bluuebunny/crossref_metadata_2025 huggingface dataset:
Progesterone Upregulates Gene Expression in Normal Human Thyroid Follicular Cells
Authors: Bertoni Ana Paula Santin , Brum Ilma Simoni , Hillebrand Ana Caroline , Furlanetto Tania Weber
Published: May 2015

Thyroid cancer and thyroid nodules are more prevalent in women than men, so female sex hormones may have an etiological role in these conditions. There are no data about direct effects of progesterone on thyroid cells, so the aim of the present study was to evaluate progesterone effects in the sodium-iodide symporterNIS, thyroglobulinTG, thyroperoxidaseTPO, andKI-67genes expression, in normal thyroid follicular cells, derived from human tissue.NIS,TG,TPO, andKI-67mRNA expression increased significantly after TSH 20 μUI/mL, respectively: 2.08 times,P<0.0001; 2.39 times,P=0.01; 1.58 times,P=0.0003; and 1.87 times,P<0.0001. In thyroid cells treated with 20 μUI/mL TSH plus 10 nM progesterone, RNA expression ofNIS,TG, andKI-67genes increased, respectively: 1.78 times,P<0.0001; 1.75 times,P=0.037; and 1.95 times,P<0.0001, andTPOmRNA expression also increased, though not significantly (1.77 times,P=0.069). These effects were abolished by mifepristone, an antagonist of progesterone receptor, suggesting that genes involved in thyroid cell function and proliferation are upregulated by progesterone. This work provides evidence that progesterone has a direct effect on thyroid cells, upregulating genes involved in thyroid function and growth.
Numerical Investigation of Rockburst Effect of Shock Wave on Underground Roadway
Authors: Lu Cai-Ping , Liu Guang-Jian , Wang Hong-Yu , Xue Jun-Hua
Published: May 2015

Using UDEC discrete element numerical simulation software and a cosine wave as vibration source, the whole process of rockburst failure and the propagation and attenuation characteristics of shock wave in coal-rock medium were investigated in detail based on the geological and mining conditions of 1111(1) working face at Zhuji coal mine. Simultaneously, by changing the thickness and strength of immediate roof overlying the mining coal seam, the whole process of rockburst failure of roadway and the attenuation properties of shock wave were understood clearly. The presented conclusions can provide some important references to prevent and control rockburst hazards triggered by shock wave interferences in deep coal mines.
A Novel ID-Based Authentication and Key Exchange Protocol Resistant to Ephemeral-Secret-Leakage Attacks for Mobile Devices
Authors: Tseng Yuh-Min , Huang Sen-Shan , Tsai Tung-Tso , Tseng Li
Published: May 2015

With the rapid development in wireless communications and cloud computing technologies, clients (users) often use handheld mobile devices to access remote servers via open network channels. To provide authentication and confidentiality between clients and servers, a large number of ID-based authentication and key exchange (ID-AKE) protocols have been proposed for mobile client-server environments. However, most of the existing ID-AKE protocols adopt the precomputation technique so that they become vulnerable to the ephemeral-secret-leakage (ESL) attacks, in the sense that an adversary could use the ephemeral secrets to reveal the private keys of clients from the corresponding exchange messages. In the paper, we propose a new ESL-secure ID-AKE protocol for mobile client-server environments. We formally prove that the proposed protocol satisfies the security requirements of both mutual authentication and key exchange while resisting the ESL attacks. When compared with previously proposed ID-AKE protocols, our protocol has higher security and retains computational performance, since it requires no bilinear pairing operation for mobile clients. Finally, we mention the possibility of adopting our protocol as an authentication method of the extensible authentication protocol (EAP) for wireless networks.
Antiedematogenic Evaluation ofCopaifera langsdorffiiLeaves Hydroethanolic Extract and Its Major Compounds
Authors: Furtado Ricardo Andrade , Bernardes Cristiane Teixeira Vilhena , Silva Mauro Nogueira da , Zoccal Karina Furlani , Faccioli Lúcia Helena , Bastos Jairo Kenupp
Published: May 2015

Inflammatory disorders affect many people worldwide, and medicinal plants are used to ameliorate these health problems. This paper reports the antiedematogenic and analgesic evaluation ofCopaifera langsdorffiiDesf. leaves hydroethanolic extract (Cop) and two of its isolated compounds: quercetin-3-O-α-L-rhamnopyranosyl (quercitrin) and kaempferol-3-O-α-L-rhamnopyranosyl (afzelin). For that, the following experimental protocols were undertaken locomotor performance, writhing induced by acetic acid, antinociceptivity induced by formalin, hot plate latency, paw oedema induced by carrageenan and dextran, and cell migration induced by lipopolysaccharide (LPS), as well as the measurement of nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10) in macrophages. Neither the extract nor the isolated compounds displayed analgesic activity. The obtained results showed thatC. langsdorffiiextract possesses antiedematogenic properties acting on peripheral sites, whereas quercitrin and afzelin are not involved. Moreover, these properties are not associated with cell migration inhibition, TNF-α, IL-6, or IL-10 regulation.
Hereditary Hemorrhagic Telangiectasia with Hepatic Vascular Malformations
Authors: Nishioka Yujiro , Akamatsu Nobuhisa , Sugawara Yasuhiko , Kaneko Junichi , Arita Junichi , Sakamoto Yoshihiro , Hasegawa Kiyoshi , Kokudo Norihiro
Published: May 2015

