bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract POSTER-TECH-1103: Aspirin, NSAIDS, and ovarian cancer survival from electronic medical records
Authors: Beeghly-Fadiel Alicia , Holman Gwendolyn , Stansel Samantha P. , Edwards Gretchen , Baeg Edward , Berke Hannah , Delahanty Ryan J. , Khabele Dineo
Published: August 2015

Background: Extensive literature indicates that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are associated with reduced cancer incidence and mortality. For ovarian cancer, a pooled analysis of 12 case-control studies recently demonstrated a significantly reduced risk for regular aspirin use and a similar but non-significant reduced risk for non-aspirin NSAID use. However, studies specifically evaluating NSAIDs and ovarian cancer survival are absent from the published literature.

Purpose: To determine if aspirin and other NSAIDs are associated with ovarian cancer survival.

Methods: Ovarian cancer cases were identified from de-identified electronic medical records (EMR) from the Vanderbilt University Medical Center. Ever use of aspirin or any NSAID was determined by MedEx, a natural language processing system designed to capture medication use from EMR. Linked tumor registry data was used to generate hazard ratios (HR) and confidence intervals (CI) for overall survival using Cox proportional hazards regression; covariates included age, race, stage of disease, histologic subtype, treatments received, and year of diagnosis.

Results: The majority of 1,147 confirmed ovarian cancer cases were Caucasian (87.0%), had serous histologic subtypes (53.6%), and late stage (III/IV, 50.0%) or stage unknown (29.3%) disease. Ovarian cancer cases with any aspirin use (207, 18.1%) had significantly longer overall survival in both unadjusted (HR: 0.56, 95% CI: 0.45-0.70) and adjusted analyses (HR: 0.59, 95% CI: 0.46-0.74). Similarly, ovarian cancer cases with any non-aspirin NSAID use (248, 21.6%) had significantly longer overall survival in both unadjusted (HR: 0.60, 95% CI: 0.48-0.74) and adjusted analyses (HR: 0.69, 95% CI: 0.54-0.88). Associations between any aspirin or other NSAID use (360, 31.4%) and longer ovarian cancer survival did not significantly differ by stage of disease (P-interaction=0.650), histologic subtype (P-interaction=0.076), or treatment with a platinum-based agent (P-interaction=0.069).

Conclusions: Indication of aspirin or non-aspirin NSAID use ascertained retrospectively from EMR was associated with improved overall ovarian cancer survival. Further evaluation, including timing and duration of use, are underway; replication of this association in additional study populations is needed.

Citation Format: Alicia Beeghly-Fadiel, Gwendolyn Holman, Samantha P. Stansel, Gretchen Edwards, Edward Baeg, Hannah Berke, Ryan J. Delahanty, Dineo Khabele. Aspirin, NSAIDS, and ovarian cancer survival from electronic medical records [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1103.
Abstract POSTER-TECH-1122: Mass spectrometric imaging of ovarian cancer mouse model tissue: searching for high-grade serous carcinoma biomarkers
Authors: Paine Martin R. L. , Bennett Rachel V. , Kim Jaeyeon , Sullards M. Cameron , Matzuk Martin M. , Fernández Facundo M.
Published: August 2015

High-grade serous carcinoma (HGSC) is the most common and deadliest ovarian cancer responsible for 90% of all ovarian cancer deaths. Studying the origin and early progression of this deadly cancer is critical in identifying biomarkers for early detection of the disease. Unfortunately, in the case of HGSC, it is virtually impossible to obtain early-stage human HGSC tissue samples because there is no diagnostic method capable of detecting early forms of HGSC. The recent breakthrough of an animal model (Dicer-Pten double-knockout mice) provides an invaluable opportunity to finally investigate the early tumor microenvironment. The model exhibits remarkable similarities to human HGSC, allowing greater insight into the biochemistry associated with nascent neoplastic changes within ovarian and fallopian tube tissues. An important aspect of determining potential biomarkers is to correlate any detected chemical changes with observed histological changes. To visualize the spatial distribution of chemical changes, tissue-based mass spectrometric imaging (MSI) can be employed as an unbiased way of visualizing the changes of proteins, metabolites, or both in cancer tissues. MSI is particularly useful for identifying molecules uniquely elevated or lowered in early tumor tissues, in which cell-type specific changes are expected to occur due to intratumoral microenvironment heterogeneity. In this study, two complementary MSI techniques – matrix-assisted laser desorption ionization (MALDI) and desorption electrospray ionization (DESI) mass spectrometry – are applied to thin tissue sections of Dicer-Pten mutant mouse ovaries and fallopian tubes. Several sulfatide lipids d18:1/C16:0, d18:1/C24:1 and d18:1/C24:0 have been implicated as potential biomarkers in human ovarian cancer. These metabolites, among others, are being included in a thorough MSI experiment to visualize molecular changes in multiple cell types in the microenvironment during early tumor progression. In addition to providing information about the early molecular changes taking place, the knowledge gained from this study will also help understand which specific cell types in the fallopian tube are more prone to early tumorigenesis.

