outpatient PC services (i.e. type, duration, frequency) used by patients with advanced HF would impact symptom burden 3 months post-discharge. METHODS: This study was conducted at a single, tertiary care medical center. Patients were recruited from the inpatient setting during an episode of acute HF exacerbation and referred for an initial PC consultation and subsequent follow-up support with the PC team. Data on PC services accessed were monitored over 3 months. Telephone surveys were conducted immediately after and 3 months post-discharge to assess symptom burden. Results: Thirty six patients completed the initial PC consultation with a PC specialist (17%) or advanced practice nurse (83%); care focused on physical and psychosocial assessment (100%), advanced care planning (100%), symptom management (81 %}, illness understanding (69%), and patient and family coping (50%). Median total time for the initial PC consultation was 75 minutes (range 50-120). Twenty-nine (83.7%) agreed to receive
Patient and Public Safety Maximized by Rapid Opioid Taper—Reply
Authors: Paul Guillod, Ellen L. Edens, William C. Becker
Journal: JAMA Internal Medicine (2017)

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Abstract P316: Cysteine-Independent Interactions of Thioredoxin-1 and Apex1: Implications for Endothelial Cell Apoptosis and Aging?
Authors: Tim-Christian Zschauer, Lisa Beissel, Joachim Altschmied, Judith Haendeler
Journal: Circulation Research (2011)

Aging processes are associated with increased intracellular formation of reactive oxygen species. One redox regulator is the ubiquitously expressed oxidoreductase Thioredoxin-1 (Trx). It contains two active site cysteines and has anti-oxidative and anti-apoptotic properties. Trx levels are reduced in senescent endothelial cells (EC), leading to increased apoptosis sensitivity. Several functions of Trx are enhanced by its interaction with AP-endonuclease 1 (APEX1). APEX1 is a multifunctional protein and in concert with Trx-1 a reductive activator of e.g. the transcription factor AP-1, suggesting at least an interaction of Trx and APEX1 in vivo. Recent evidence suggests that also APEX1 levels are decreased in senescent cells. Therefore, the aim of this study is to understand the function of APEX1 in concert with Trx in EC. We first investigated whether APEX1, similar to Trx has anti-apoptotic properties in EC. Indeed, overexpression of APEX1 inhibited apoptosis. To analyze where the Trx/APEX1 interaction occurs, we performed fluorescence microscopy demonstrating a colocalization throughout the whole cell. To study the interaction in more detail, we carried out coimmunoprecipitations from nuclear and cytosolic extracts and demonstrated their association in both fractions. To determine whether disulfide bridges are involved in the Trx/APEX1 association, we mutated APEX1 cysteines 65, 93 and 310 previously shown to interact with cysteines in other proteins, to serines. This mutant bound Trx in the nucleus and cytosol of EC with the same efficiency as APEX1 wildtype. Moreover, a Trx mutant with serine mutations of active site cysteines (Trx(C32S/C35S)) was still able to bind to endogenous APEX1. These data demonstrate that the Trx/APEX-1 interaction is independent of disulfide bridge formation. We are currently analyzing a set of APEX1 deletion mutants for their interaction with Trx-1 and a potential loss of anti-apoptotic properties Exact delineation of the Trx/APEX1 interaction surface will in the future allow the development of small peptides containing the interaction domains of Trx or APEX1 respectively, in order to enhance transcription factor activity and bypass the loss of antioxidative capacity during aging processes.
E-selectin-targeted Sialic Acid-PEG-dexamethasone Micelles for Enhanced Anti-Inflammatory Efficacy for Acute Kidney Injury
Authors: Jing-Bo Hu, Xu-Qi Kang, Jing Liang, Xiao-Juan Wang, Xiao-Ling Xu, Ping Yang, Xiao-Ying Ying, Sai-Ping Jiang, Yong-Zhong Du
Journal: Theranostics (2017)

The effective treatment for acute kidney injury (AKI) is currently limited, and care is primarily supportive.Sialic acid (SA) is main component of Sialyl Lewis x antigen on the mammalian cell surface, which participates in E-selectin binding.Therefore, dexamethasone(DXM)-loaded E-selectin-targeting sialic acid-polyethylene glycol-dexamethasone (SA-PEG-DXM/DXM) conjugate micelles are designed for ameliorating AKI.The conjugates are synthesized via the esterification reaction between PEG and SA or DXM, and can spontaneously form micelles in an aqueous solution with a 65.6 µg/mL critical micelle concentration.Free DXM is incorporated into the micelles with 6.28 ± 0.21% drug loading content.In vitro DXM release from SA-PEG-DXM/DXM micelles can be prolonged to 48h.Much more SA-PEG-DXM micelles can be internalized by lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs) in comparison to PEG-DXM micelles due to specific interaction between SA and E-selectin expressed on HUVECs, and consequently more SA-PEG-DXM micelles are accumulated in the kidney of AKI murine model.Furthermore, SA in SA-PEG-DXM conjugates can significantly ameliorate LPS-induced production of pro-inflammatory cytokines via suppressing LPS-activated Beclin-1/Atg5-Atg12-mediated autophagy to attenuate toxicity.Compared with free DXM and PEG-DXM/DXM micelles, SA-PEG-DXM/DXM micelles show better therapeutical effects, as reflected by the improved renal function, histopathological changes, pro-inflammatory cytokines, oxidative stress and expression of apoptotic related proteins.