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disease. Early diagnosis is important to avoid complications from vascular lesions, but diagnosis is difficult in asymptomatic patients. A 69-year-old Japanese male patient was referred to our hospital for evaluation of hepatic vascular malformations. He had mild anemia with iron deficiency, and dynamic contrast-enhanced computed tomography revealed significant arteriovenous and arterioportal shunts throughout the liver. Telangiectasia from the pharynx to the duodenum was confirmed by gastrointestinal endoscopy. The patient history revealed episodes of epistaxis as well as a family history of epistaxis. He was diagnosed with HHT, although no other family member had been diagnosed with definite HHT. A diagnosis of HHT must be considered in patients with hepatic vascular malformations.
The MicroRNA3686 Inhibits the Proliferation of Pancreas Carcinoma Cell Line by Targeting the Polo-Like Kinase 1
Authors: Jin Hong-Yi , Qiu Xin-Guang , Yang Bo
Published: May 2015

The Polo-like kinase 1 (PLK1) is one member of the so-called Polo-like kinase family which plays an important role in tumorigenesis. By analyzing the potential complementary microRNA (miRNA) targeting sequence of PLK1, we identified that miRNA-3686 (hereby and thereafter mir3696) could be the potential regulator for PLK1. Real-time PCR demonstrated that the mir3686 has a relatively higher expression in the immortalized pancreas cell HPDE6C7 than pancreas carcinoma derived cell line PANC1. The upregulation of mir3686 in HPDE6C7 cell corresponded with the low expression of PLK1 as well. Both luciferase based reporter assay and evaluation of endogenous PLK1 expression demonstrated that mir3686 regulated PLK1, which confirms our speculation. Moreover, we found that transfection of mir3686 in PANC1 cell could lead to proliferation inhibition and promote apoptosis. Further analysis demonstrated that mir3686 transfection in PANC1 cell also inhibited cell invasion, and clone formation in cell invasion assay and clonogenic cell survival assay, respectively. In contrast, inhibition of mir3686 expression in HPDE6C7 cell enhanced the capability of proliferation, cell invasion and clone formation. Taken together, our results indicated that mir3686 could target PLK1 to inhibit the cell proliferation in pancreas cancer derived cell line and mir3686 could be a new therapeutic target for pancreas cancer treatment.
The Microphone Feedback Analogy for Chatter in Machining
Authors: Schmitz Tony
Published: May 2015

This paper provides experimental evidence for the analogy between the time-delay feedback in public address systems and chatter in machining. Machining stability theory derived using the Nyquist criterion is applied to predict the squeal frequency in a microphone/speaker setup. Comparisons between predictions and measurements are presented.
Plasma C-Reactive Protein and Risk of Breast Cancer in Two Prospective Studies and a Meta-analysis
Authors: Wang Jun , Lee I-Min , Tworoger Shelley S. , Buring Julie E. , Ridker Paul M. , Rosner Bernard , Hankinson Susan E.
Published: May 2015

Background: C-reactive protein (CRP) has been evaluated as a risk factor for breast cancer in epidemiologic studies. However, results from prospective studies are inconsistent.

Methods: We evaluated the association using prediagnostic blood samples in a case–control study nested within the Nurses' Health Study (NHS) and the full cohort of the Women's Health Study (WHS). A total of 943 cases in the NHS and 1,919 cases in the WHS contributed to the analysis. Conditional logistic regression and Cox proportional hazards model were used in the NHS and WHS, respectively. We pooled our results with prior prospective studies using random effect meta-analysis.

Results: In the NHS, higher CRP levels were associated with a suggestively increased risk of breast cancer [quintile 5 vs. 1: relative risk (RR), 1.27; 95% confidence interval (CI), 0.93–1.73; Ptrend = 0.02]; results did not vary significantly by tumor invasiveness or hormone receptor status. However, no association was observed in the WHS for overall risk (quintile 5 vs. 1: RR, 0.89; 95% CI, 0.76–1.06; Ptrend = 0.38) or by tumor invasiveness or hormone receptor status. The meta-analysis (including 5,371 cases from 11 studies) showed a modestly increased risk among women in the highest versus lowest categories of CRP (RR, 1.26; 95% CI, 1.07–1.49).

Conclusions: Existing data from prospective studies suggest that CRP, a nonspecific marker of inflammation, is modestly positively associated with breast cancer risk.

Impact: Our findings provide support to the concept that inflammation can influence breast cancer development. Cancer Epidemiol Biomarkers Prev; 24(8); 1199–206. ©2015 AACR.
PIK3CA Somatic Mutation Status in Relation to Patient and Tumor Factors in Racial/Ethnic Minorities with Colorectal Cancer
Authors: Phipps Amanda I. , Ahnen Dennis J. , Cheng Iona , Newcomb Polly A. , Win Aung Ko , Burnett Terrilea
Published: May 2015

Background: Approximately 10% to 20% of colorectal cancers exhibit somatic mutations in the phosphoinositide-3-kinase, catalytic, alpha polypeptide gene (PIK3CA). We evaluated the relationship of PIK3CA mutation status in colorectal cancer with race/ethnicity, colorectal cancer survival, and other patient and tumor factors.