(Grant support: Marsha Rivkin Ovarian Cancer Challenge Grant)

Citation Format: Martin R. L. Paine, Rachel V. Bennett, Jaeyeon Kim, M. Cameron Sullards, Martin M. Matzuk, Facundo M. Fernández. Mass spectrometric imaging of ovarian cancer mouse model tissue: searching for high-grade serous carcinoma biomarkers [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1122.
Abstract POSTER-THER-1409: Targeting p53-FoxM1 axis in ovarian cancer
Authors: Zhang Xuan , Cheng Lihua , Minn Kay , Waggoner Magdalena , Parelkar Nikhil K. , Jokar Iman , Vielhauer George A. , Madan Rashna , Godwin Andrew K. , Shridhar Viji , Chien Jeremy
Published: August 2015

FoxM1, a member of the Forkhead transfection factors, has been found to be overexpressed in many human cancers including ovarian cancer. Although FoxM1 is known to be downregulated by p53, the molecular mechanisms are not well characterized. In this study, we used the MDM2 inhibitor Nutlin-3 as a tool to modulate p53 expression and investigated the mechanism by which p53 regulates FoxM1 expression in ovarian cancer cells. We observed that Nutlin-3 upregulated p53 protein and downregulated FoxM1 mRNA and protein levels in ovarian cancer cell lines with wild type TP53, but not in cell lines with mutant TP53. This effect was at least partially blocked by cycloheximide or actinomycin D, indicating a transcription- and translation-dependent mechanism. Pulse-chase studies revealed that downregulation of FoxM1 by Nutlin-3 is due to enhanced FoxM1 mRNA decay. Knockdown of p53 using shRNAs abrogated the suppression of FoxM1 expression by Nutlin-3, indicating a p53-dependent mechanism. Furthermore, silencing of FoxM1 by shRNAs in ovarian cancer cells with or without wild-type TP53 led to a significant decrease in cell proliferation. The FoxM1 inhibitor, thiostrepton, induces cytotoxicity in ovarian cancer cell lines and enhances sensitivity to cisplatin in these cells. Thiostrepton downregulates FoxM1 expression in several ovarian cancer cell lines and enhances sensitivity to carboplatin in vivo. Finally, FoxM1 expression is elevated in nearly all (47/48) ovarian tumors. In summary, the present study provides novel evidence that p53 downregulates FoxM1 in ovarian cancer cells at least in part by destabilizing FoxM1 mRNA and that FoxM1 may be targeted for therapeutic benefits in ovarian cancer.

Citation Format: Xuan Zhang, Lihua Cheng, Kay Minn, Magdalena Waggoner, Nikhil K. Parelkar, Iman Jokar, George A. Vielhauer, Rashna Madan, Andrew K. Godwin, Viji Shridhar,, Jeremy Chien. Targeting p53-FoxM1 axis in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1409.
Abstract POSTER-THER-1411: MM-141, an IGF-1R and ErbB3 directed tetravalent bispecific antibody, inhibits ovarian cancer cell growth in vitro
Authors: Curley Michael , Czibere Akos , Lugovskoy Alexey
Published: August 2015

PURPOSE OF STUDY: Insulin-like growth factor receptor 1 (IGF-1R) signaling has been implicated in the pathogenesis of ovarian cancer. However, IGF-1R inhibitors have had limited efficacy in clinical trials to date. ErbB3, a member of the ErbB receptor tyrosine kinase family, can activate AKT survival signaling through binding of its ligand heregulin (HRG) in a majority of IGF-1 sensitive human cancer cell lines. ErbB3 and pAKT expression are upregulated following IGF-1R blockade and thus activated ErbB3 signaling may represent a potential escape route in the development of resistance to therapy. MM-141, an IGF-1R and ErbB3 directed bispecific antibody, blocks and degrades IGF-1R and ErbB3 containing receptor complexes leading to inhibition of downstream tumor pro-survival signaling to a greater extent as compared to anti-IGF-1R and ErbB3 antibodies. Here we explore the activity of MM-141 in ovarian cancer cell lines in vitro.

EXPERIMENTAL PROCEDURES: Growth inhibitory activity of MM-141 was tested on a panel of established ovarian cancer cell lines in vitro. The ability of MM-141 to inhibit basal and IGF-1- and HRG-induced signaling was explored by ELISA and western blotting analyses.

DATA SUMMARY: Inhibition of cell proliferation mediated by MM-141 varied among the ovarian cancer cell lines profiled in vitro. Furthermore, MM-141 treatment inhibited basal and ligand-activated IGF-1R, ErbB3 and downstream signaling in a selection of these ovarian cell lines.

CONCLUSIONS: Our findings suggest that co-inhibition of IGF-1R and ErbB3 signaling with MM-141 has the potential to be an effective therapy for ovarian cancer patients by blocking redundant survival pathway activation.

Citation Format: Michael Curley, Akos Czibere, Alexey Lugovskoy. MM-141, an IGF-1R and ErbB3 directed tetravalent bispecific antibody, inhibits ovarian cancer cell growth in vitro [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1411.
Abstract POSTER-THER-1421: Epigenetic targeting of ovarian cancer stem cells
Authors: Wang Yinu , Cardenas Horacio , Fang Fang , Condello Salvatore , Taverna Pietro , Segar Matthew , Liu Yunlong , Matei Daniela , Nephew Kenneth P.
Published: August 2015