Methods: This study comprised 377 racial/ethnic minorities with incident invasive colorectal cancer, enrolled in the Colon Cancer Family Registry via population-based cancer registries. Tumor specimens were tested for PIK3CA mutations in exon 9 and 20 hotspots, BRAF p.V600E mutations, and DNA mismatch repair (MMR). In logistic regression models, we evaluated the association between PIK3CA mutation status and race/ethnicity, overall, and by mutation site. Using Cox regression, we evaluated the association between PIK3CA mutation status and survival after colorectal cancer diagnosis.

Results: PIK3CA mutations were detected in 42 cases (11%), with a similar prevalence across racial/ethnic groups. Individuals with PIK3CA-mutated colorectal cancer were significantly more likely than those with PIK3CA-wildtype disease to have proximal colon cancer, MMR-deficient tumors, and a germline MMR mutation (P ≤ 0.01). There was no evidence for an association between PIK3CA and overall survival (HR, 0.77; 95% confidence interval, 0.43–1.39).

Conclusions: The prevalence of PIK3CA mutation status in colorectal cancer does not differ according to race/ethnicity, but may vary according to other relevant clinicopathologic and etiologic factors, including germline MMR mutation status, tumor MMR status, and tumor site.

Impact: These findings underscore the importance of PIK3CA mutation status in colorectal cancer epidemiology and provide evidence that the prevalence of such mutations is similar across several racial/ethnic groups. Cancer Epidemiol Biomarkers Prev; 24(7); 1046–51. ©2015 AACR.
Model Matters: Differences in Orthotopic Rat Hepatocellular Carcinoma Physiology Determine Therapy Response to Sorafenib
Authors: Groß Claudia , Steiger Katja , Sayyed Sufyan , Heid Irina , Feuchtinger Annette , Walch Axel , Heß Julia , Unger Kristian , Zitzelsberger Horst , Settles Marcus , Schlitter Anna Melissa , Dworniczak Juliane , Altomonte Jennifer , Ebert Oliver , Schwaiger Markus , Rummeny Ernst , Steingötter Andreas , Esposito Irene , Braren Rickmer
Published: May 2015

Purpose: Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology noninvasively and identify differences between the models.

Experimental Design: DEN and McA tumor development was monitored by MRI and PET. A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors.

Results: Histologically and biochemically confirmed liver damage resulted in increased 18F-fluorodeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1–3 grading compared with uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared with McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only.

Conclusions: This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies. Clin Cancer Res; 21(19); 4440–50. ©2015 AACR.

See related commentary by Weber et al., p. 4254
Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor
Authors: Dorr Casey , Janik Callie , Weg Madison , Been Raha A. , Bader Justin , Kang Ryan , Ng Brandon , Foran Lindsey , Landman Sean R. , O'Sullivan M. Gerard , Steinbach Michael , Sarver Aaron L. , Silverstein Kevin A.T. , Largaespada David A. , Starr Timothy K.
Published: May 2015

Non–small cell lung cancers (NSCLC) harbor thousands of passenger events that hide genetic drivers. Even highly recurrent events in NSCLC, such as mutations in PTEN, EGFR, KRAS, and ALK, are detected, at most, in only 30% of patients. Thus, many unidentified low-penetrant events are causing a significant portion of lung cancers. To detect low-penetrance drivers of NSCLC, a forward genetic screen was performed in mice using the Sleeping Beauty (SB) DNA transposon as a random mutagen to generate lung tumors in a Pten-deficient background. SB mutations coupled with Pten deficiency were sufficient to produce lung tumors in 29% of mice. Pten deficiency alone, without SB mutations, resulted in lung tumors in 11% of mice, whereas the rate in control mice was approximately 3%. In addition, thyroid cancer and other carcinomas, as well as the presence of bronchiolar and alveolar epithelialization, in mice deficient for Pten were also identified. Analysis of common transposon insertion sites identified 76 candidate cancer driver genes. These genes are frequently dysregulated in human lung cancers and implicate several signaling pathways. Cullin3 (Cul3), a member of a ubiquitin ligase complex that plays a role in the oxidative stress response pathway, was identified in the screen and evidence demonstrates that Cul3 functions as a tumor suppressor.

Implications: This study identifies many novel candidate genetic drivers of lung cancer and demonstrates that CUL3 acts as a tumor suppressor by regulating oxidative stress. Mol Cancer Res; 13(8); 1238–47. ©2015 AACR.
Cyclic Mechanical Stretching Induces Autophagic Cell Death in Tenofibroblasts Through Activation of Prostaglandin E2 Production
Authors: Chen Hua , Chen Liyang , Cheng Biao , Jiang Chaoyin
Published: May 2015

Background/Aims: Autophagic cell death has recently been implicated in the pathophysiology of tendinopathy. Prostaglandin E2 (PGE2), a known inflammatory mediator of tendinitis, inhibits tenofibroblast proliferation in vitro; however, the underlying mechanism is unclear. The present study investigated the relationship between PGE2 production and autophagic cell death in mechanically loaded human patellar tendon fibroblasts (HPTFs) in vitro. Methods: Cultured HPTFs were subjected to exogenous PGE2 treatment or repetitive cyclic mechanical stretching. Cell death was determined by flow cytometry with acridine orange/ethidium bromide staining. Induction of autophagy was assessed by autophagy markers including the formation of autophagosomes and autolysosomes (by electron microscopy, AO staining, and formation of GPF-LC3-labeled vacuoles) and the expression of LC3-II and BECN1 (by western blot). Stretching-induced PGE2 release was determined by ELISA. Results: Exogenous PGE2 significantly induced cell death and autophagy in HPTFs in a dose-dependent manner. Blocking autophagy using inhibitors 3-methyladenine and chloroquine, or small interfering RNAs against autophagy genes Becn-1 and Atg-5 prevented PGE2-induced cell death. Cyclic mechanical stretching at 8% and 12% magnitudes for 24 h significantly stimulated PGE2 release by HPTFs in a magnitude-dependent manner. In addition, mechanical stretching induced autophagy and cell death. Blocking PGE2 production using COX inhibitors indomethacin and celecoxib significantly reduced stretching-induced autophagy and cell death. Conclusion: Taken together, cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of PGE2 production.
Chloroquine Inhibits Ca2+ Signaling in Murine CD4+ Thymocytes
Authors: Xu Jin-Chao , Peng Yong-Bo , Wei Ming-Yu , Wu Yi-Fan , Guo Donglin , Qin Gangjian , Ji Guangju , Shen Jinhua , Liu Qing-Hua
Published: May 2015