In ovarian and other cancers, emerging data indicate that cancer stem cells contribute to chemoresistance and that their persistence alters clinical outcome. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may play a critical role in targeting this subpopulation. Epigenetic aberrations, especially DNA methylation, result in silencing of tumor suppressor and differentiation-associated genes and regulate ovarian cancer stem cell (OCSCs) survival. To test the hypothesis that DNA hypomethylating agents “reset” OCSCs towards differentiation, we investigated the effect of the new DNA methytransferase inhibitor SGI-110 on OCSCs, defined as aldehyde dehydrogenase 1 (ALDH)(+) cells. We demonstrated that ALDH(+) OC cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low dose SGI-110 reduced the stemness properties of ALDH(+) cells, including their tumor initiating capacity, resensitized these OCSCs to platinum, and induced re-expression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSCs, caused profound global tumor hypomethylation, and delayed tumor progression, supporting epigenomic targeting as a novel strategy after platinum-based therapy in OC. Collectively, our data suggest that a strategy targeting DNA methylation in OC exerts potent anti-tumor activity by allowing elimination of OCSCs enriched in residual, platinum resistant tumors. Our study provides the first evidence that epigenome targeting strategies delay tumor progression by targeting and reprogramming residual cancer stem cells, suggesting that SGI-110 in combination with platinum has the potential to prevent recurrent and chemoresistant OC.

Citation Format: Yinu Wang, Horacio Cardenas, Fang Fang, Salvatore Condello, Pietro Taverna, Matthew Segar, Yunlong Liu, Daniela Matei, Kenneth P. Nephew. Epigenetic targeting of ovarian cancer stem cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1421.
Abstract POSTER-THER-1427: Epidermal growth factor receptor mediated alterations in DNA methylation associated with the development of platinum resistance in ovarian cancer cells
Authors: Samudio-Ruiz Sabrina L. , Granados Michaela L. , Hudson Laurie G.
Published: August 2015

Acquisition of platinum resistance following first line platinum-taxane therapy occurs in a large portion of ovarian cancer patients and continues to be a major challenge in clinical effectiveness. To date, there are limited interventions available to prevent or reverse platinum resistance; however, there has been some advances in the use of demethylating agents in the resensitization of patients to platinum based therapy. This highlights epigenetic alterations, in particular DNA methylation, as critical contributors to the acquisition of drug resistance in ovarian cancer. The Epidermal Growth Factor Receptor (EGFR) has also been linked to chemoresistance and is known to be activated by cisplatin treatment. We previously published that activation of the EGFR can increase DNA methyltransferase (DMNT) activity and, over extended activation, can significantly increase global DNA methylation in ovarian cancer cells. We hypothesized that cisplatin induced activation of the EGFR could mediate changes in DNA methylation associated with the development of platinum resistance. To investigate this, we used an in vitro model of platinum resistance and evaluated EGFR signaling and DNMT activity after acute cisplatin and in platinum resistant cells. We found that cisplatin treatment activates the EGFR and downstream signaling pathways JAK and AKT. Cisplatin also increased DNMT activity and this increase was dependent on EGFR activation. Over repeated sequential treatments of cisplatin, we successfully developed platinum resistant cells that possessed significant increases in DNMT activity and had moderate, but significant, increases in global DNA methylation. Preliminary data using the EGFR inhibitor Erlotinib during the development of platinum resistant cells suggest that the EGFR plays an integral role in the acquisition of platinum resistance. This work implicates EGFR driven alterations to DNMT activity and DNA methylation as a novel mechanism for development of platinum resistance. Further studies are currently being done to evaluate potential alterations in activation of downstream signaling pathways, levels of DNA methyltransferases and other changes in expression associated with platinum resistance.

Citation Format: Sabrina L. Samudio-Ruiz, Michaela L. Granados, Laurie G. Hudson. Epidermal growth factor receptor mediated alterations in DNA methylation associated with the development of platinum resistance in ovarian cancer cells [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1427.
Downregulation of IL6 Targeted MiR-376b May Contribute to a Positive IL6 Feedback Loop During Early Liver Regeneration in Mice
Authors: Lu Shan , Jiao Heng , Xu Juan , Zheng Yongxia , Sun Yimin , Chen Huan
Published: August 2015

Background/Aims: MicroRNAs (miRNAs) are a group of endogenous, small, noncoding RNAs implicated in a variety of biological processes, including cell proliferation, apoptosis, differentiation and metabolism. The present study aims to explore the potential role and molecular mechanism of miR-376b during the early phase of liver regeneration. Methods: MiRNA profiling microarrays were used to assess the changes in miRNA expression. For functional analysis, cell proliferation, apoptosis assays, real time quantitative PCR and westernblot analysis were performed. Results: The comprehensive miRNA expression profiling assays on regenerating liver tissues 4 h after partial hepatectomy (PH) showed that three miRNAs (miR-127, miR-376b and miR-494) located in the Dlk1-Gtl2 miRNA cluster were significantly downregulated. In vitro functional studies demonstrated that high-level interleukin 6 (IL6) inhibited the expression of miR-376b, and miR-376b mimics treatment decreased cell proliferation and increased apoptosis. Further target analysis showed that miR-376b reduced the mRNA and protein expression levels of NF-kappa-B inhibitor zeta (NFKBIZ) and signal transducers and transcription activators 3 (STAT3). Additionally, IL6-induced miR-376b downregulation would, in turn, increase the expression of IL-6 possibly via a feedback loop involving NFKBIZ or/and STAT3. Conclusion: During the early phase of liver regeneration, miR-376b expression was significantly decreased. Our findings reveal that a regulatory circuitry between miR-376b and IL-6 may exist, which trigger the initiation of liver regeneration.
Breakdown of Sensorimotor Network Communication in Leukoaraiosis
Authors: Wu Xia , Lai Youzhi , Zhang Yumei , Yao Li , Wen Xiaotong
Published: August 2015

Background: Leukoaraiosis (LA) patients may suffer from sensorimotor dysfunctions. The relationship between behavioral disturbances and changes in the sensorimotor network (SMN) has not been thoroughly elucidated. Objective: This study investigated the hypothesized breakdown of communication of SMN and its behavioral consequences in LA. Methods: Fluid-attenuated inversion recovery (FLAIR) images, resting-state functional magnetic resonance images (fMRI) and behavioral data were collected from 30 LA patients and 26 healthy individuals (normal controls, NC). The subjects were grouped according to LA severity, as indicated by their FLAIR images. Group independent component analysis was applied to the fMRI data to map the functional connectivity of SMN for NC and LA patients. A whole-brain, voxel-wise analysis was employed to investigate the functional connectivity alteration of SMN in LA. The relationships between LA severity, functional connectivity alteration of the SMN and behavioral clinical symptoms were examined by correlation analysis. Results: The right cingulate motor area (rCMA), left posterior insula and left ventral premotor area showed attenuated functional connectivity in the LA patients. The extent of the attenuation was related to the severity of the disease. Furthermore, the attenuation in the rCMA was associated with worse sensorimotor integration performance. Conclusions: These results suggest that LA impairs sensorimotor integration by interfering with the communication or coordination of these aforementioned regions related to the SMN.
New Strategies in the Prevention of Actinic Keratosis: A Critical Review
Authors: Krutmann Jean , Berking Carola , Berneburg Mark , Diepgen Thomas L. , Dirschka Thomas , Szeimies Markus
Published: August 2015

Actinic keratosis (AK) or lesions of epidermal dysplasia occurring in skin chronically exposed to solar radiation is very prevalent in lighter skin persons, with chronic long-term sun exposure being the major risk factor. With an aging population it is expected that the prevalence of AK will further increase. AK can progress to nonmelanoma skin cancer (NMSC) and is a public health concern. Six leading dermatologists with expertise in AK and NMSC from Germany met to discuss the nature of the disease and the prevention and treatment strategies available to dermatologists today. While cosmetic sunscreen products form an essential element of sun protection strategies, they are not adequate when damage has already been inflicted. Newly developed products of the medical device category offer DNA repair function paired with high sun protection factor (SPF) UV protection. An adjuvant treatment algorithm for various risk levels of AK was developed. For patients with low and moderate risk, sunscreen only is recommended. For patient groups with high and very high risk, a very high photoprotection and photorepair action (DNA repair enzymes) in medical device products all year round is recommended.
Stress, Immune Function and Collegiate Holiday Drinking: A Pilot Study
Authors: Ceballos Natalie A. , Sharma Shobhit , Patterson Thomas L. , Graham Reiko , Howard Krista
Published: August 2015

Background/Aims: Social aspects of collegiate holiday drinking have been studied frequently, but physiological consequences are often overlooked. This study examined self-reported stress, endocrine and immune indicators in students at an American university before and after their week-long spring break (SB) holiday. Methods: Participants (n = 27; 9 males) provided saliva samples and completed surveys pre- and post-SB. Based on their cortisol reaction to SB, participants were grouped as cortisol nonresponders (CNR; n = 14) or increasers (CI; n = 13). Groups were matched on demographics, baseline alcohol use, family history of alcoholism, and SB plans. Differences over time and between groups were examined for α-amylase, quantity/frequency of alcohol use (quantity/frequency index, QFI) and the immunoglobulin A (IgA) to albumin ratio (IgA:albumin). Results: α-Amylase decreased over time. A time × group interaction was noted for QFI, in which CNRs increased drinking over SB, but CIs did not. Time and time × group effects occurred for IgA:albumin. CIs decreased IgA:albumin over SB, whereas CNRs did not. Pre-SB QFI and pre-/post-SB QFI changes were correlated with changes in IgA:albumin. Conclusion: These findings support previously published relationships between blunted cortisol responses and risk for problem drinking, as well as elevated cortisol and decreased immune response. These data also highlight the importance of physiological measures in the study of collegiate holiday drinking.
Citrate Formulation Determines Filter Lifespan during Continuous Veno-Venous Hemofiltration: A Prospective Cohort Study
Authors: Jacobs Rita , Honoré Patrick M. , Bagshaw Sean M. , Diltoer Marc , Spapen Herbert D.
Published: August 2015

Introduction: We conducted an 8-month prospective single-center observational study in patients with acute kidney injury treated with continuous veno-venous hemofiltration (CVVH) to compare the impact of two citrate formulations on filter lifespan (FLS). Methods: Patients received CVVH at a delivered dose of 25 ml/kg/h. Multivariable linear regression was performed to assess the influence of different variables on circuit lifespan. Results: We included 59 patients, 28 received the 10/2 formulation and 31 received the 18/0 formulation. Median (interquartile range) FLS was significantly prolonged with the 18/0 solution compared with the 10/2 solution (4.10 (2.45-5.75) vs. 2.68 (0.47-4.99) days, p = 0.001). No confounding variables (difference in ionized calcium target, citrate flow or dose, platelet count, hematocrit, vascular access location) affecting filter capacity or lifespan between the 2 formulations were identified. Conclusions: Under similar conditions of CVVH and calcium targets, a Prismocitrate 18/0 formulation significantly improved FLS as compared with Prismocitrate 10/2.
Novel Histone Deacetylase Inhibitor Modulates Cardiac Peroxisome Proliferator-Activated Receptors and Inflammatory Cytokines in Heart Failure
Authors: Lkhagva Baigalmaa , Lin Yung-Kuo , Kao Yu-Hsun , Chazo Tze-Fan , Chung Cheng-Chih , Chen Shih-Ann , Chen Yi-Jen
Published: August 2015