Background/Aims: Bitter-tasting chloroquine can suppress T cell activation by inhibiting Ca2+ signaling. However, the mechanism of inhibition remains largely unclear. Methods: In this study, CD4+ T cells were isolated from the thymus, and the calcium content of CD4+ thymocytes was measured using fura-2 AM and a TILL imaging system. Pyrazole-3 (Pyr3), thapsigargin (TG), and caffeine were used to assess the effects of chloroquine on the intracellular Ca2+ content of CD4+ T cells. Results: In murine CD4+ thymocytes, chloroquine decreased the TG-triggered intracellular Ca2+ increase in a dose-dependent manner. In the absence of chloroquine under Ca2+-free conditions (0 mM Ca2+ and 0.5 mM EGTA), TG induced a transient Ca2+ increase. After restoration of the extracellular Ca2+ concentration to 2 mM, a dramatic Ca2+ increase occurred. This elevation was completely blocked by chloroquine and was markedly inhibited by Pyr3, a selective antagonist of transient receptor potential C3 (TRPC3) channel and stromal interaction molecule (STIM)/Orai channel. Furthermore, the TG-induced transient Ca2+ increase under Ca2+-free conditions was eliminated in the presence of chloroquine. Chloroquine also blocked the dialyzed inositol-1,4,5-trisphosphate (IP3)-induced intracellular Ca2+ increase. However, chloroquine was not able to decrease the caffeine-induced Ca2+ increase. Conclusion: These data indicate that chloroquine inhibits the elevation of intracellular Ca2+ in thymic CD4+ T cells by inhibiting IP3 receptor-mediated Ca2+ release from intracellular stores and TRPC3 channel-mediated and/or STIM/Orai channel-mediated Ca2+ influx.
MiR-132 Regulates Rem Expression in Cardiomyocytes During Long-Term β-Adrenoceptor Agonism
Authors: Carrillo Elba D. , Sampieri Raúl , Hernández Ascención , García María C. , Sánchez Jorge A.
Published: May 2015

Aims: To characterize the effects of long-term β-adrenergic receptor stimulation on Rem protein and mRNA expression in rat heart and possible involvement of miR-132. Methods: Adult rats were treated with isoproterenol (ISO, 150 µg.kg.h-1) for 2 d and Rem, miR-132, and α1c (the principal subunit of Cav1.2 channels) were measured at protein and mRNA levels with western blot and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) experiments, respectively. Ca2+ currents and intracellular Ca2+ signals were evaluated in isolated cardiomyocytes. Results: Systemic administration of ISO led to decreases in Rem protein and mRNA levels (down to 49%). Furthermore, levels of the microRNAs (miRs) miR-132 and miR-214 were upregulated 5- and 9-fold, respectively. Transfection of miR-132, but not miR-214, into HEK293 cells reduced the expression of a luciferase reporter gene controlled by a conserved 3´-untranslated region (UTR) of Rem by half. Chronic ISO administration also led to a 25% decrease in the amplitude of peak L-type Ca2+ currents, a 40% decrease in α1c subunit protein abundance at the membrane level, and a 60% decrease in expression of α1c channel subunit mRNA. Conclusions: These results suggest that Rem expression is down-regulated posttranscriptionally by miR-132 in response to long-term activation of β-adrenergic signaling, but this down-regulation does not produce a larger Ca2+ influx through Cav1.2 channels.
A Single Nucleotide Polymorphism in 3' Untranslated Region of Epithelial Growth Factor Receptor Confers Risk for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease
Authors: Zhou Sijing , Li Min , Zeng Daxiong , Xu Xuan , Fei Liming , Zhu Qingqing , Zhang Yan , Wang Ran
Published: May 2015

Objective: Polymorphisms located at microRNA (miRNA) binding sites may interfere with the miRNA/mRNA interaction. The objective of this study was to identify the association between a single nucleotide polymorphism (774 T>C) in 3'-untranslated region (3'-UTR) of Epithelial Growth Factor Receptor (EGFR) and development of pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) as well as to explore the molecular mechanism. Methods and Results: In this study, we validated EGFR as a target of miR-214 in pulmonary artery smooth muscle cell (PASMC), which was further confirmed by the observation that exogenous overexpression of miR-214 significantly downregulated the expression of EGFR in the PASMCs genotyped as TT or TC, but not in CC group. Meanwhile, we found COPD patients with CC genotype had significantly higher risk for PH (OR = 1.965, p = 0.0095), compared with TT and TC genotypes,. Additionally, the PASMCs were isolated from 72 COPD patients, with which miR-214 and EGFR expression levels were determined, and we found that miR-214 level was comparable between each genotype group, the concentration of EGFR in CC genotype group was significantly higher than in TT or TC genotype group. Conclusion: Our study confirmed that EGFR 3'UTR 774 T>C polymorphism interfered with miRNA/mRNA interaction, and showed that the minor allele was associated with an elevated risk for development of PH in COPD.
Baicalein Inhibits MMPs Expression via a MAPK-Dependent Mechanism in Chondrocytes
Authors: Chen Wei-Ping , Xiong Yan , Hu Peng-Fei , Bao Jia-Peng , Wu Li-Dong
Published: May 2015

Background: Baicalein is a flavonoid isolated from Scutellaria baicalensis Georgi. Here, we investigated the anti-osteoarthritic effect of baicalein in vitro and in vivo. Methods: Interleukin-1 beta (IL-1β)-induced chondrocytes were treated with different concentrations of baicalein, real-time PCR and ELISA were performed to detect the matrix metalloproteinases (MMPs) expression. Western blot was used to evaluate the mitogen-activated protein kinase (MAPK) expression. In experimental osteoarthritis (OA), rabbits were treated with baicalein, gross morphological and histological assessment was performed to evaluate the cartilage damage. Results: Baicalein significantly reduced the expression of MMPs in vitro and in vivo. Moreover, baicalein significantly reduced the phosphorylation of p38 and extracellular signal regulated kinase (ERK), but not of c-Jun N-terminal kinase (JNK). In addition, intra-articular injection of baicalein ameliorated the cartilage damage in a rabbit model of OA induced by anterior cruciate ligament transection (ACLT). Conclusions: The results indicate that baicalein may be considered as a potential agent for OA treatment.
Management of Spontaneous Hepatic Rupture on Top of HELLP Syndrome: Case Report and Review of the Literature
Authors: Troja Achim , Abdou Ahmed , Rapp Christiane , Wienand Swantje , Malik Eduard , Raab Hans-Rudolf
Published: May 2015

Introduction: We report the case of a patient with antepartum HELLP syndrome and simultaneous rupture of the right liver lobe. An emergency caesarean section was performed and the liver rupture was managed surgically via perihepatic packing. The mother and her child recovered well and were discharged 19 days after admission. Case Report: We describe a case report and review the literature. Based on our own experience and the most common clinical presentations of such patients, we were able to establish an algorithm for managing such cases. Conclusion: An association between liver rupture and HELLP syndrome is rare but was previously described in several case reports. In pregnant women with HELLP syndrome and acute onset abdominal pain, a potential spontaneous hepatic rupture should be taken into consideration.
Primary Hormone Therapy in Elderly Women with Hormone-Sensitive Locoregional Breast Cancer: Endocrine Therapy Alone Is a Reasonable Alternative in Selected Patients
Authors: Quiroga-García Vanesa , Cirauqui-Cirauqui Beatriz , Bugés-Sánchez Cristina , Luna-Tomás Miguel Ángel , Castellà-Fernández Eva María , Mariscal-Martínez Antonio , Margelí-Vila Mireia
Published: May 2015

Background: Treatment with aromatase inhibitors (AIs) followed by surgery is often recommended for women with locoregional hormone-sensitive breast cancer. However, no study has compared the efficacy of AIs alone versus AIs followed by surgery. Methods: 33 postmenopausal breast cancer patients were treated with primary hormone therapy. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor type 2 receptor (HER2) expression levels were analyzed by immunohistochemistry. After hormone therapy, eligible patients underwent surgery, and those who were not candidates for surgery continued on hormone therapy. We retrospectively analyzed time to progression, overall survival, response, and impact of surgery on outcome. Results: All patients were ER+. HER2 was successfully analyzed in 30 patients, all of whom were HER2-. The median time to progression was 94 months, and the median overall survival was not reached, while the mean overall survival was 123 months. The overall response rate was 63.6%, with 9.1% complete responses. No significant differences in time to progression or survival were observed between patients who underwent surgery and those who did not. Conclusions: Primary hormone therapy with AIs is effective in elderly breast cancer patients with high levels of hormone receptors and may provide a feasible and tolerable alternative to surgery in selected hormone-sensitive breast cancer patients.
Dexmedetomidine Attenuates Blood-Spinal Cord Barrier Disruption Induced by Spinal Cord Ischemia Reperfusion Injury in Rats
Authors: Fang Bo , Li Xiao-Qian , Bi Bo , Tan Wen-Fei , Liu Gang , Zhang Ying , Ma Hong
Published: May 2015