Background: Heart failure (HF) affects cardiac metabolism and inflammation. Histone deacetylases (HDACs) play a critical role in cardiac pathophysiology. This study investigated whether HDAC inhibition can regulate HF by modifying cardiac inflammation and peroxisome proliferator-activated receptor (PPAR) isoforms. Methods: Echocardiography, electrocardiography, ELISA and Western blot were performed in rats with isoproterenol-induced HF, with and without orally administered MPT0E014 (a novel HDAC inhibitor, 50 mg/kg for 7 consecutive days). Results: The left ventricles (LVs) of HF rats expressed significantly higher levels of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 than the healthy LVs did. HF rats treated with MPT0E014 exhibited improved cardiac fraction shortening with reducing chamber size. The MPT0E014-treated HF LVs exhibited a smaller increase in the expression of interleukin (IL)-6, p22, SMAD2/3, extracellular signal-regulated kinase 1/2, PPAR isoforms and circulatory tumor growth factor-β1 than the untreated HF LVs did. Moreover, MPT0E014-treated HF LVs expressed less fibroblast growth factor receptor than untreated HF LVs did. Conclusions: HDAC inhibition can improve cardiac function and attenuate the effects of HF on cardiac metabolism and inflammation, which might contribute to the beneficial effects of HDAC inhibition in HF.
Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18
Authors: Hamad Osama A. , Mitroulis Ioannis , Fromell Karin , Kozarcanin Huda , Chavakis Triantafyllos , Ricklin Daniel , Lambris John D. , Ekdahl Kristina N. , Nilsson Bo
Published: August 2015

Complement component C3 has a potential role in thrombotic pathologies. It is transformed, without proteolytic cleavage, into C3(H2O) upon binding to the surface of activated platelets. We hypothesise that C3(H2O) bound to activated platelets and to platelet-derived microparticles (PMPs) contributes to platelet-PMN complex (PPC) formation and to the binding of PMPs to PMNs. PAR-1 activation of platelets in human whole blood from normal individuals induced the formation of CD16+/CD42a+ PPC. The complement inhibitor compstatin and a C5a receptor antagonist inhibited PPC formation by 50 %, while monoclonal antibodies to C3(H2O) or anti-CD11b inhibited PPC formation by 75–100 %. Using plasma protein-depleted blood and blood from a C3-deficient patient, we corroborated the dependence on C3, obtaining similar results after reconstitution with purified C3. By analogy with platelets, PMPs isolated from human serum were found to expose C3(H2O) and bind to PMNs. This interaction was also blocked by the anti-C3(H2O) and anti-CD11b monoclonal antibodies, indicating that C3(H2O) and CD11b are involved in tethering PMPs to PMNs. We confirmed the direct interaction between C3(H2O) and CD11b by quartz crystal microbalance analysis using purified native C3 and recombinant CD11b/CD18 and by flow cytometry using PMP and recombinant CD11b. Transfectants expressing CD11b/CD18 were also shown to specifically adhere to surface-bound C3(H2O). We have identified contact-activated C3(H2O) as a novel ligand for CD11b/CD18 that mediates PPC formation and the binding of PMPs to PMNs. Given the various roles of C3 in thrombotic reactions, this finding is likely to have important pathophysiological implications.
Post-Transcriptional Regulation of Endothelial Nitric Oxide Synthase Expression by Polypyrimidine Tract–Binding Protein 1
Authors: Yi Bing , Ozerova Maria , Zhang Guan-Xin , Yan Guijun , Huang Shengdong , Sun Jianxin
Published: August 2015

Objective—

Endothelial nitric oxide synthase (eNOS) is an important regulator of vascular function and its expression is regulated at post-transcriptional levels through a yet unknown mechanism. The purpose of this study is to elucidate the post-transcriptional factors regulating eNOS expression and function in endothelium.

Approaches and Results—

To elucidate the molecular basis of tumor necrosis factor (TNF)-α–mediated eNOS mRNA instability, biotinylated eNOS 3′-untranslational region (UTR) was used to purify its associated proteins by RNA affinity chromatography from cytosolic fractions of TNF-α-stimulated human umbilical vein endothelial cells (HUVECs). We identified 2 cytosolic proteins, with molecular weight of 52 and 57 kDa, which specifically bind to eNOS 3′-UTR in response to TNF-α stimulation. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis identified the 57-kDa protein as polypyrimidine tract–binding protein 1 (PTB1). RNA gel mobility shift and UV cross-linking assays demonstrated that PTB1 binds to a UCUU-rich sequence in eNOS 3′-UTR, and the C-terminal half of PTB1 is critical to this interaction. Importantly, PTB1 overexpression leads to decreased activity of luciferase gene fused with eNOS 3′-UTR as well as reduced eNOS expression and activity in human ECs. In HUVECs, we show that TNF-α markedly increased PTB1 expression, whereas adenovirus-mediated PTB1 overexpression decreased eNOS mRNA stability and reduced protein expression and endothelium-dependent relaxation. Furthermore, knockdown of PTB1 substantially attenuated TNF-α-induced destabilization of eNOS transcript and downregulation of eNOS expression.