Background/Aims: Dexmedetomidine has beneficial effects on ischemia reperfusion (I/R) injury to the spinal cord, but the underlying mechanisms are not fully understood. This study investigated the effects and possible mechanisms of dexmedetomidine on blood-spinal cord barrier (BSCB) disruption induced by spinal cord I/R injury. Methods: Rats were intrathecally pretreated with dexmedetomidine or PBS control 30 minutes before undergoing 14-minute occlusion of aortic arch. Hind-limb motor function was assessed using Tarlov criteria, and motor neurons in the ventral gray matter were counted by histological examination. The permeability of the BSCB was examined using Evans blue (EB) as a vascular tracer. The spinal cord edema was evaluated using the wet-dry method. The expression and localization of matrix metalloproteinase-9 (MMP-9), Angiopoietin-1 (Ang1) and Tie2 were assessed by western blot, real-time polymerase chain reaction, and immunofluorescence. Results: Intrathecal preconditioning with dexmedetomidine minimized the neuromotor dysfunction and histopathological deficits, and attenuated EB extravasation after spinal cord I/R injury. In addition, dexmedetomidine preconditioning suppressed I/R-induced increase in MMP-9. Finally, Dexmedetomidine preconditioning enhanced the Ang1-Tie2 system activity after spinal cord I/R injury. Conclusions: Dexmedetomidine preconditioning stabilized the BSCB integrity against spinal cord I/R injury by inhibition of MMP-9, and enhancing the Ang1-Tie2 system.
Selection, management, and outcome of vitamin K antagonist-treated patients with atrial fibrillation not switched to novel oral anticoagulants
Authors: Michalski Franziska , Tittl Luise , Werth Sebastian , Hänsel Ulrike , Pannach Sven , Sahin Kurtulus , Weiss Norbert , Beyer-Westendorf Jan
Published: May 2015

Atrial fibrillation (AF) patients treated with well-controlled vitamin K antagonists (VKAs) may benefit less from non-vitamin K antagonist oral anticoagulants (NOACs) because they are supposed to be at low risk of thromboembolic and bleeding complications. However, little is known about the selection, management, and outcome of such “stable” VKA patients in current practice. We assessed characteristics, VKA persistence and 12 months' outcome of AF patients selected for VKA continuation. On March 1, 2013, the Dresden NOAC registry opened recruitment of patients continuing on VKA for sites that had been actively recruiting AF patients treated with NOACs in the prior 18 months. Patient characteristics were compared with those of NOAC patients from the same sites. Four hundred twenty-seven VKA patients had a significantly lower bleeding risk profile compared with 706 patients selected for NOAC treatment. For VKA, international normalised ratio time-in-therapeutic range before enrolment was 71% and increased to 75% during a mean follow-up of 15 months. Rates of stroke/transient ischaemic attack/systemic embolism were 1.3/100 patient-years (intention-to-treat) and 0.94/100 patient-years (as-treated). On-treatment rate of ISTH major bleeding was 4.15/100 patient-years (95% CI 2.60–6.29) with a case-fatality rate of 16.3% (all-cause mortality at day 90 after major bleeding). In conclusion, in daily care, AF patients selected for VKA therapy are healthier than those treated with NOAC, demonstrate a high quality of anticoagulant control and very low stroke rates. However, despite adequate patient selection and INR control, the risk of major VKA bleeding is unacceptably high and bleeding outcome is poor.
Proteotoxicity and Cardiac Dysfunction
Authors: McLendon Patrick M. , Robbins Jeffrey
Published: May 2015

Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally, and this depends on them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may use for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathological stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes because these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell’s ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored.
How Mitochondrial Dynamism Orchestrates Mitophagy
Authors: Shirihai Orian S. , Song Moshi , Dorn Gerald W.
Published: May 2015

Mitochondria are highly dynamic, except in adult cardiomyocytes. Yet, the fission and fusion-promoting proteins that mediate mitochondrial dynamism are highly expressed in, and essential to the normal functioning of, hearts. Here, we review accumulating evidence supporting important roles for mitochondrial fission and fusion in cardiac mitochondrial quality control, focusing on the PTEN-induced putative kinase 1–Parkin mitophagy pathway. Based in part on recent findings from in vivo mouse models in which mitofusin-mediated mitochondrial fusion or dynamin-related protein 1–mediated mitochondrial fission was conditionally interrupted in cardiac myocytes, we propose several new concepts that may provide insight into the cardiac mitochondrial dynamism–mitophagy interactome.
Association of Discharge Aspirin Dose With Outcomes After Acute Myocardial Infarction
Authors: Xian Ying , Wang Tracy Y. , McCoy Lisa A. , Effron Mark B. , Henry Timothy D. , Bach Richard G. , Zettler Marjorie E. , Baker Brian A. , Fonarow Gregg C. , Peterson Eric D.
Published: May 2015

Background—

Aspirin is the most widely used antiplatelet drug postmyocardial infarction, yet its optimal maintenance dose after percutaneous coronary intervention with stenting remains uncertain.

Methods and Results—

We compared outcomes of 10 213 patients with myocardial infarction who underwent percutaneous coronary intervention and were discharged on dual-antiplatelet therapy at 228 US hospitals in the Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) study from 2010 to 2012. Major adverse cardiovascular events and bleeding within 6 months postdischarge were compared between high-dose (325 mg) and low-dose aspirin (81 mg) by using regression models with inverse probability-weighted propensity adjustment. Overall, 6387 patients (63%) received high-dose aspirin at discharge. Major adverse cardiovascular events risk was not significantly different between groups (high versus low: unadjusted 8.2% versus 9.2%; adjusted hazard ratio, 0.99; 95% confidence interval, 0.85–1.17). High-dose aspirin use was associated with greater risk of any Bleeding Academic Research Consortium–defined bleeding events (unadjusted 24.2% versus 22.7%; adjusted odds ratio, 1.19; 95% confidence interval, 1.06–1.33), driven mostly by minor Bleeding Academic Research Consortium type 1 or 2 bleeding events not requiring hospitalization (unadjusted 21.4% versus 19.5%; adjusted odds ratio, 1.19; 95% confidence interval, 1.05–1.34). Bleeding events requiring hospitalization were similar by aspirin dosing groups (unadjusted 2.8% versus 3.2%, adjusted odds ratio, 1.22; 95% confidence interval, 0.87–1.70). Similar associations were observed in landmark analyses accounting for aspirin dosing change over time, and across subgroup analyses by age, sex, baseline aspirin use, and type of ADP receptor inhibitor (clopidogrel versus prasugrel/ticagrelor).