Conclusions—

These results indicate that PTB1 is essential for regulating eNOS expression at post-transcriptional levels and suggest a novel therapeutic target for treatment of vascular diseases associated with inflammatory endothelial dysfunction.
Monocyte-Derived Dendritic Cells Upregulate Extracellular Catabolism of Aggregated Low-Density Lipoprotein on Maturation, Leading to Foam Cell Formation
Authors: Haka Abigail S. , Singh Rajesh K. , Grosheva Inna , Hoffner Haley , Capetillo-Zarate Estibaliz , Chin Harvey F. , Anandasabapathy Niroshana , Maxfield Frederick R.
Published: August 2015

Objective—

Although dendritic cells are known to play a role in atherosclerosis, few studies have examined the contribution of the wide variety of dendritic cell subsets. Accordingly, their roles in atherogenesis remain largely unknown. We investigated the ability of different dendritic cell subsets to become foam cells after contact with aggregated low-density lipoprotein (LDL; the predominant form of LDL found in atherosclerotic plaques).

Approach and Results—

We demonstrate that both murine and human monocyte-derived dendritic cells use exophagy to degrade aggregated LDL, leading to foam cell formation, whereas monocyte-independent dendritic cells are unable to clear LDL aggregates by this mechanism. Exophagy is a catabolic process in which objects that cannot be internalized by phagocytosis (because of their size or association with extracellular structures) are initially digested in an extracellular acidic lytic compartment. Surprisingly, we found that monocyte-derived dendritic cells upregulate exophagy on maturation. This contrasts various forms of endocytic internalization in dendritic cells, which decrease on maturation. Finally, we show that our in vitro results are consistent with dendritic cell lipid accumulation in plaques of an ApoE
−/−
mouse model of atherosclerosis.

Conclusions—

Our results show that monocyte-derived dendritic cells use exophagy to degrade aggregated LDL and become foam cells, whereas monocyte-independent dendritic cells are unable to clear LDL deposits. Furthermore, we find that exophagy is upregulated on dendritic cell maturation. Thus, exophagy-mediated foam cell formation in monocyte-derived dendritic cells could play a significant role in atherogenesis.
Prediction of Causal Candidate Genes in Coronary Artery Disease Loci
Authors: Brænne Ingrid , Civelek Mete , Vilne Baiba , Di Narzo Antonio , Johnson Andrew D. , Zhao Yuqi , Reiz Benedikt , Codoni Veronica , Webb Thomas R. , Foroughi Asl Hassan , Hamby Stephen E. , Zeng Lingyao , Trégouët David-Alexandre , Hao Ke , Topol Eric J. , Schadt Eric E. , Yang Xia , Samani Nilesh J. , Björkegren Johan L.M. , Erdmann Jeanette , Schunkert Heribert , Lusis Aldons J.
Published: August 2015

Objective—

Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes.

Approach and Results—

All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters. The latter included expression quantitative trait loci, tissue specificity, and miRNA binding. High priority candidate genes were further identified based on literature searches and our experimental data. We conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, we obtained evidence that genetic variants at CAD loci affect 98 genes which had not been linked to CAD previously.

Conclusions—

Our results substantially revise the list of likely candidates for CAD and suggest that genome-wide association studies efforts in other diseases may benefit from similar bioinformatics analyses.
Cryoballoon Ablation for Pulmonary Vein Isolation in Patients With Persistent Atrial Fibrillation
Authors: Koektuerk Buelent , Yorgun Hikmet , Hengeoez Oezlem , Turan Cem H. , Dahmen Alina , Yang Alexander , Bansmann Paul M. , Gorr Eduard , Hoppe Christian , Turan Ramazan G. , Horlitz Marc
Published: August 2015

Background—

Data regarding the freedom from atrial fibrillation (AF) in the follow-up of persistent AF patients is limited. The second-generation cryoballoon has better cooling properties compared with first-generation cryoballon. In this study, we aimed to assess the medium-term efficacy of second-generation cryoballoon in patients with persistent AF.

Methods and Results—

A total of 100 patients (63±10 years, 80% male) with symptomatic persistent AF, despite ≥1 antiarrhythmic drug(s), who were scheduled for pulmonary vein isolation using second-generation cryoballoon were enrolled in this study. Follow-up was based on outpatient clinic visits, including Holter ECGs. Recurrence was defined as a symptomatic or documented arrhythmia episode of >30 seconds excluding a 3-month blanking period. As a result, 393 pulmonary veins (7 patients with common ostium) were successfully isolated. Mean procedural and fluoroscopy times were 96.2±21.3 and 19.7±6.7 minutes, respectively. Phrenic nerve palsy occurred in 3% (3/100) of the patients. At a mean follow-up duration of 10.6±6.3 months, 67% of the patients were in sinus rhythm. Stepwise multivariable Cox proportional hazard regression analysis showed that early AF recurrence (hazard ratio 3.83, 95% confidence interval 1.91–7.68,
P
<0.001) was the only independent predictor for late AF recurrence apart from other clinical and echocardiographic variables.

Conclusions—

Our findings indicated that second-generation cryoballoon use is associated with favorable outcomes in patients with persistent AF. Recurrence at blanking period was the only predictor of long-term AF recurrence.
Periprocedural Myocardial Infarction After Carotid Endarterectomy and Stenting
Authors: Boulanger Marion , Camelière Lucie , Felgueiras Rui , Berger Ludovic , Rerkasem Kittipan , Rothwell Peter M. , Touzé Emmanuel
Published: August 2015

Background and Purpose—

Carotid angioplasty and stenting (CAS) is associated with higher risk of periprocedural stroke and death when compared with carotid endarterectomy (CEA). By contrast, the risk of myocardial infarction (MI) was higher after CEA than after CAS in randomized trials. However, numbers were small, and risk factors are unknown.