Conclusions—

Among percutaneous coronary intervention–treated patients with myocardial infarction, high-maintenance-dose aspirin was associated with similar rates of major adverse cardiovascular events, but a greater risk of minor bleeding than those discharged on low-dose aspirin.
Circulating Exosomes Induced by Cardiac Pressure Overload Contain Functional Angiotensin II Type 1 Receptors
Authors: Pironti Gianluigi , Strachan Ryan T. , Abraham Dennis , Mon-Wei Yu Samuel , Chen Minyong , Chen Wei , Hanada Kenji , Mao Lan , Watson Lewis J. , Rockman Howard A.
Published: May 2015

Background—

Whether biomechanical force on the heart can induce exosome secretion to modulate cardiovascular function is not known. We investigated the secretion and activity of exosomes containing a key receptor in cardiovascular function, the angiotensin II type I receptor (AT1R).

Methods and Results—

Exosomes containing AT1Rs were isolated from the media overlying AT1R-overexpressing cells exposed to osmotic stretch and from sera of mice undergoing cardiac pressure overload. The presence of AT1Rs in exosomes was confirmed by both electron microscopy and radioligand receptor binding assays and shown to require β-arrestin2, a multifunctional adaptor protein essential for receptor trafficking. We show that functional AT1Rs are transferred via exosomes in an in vitro model of cellular stretch. Using mice with global and cardiomyocyte conditional deletion of β-arrestin2, we show that under conditions of in vivo pressure overload the cellular source of the exocytosis of exosomes containing AT1R is the cardiomyocyte. Exogenously administered AT1R-enriched exosomes target cardiomyocytes, skeletal myocytes, and mesenteric resistance vessels and are sufficient to confer blood pressure responsiveness to angiotensin II infusion in AT1R knockout mice.

Conclusions—

AT1R-enriched exosomes are released from the heart under conditions of in vivo cellular stress to likely modulate vascular responses to neurohormonal stimulation. In the context of the whole organism, the concept of G protein–coupled receptor trafficking should consider circulating exosomes as part of the reservoir of functional AT1Rs.
Increased Stiffness Is the Major Early Abnormality in a Pig Model of Severe Aortic Stenosis and Predisposes to Congestive Heart Failure in the Absence of Systolic Dysfunction
Authors: Ishikawa Kiyotake , Aguero Jaume , Oh Jae Gyun , Hammoudi Nadjib , A. Fish Lauren , Leonardson Lauren , Picatoste Belén , Santos‐Gallego Carlos G. , M. Fish Kenneth , Hajjar Roger J.
Published: May 2015

Background

It remains unclear whether abnormal systolic function and relaxation are essential for developing heart failure in pathophysiology of severe aortic stenosis.

Methods and Results

Yorkshire pigs underwent surgical banding of the ascending aorta. The animals were followed for up to 5 months after surgery, and cardiac function was assessed comprehensively by invasive pressure–volume measurements, 3‐dimensional echocardiography, echocardiographic speckle‐tracking strain, and postmortem molecular and histological analyses. Pigs with aortic banding (n=6) exhibited significant left ventricular hypertrophy with increased stiffness compared with the control pigs (n=7) (end‐diastolic pressure–volume relationship β: 0.053±0.017 versus 0.028±0.009 mm Hg/mL,
P
=0.007); however, all other parameters corresponding to systolic function, including ejection fraction, end‐systolic pressure–volume relationship, preload recruitable stroke work, echocardiographic circumferential strain, and longitudinal strain, were not impaired in pigs with aortic banding. Relaxation parameters were also similar between groups. Sarcoplasmic reticulum calcium (Ca
2+
)
ATP
ase protein levels in the left ventricle were similar. There were significant increases in 3‐dimensional echocardiographic left atrial volumes, suggesting the usefulness of these indexes to detect increased stiffness. Right atrial pacing with a heart rate of 120 beats per minute induced increased end‐diastolic pressure in pigs with aortic banding in contrast to decreased end‐diastolic pressure in the control pigs. Histological evaluation revealed that increased stiffness was accompanied by cardiomyocyte hypertrophy and increased perimysial and perivascular fibrosis.

Conclusion

Increased stiffness is the major early pathological process that predisposes to congestive heart failure without abnormalities in systolic function and relaxation in a clinically relevant animal model of aortic stenosis.
The Sensitivity of Simulated Shallow Cumulus Convection and Cold Pools to Microphysics
Authors: Li Zhujun , Zuidema Paquita , Zhu Ping , Morrison Hugh
Published: May 2015

The sensitivity of nested WRF simulations of precipitating shallow marine cumuli and cold pools to microphysical parameterization is examined. The simulations differ only in their use of two widely used double-moment rain microphysical schemes: the Thompson and Morrison schemes. Both simulations produce similar mesoscale variability, with the Thompson scheme producing more weak cold pools and the Morrison scheme producing more strong cold pools, which are associated with more intense shallow convection. The most robust difference is that the cloud cover and LWP are significantly larger in the Morrison simulation than in the Thompson simulation. One-dimensional kinematic simulations confirm that dynamical feedbacks do not mask the impact of microphysics. These also help elucidate that a slower autoconversion process along with a stronger accretion process explains the Morrison scheme’s higher cloud fraction for a similar rain mixing ratio. Differences in the raindrop terminal fall speed parameters explain the higher evaporation rate of the Thompson scheme at moderate surface rain rates. Given the implications of the cloud-cover differences for the radiative forcing of the expansive trade wind regime, the microphysical scheme should be considered carefully when simulating precipitating shallow marine cumulus.
The Role of Whitecapping in Thickening the Ocean Surface Boundary Layer
Authors: Gerbi Gregory P. , Kastner Samuel E. , Brett Genevieve
Published: May 2015

The effects of wind-driven whitecapping on the evolution of the ocean surface boundary layer are examined using an idealized one-dimensional Reynolds-averaged Navier–Stokes numerical model. Whitecapping is parameterized as a flux of turbulent kinetic energy through the sea surface and through an adjustment of the turbulent length scale. Simulations begin with a two-layer configuration and use a wind that ramps to a steady stress. This study finds that the boundary layer begins to thicken sooner in simulations with whitecapping than without because whitecapping introduces energy to the base of the boundary layer sooner than shear production does. Even in the presence of whitecapping, shear production becomes important for several hours, but then inertial oscillations cause shear production and whitecapping to alternate as the dominant energy sources for mixing. Details of these results are sensitive to initial and forcing conditions, particularly to the turbulent length scale imposed by breaking waves and the transfer velocity of energy from waves to turbulence. After 1–2 days of steady wind, the boundary layer in whitecapping simulations has thickened more than the boundary layer in simulations without whitecapping by about 10%–50%, depending on the forcing and initial conditions.
How is the Balance of a Forecast Ensemble Affected by Adaptive and Nonadaptive Localization Schemes?
Authors: Bannister Ross N.
Published: May 2015

This paper investigates the effect on balance of a number of Schur product–type localization schemes that have been designed with the primary function of reducing spurious far-field correlations in forecast error statistics. The localization schemes studied comprise a nonadaptive scheme (where the moderation matrix is decomposed in a spectral basis), and two adaptive schemes: a simplified version of Smoothed Ensemble Correlations Raised to a Power (SENCORP) and Ensemble Correlations Raised to a Power (ECO-RAP). The paper shows, the author believes for the first time, how the degree of balance (geostrophic and hydrostatic) implied by the error covariance matrices localized by these schemes can be diagnosed. Here it is considered that an effective localization scheme is one that reduces spurious correlations adequately, but also minimizes disruption of balance (where the “correct” degree of balance or imbalance is assumed to be possessed by the unlocalized ensemble). By varying free parameters that describe each scheme (e.g., the degree of truncation in the schemes that use the spectral basis, the “order” of each scheme, and the degree of ensemble smoothing), it is found that a particular configuration of the ECO-RAP scheme is best suited to the convective-scale system studied. According to the diagnostics this ECO-RAP configuration still weakens geostrophic and hydrostatic balance, but overall this is less so than for other schemes.
Undetectable pregnancy-associated plasma protein-A in antenatal serum Down’s syndrome screening: a case of assay interference
Authors: Williams C , Hambridge K , Petchey M , Martin JA , Spencer K
Published: May 2015

Serum pregnancy-associated plasma protein-A (PAPP-A) is measured in Down’s syndrome screening, routinely offered to women in pregnancy. We present the case of an undetectable pregnancy-associated plasma protein-A concentration on the PerkinElmer AutoDELFIA system where immunoassay interference was suspected. Investigations performed, including dilution and recovery studies and antibody-blocking tube incubations, all yielded serum pregnancy-associated plasma protein-A concentrations of <25 mU/L. Pregnancy-associated plasma protein-A was also undetectable on two alternative pregnancy-associated plasma protein-A assays. An experimental manual Delfia procedure suggested the site of interference was between the secondary antibody and the pregnancy-associated plasma protein-A molecule. This case of negative interference in the PerkinElmer pregnancy-associated plasma protein-A assay produced a falsely high Down’s syndrome risk that might have led to an unnecessary invasive procedure with the potential for fetal loss. This highlights the need for Down’s syndrome screening laboratories to be vigilant to immunoassay interference due to the significant impact of the results on patient decision outcome.
The Role of Human Factors/Ergonomics in the Science of Security
Authors: Proctor Robert W. , Chen Jing
Published: May 2015

Objective:

The overarching goal is to convey the concept of science of security and the contributions that a scientifically based, human factors approach can make to this interdisciplinary field.

Background:

Rather than a piecemeal approach to solving cybersecurity problems as they arise, the U.S. government is mounting a systematic effort to develop an approach grounded in science. Because humans play a central role in security measures, research on security-related decisions and actions grounded in principles of human information-processing and decision-making is crucial to this interdisciplinary effort.

Method:

We describe the science of security and the role that human factors can play in it, and use two examples of research in cybersecurity—detection of phishing attacks and selection of mobile applications—to illustrate the contribution of a scientific, human factors approach.

Results:

In these research areas, we show that systematic information-processing analyses of the decisions that users make and the actions they take provide a basis for integrating the human component of security science.

Conclusion:

Human factors specialists should utilize their foundation in the science of applied information processing and decision making to contribute to the science of cybersecurity.