Methods—

We performed a systematic review and a meta-analysis of studies published from January 1980 to June 2014 and collected unpublished data. We extracted data on 9 predefined risk factors (age, contralateral carotid occlusion, coronary artery disease, diabetes mellitus, sex, hypertension, peripheral artery disease, type stenosis, and clinical presentation). We selected studies with data available on MI in at least 1 subgroup, calculated absolute and relative risks, and identified differential effects on risks of MI.

Results—

The 30-day absolute risk of MI was 0.87% (95% confidence interval, 0.69–1.07) after CEA and 0.70% (95% confidence interval, 0.54–0.88) after CAS (
P
int
=0.38). After CAS, patients with symptomatic stenosis and restenosis were at higher risk of MI, whereas men were at lower risk. After CEA, age, history of coronary artery disease, peripheral artery disease, and restenosis increased the risk of MI. Only the effect of sex differed between CAS and CEA with men being at lower risk of MI than women after CAS, whereas there was no difference between after CEA (
P
int
=0.01).

Conclusions—

The risk of MI after CEA and CAS did not significantly differ. Risk factors for MI are overall similar in both techniques except that men are at lower risk of MI after CAS but not after CEA.
Ethnic Differences in Poststroke Quality of Life in the Brain Attack Surveillance in Corpus Christi (BASIC) Project
Authors: Reeves Sarah L. , Brown Devin L. , Baek Jonggyu , Wing Jeffrey J. , Morgenstern Lewis B. , Lisabeth Lynda D.
Published: August 2015

Background and Purpose—

Mexican Americans (MAs) have an increased risk of stroke and experience worse poststroke disability than non-Hispanic whites, which may translate into worse poststroke quality of life (QOL). We assessed ethnic differences in poststroke QOL, as well as potential modification of associations by age, sex, and initial stroke severity.

Methods—

Ischemic stroke survivors were identified through the biethnic, population-based Brain Attack Surveillance in Corpus Christi (BASIC) Project. Data were collected from medical records, baseline interviews, and 90-day poststroke interviews. Poststroke QOL was measured at ≈90 days by the validated short-form stroke-specific QOL in 3 domains: overall, physical, and psychosocial (range, 0–5; higher scores represent better QOL). Tobit regression was used to model associations between ethnicity and poststroke QOL scores, adjusted for demographics, clinical characteristics, and prestroke cognition and function.

Results—

Among 290 eligible stroke survivors (66% MA, 34% non-Hispanic whites, median age=69 years), median scores for overall, physical, and psychosocial poststroke QOL were 3.3, 3.8, and 2.7, respectively. Poststroke QOL was lower for MAs than non-Hispanic whites both overall (mean difference, −0.30; 95% confidence interval, −0.59, −0.01) and in the physical domain (mean difference, −0.47; 95% confidence interval, −0.81, −0.14) after multivariable adjustment. No ethnic difference was found in the psychosocial domain. Age modified the associations between ethnicity and poststroke QOL such that differences were present in older but not in younger ages.

Conclusions—

Disparities exist in poststroke QOL for MAs and seem to be driven by differences in older stroke patients. Targeted interventions to improve outcomes among MA stroke survivors are urgently needed.
Benito Cereno and the Impossibility of Civility
Authors: Van Wyck James M.
Published: August 2015

In Benito Cereno, Melville indicts Northern moderates who thought that civil relations between Northern and Southern whites could bind together a splintering nation. Mocking the notion of benevolent white authority, he explores the danger—and the impossibility—of omitting black men and women from meaningful conceptions of sociality.
Records on the distribution of Ptychanthoideae (subfam. of Lejeuneaceae, Hepaticae) in Australia

Authors: Sass-Gyarmati A.
Published: August 2015

Three species are new for the Northern Territory of Australia: Acrolejeunea securifolia (Nees) Steph. ex Watts ssp. securifolia, Archilejeunea planiuscula (Mitt.) Steph. and Mastigolejeunea ligulata (Lehm. & Lindenb.) Schiffn., and one for Queensland: Thysananthus australis (Steph.) B. Thiers & Gradst. New records of species are given, which were previously known only from one or very few localities, including: Caudalejeunea cristiloba (Steph.) Gradst. and Lopholejeunea plicatiscypha (Taylor) Steph.
Two new species of Vatica (Dipterocarpaceae) from Peninsular Malaysia
Authors: Chua Lillian Swee-Lian , Thani Nor-Ezzawanis Abdullah , Yong Wendy Sze Yee , Mamat Hamidah
Published: August 2015

Two new species of Dipterocarpaceae, Vatica mizaniana and V. abdulrahmaniana are described from Peninsular Malaysia. Vatica mizaniana differs markedly from V. pedicellata, a Bornean endemic, in characters of the leaf and nut. Vatica abdulrahmaniana is differentiated from similar species V. nitens, by its pubescent stellate hairs on young and flowering twigs and semi-persistent floral bracts. The species description is accompanied with illustrations, distribution maps and ecological notes.
New species of Tauala Wanless, 1988 from Australia (Araneae: Salticidae: Astioida: Astiae), with a redefinition of the genus
Authors: ŻABKA MAREK , PATOLETA BARBARA M.
Published: August 2015

Five species of the genus Tauala Wanless, 1988, namely T. zborowskii sp. nov. (f), T. ottoi sp. nov. (f), T. palumaensis sp. nov. (m), T. bilobatus sp. nov. (m) and T. setosus sp. nov. (m), are diagnosed, described and illustrated. Additional colour plates with the females of T. lepidus Wanless, 1988 and T. athertonensis Gardzińska, 1996 and the male of T. splendidus Wanless, 1988 are provided, as well as distributional maps for these three species. Tauala elongata Peng & Li, 2002 is considered a non-congener. A revised definition of the genus is proposed and its distribution and relationships are discussed.
Molecular and morphological characterization of Veleshkinema iranicum n. gen., n. sp. (Nematoda: Hexatylina, Sphaerularioidea) from Iran
Authors: MIRAEIZ ESMAEIL , HEYDARI RAMIN , ÁLVAREZ-ORTEGA SERGIO , PEDRAM MAJID , ATIGHI MOHAMMAD REZA
Published: August 2015

Veleshkinema  iranicum n. gen., n. sp. is described and illustrated based on morphological, morphometric and molecular characters. The new genus is characterized by having slender females and males, stylet with asymmetrical knobs, dorsal gland orifice just posterior to subventral knob, lip region with flattened apex and eight sectors, pharynx with a non-muscular and non-valvular median bulb, pharyngeal glands slightly overlapping intestine dorsally, visible cellular cardia, female with a single gonad having a quadricolumellate crustaformeria with 8–10 cells in each column, no postvulval uterine sac and rounded and offset spermatheca containing spheroid sperm cells, males with arcuate tylenchoid spicules and subterminal bursa. The new genus is morphologically compared with four genera: Abursanema, Deladenus, Prothallonema and Sphaerularia. Molecular phylogenetic studies of the new genus using 808 bp partial sequences of SSU ribosomal RNA gene placed the new genus in a clade with Sphaerularia spp. In phylogenetic analyses using 756 bp partial sequences of the 28S ribosomal RNA gene (D2–D3 segments), the new genus formed a monophyletic group with Abursanema iranicum and Sphaerularia spp.
A new species of Isopsestis (Lepidoptera: Thyatiridae) from Yunnan, China
Authors: ZHUANG HAILING , OWADA MAMORU , WANG MIN
Published: August 2015

A new species of genus Isopsestis Werny, 1968 (Lepidoptera: Thyatiridae), Isopsestis poculiformis sp. nov., is described from the locality 2660m elevation in Northeast Yunnan, China, and compared with its closest ally. Male adult and genitalia of the new species are illustrated and a distribution map of the genus Isopsestis Werny, 1968 is provided.
The genus Leucophenga (Diptera, Drosophilidae), part V: the mutabilis species group from East Asia, with morphological and molecular evidence
Authors: Zhou Lan , Chen Hong-wei
Published: August 2015

A total of seven known species of the Leucophenga mutabilis species group are resurveyed from the East Asia: L. angusta Okada, 1956; L. bellula Bergroth, 1894; L. magnipalpis Duda, 1924; L. nigripalpis Duda, 1924; L. orientalis Lin & Wheeler, 1972; L. striatipennis Okada, 1989 and L. taiwanensis Lin & Wheeler, 1972. The diagnosis of the mutabilis group is revised, and a key to the seven species of this group is provided. DNA sequences of the mitochondrial COI (cytochrome c oxidase subunit I) gene with BOLD process ID and GenBank accession numbers are provided for these species. The pairwise intra- and interspecific Kimura two-parameter COI distances among the aforementioned seven known species are summarized; and the utility of DNA barcoding in the genus Leucophenga is discussed.
The family Caprellidae (Amphipoda: Caprelloidea: Caprellidae) from Campos Basin, Southwestern Atlantic, with a key of species occurring in Brazil
Authors: MAURO FÁBIO DA MOTTA , SEREJO CRISTIANA SILVEIRA
Published: August 2015

Caprellid material of the present study was collected between 25–3000 m depth from the Campos Basin area, Southwestern Atlantic. As a result, Deutella incerta was found as a new record to the Southwestern Atlantic and two new species are described: Liropus guerragarciai sp. nov. and Mayerella sittropiae sp. nov. Besides, Paracaprella pusilla is herein redescribed as a common component of the Campos Basin amphipod community. Caprellids are a diverse and abundant group that can be found among algae and general biological substrates of the continental shelf area. As more deep sea samples are coming into light, they are turning out to be also a common component in this habitat. Including the present data, there are 25 caprellid species recorded in Brazil, being four of them restricted to the slope areas and 14 endemic to the Brazilian coast. A key to the Caprellidae species from Brazil is provided.
A new species of Bambusaspis Cockerell (Hemiptera: Sternorrhyncha: Coccomorpha) colonising bamboo in Malaysia
Authors: ŁAGOWSKA BOZENA , MARTIN JON H. , HODGSON CHRIS J.
Published: August 2015

All life stages (adult female and male, first-instar nymph, second-instar male and female nymphs, and prepupa and pupa) of a new species of Asterolecaniidae, Bambusaspis transversa Lagowska & Martin sp. n., from bamboo in Malaysia, are described and illustrated. The adult female and first-instar nymphs are compared with those Bambusaspis species considered to be closest to the new species.