bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of New QCA LFSR and NLFSR for Grain-128 Stream Cipher
Authors: Sabbaghi-Nadooshan Reza , Shahosseini Zahra , Rezaeipour Davood
Published: September 2015

The use of quantum-dot cellular automata (QCA) technology for the design of logic circuits has shown to increase data transfer rates up to 2 THz. In QCA technology, circuits are designed to have an ultra-small feature size as well as ultra-low power consumption. Grain-128 is one of the best stream ciphers in the final list of the eSTREAM project. In this paper, we have designed and simulated the main blocks of this algorithm including XOR gate, linear-feedback shift register (LFSR) and nonlinear-feedback shift register (NLFSR) using QCA technology. The designs of these blocks using the QCA Designer simulator are given and the main factors such as area, complexity and delay are estimated. Furthermore, ModelSim software is used to simulate HDLQ model of the QCA Grain-128 stream cipher algorithm. The results indicate that the main parameters of the proposed Grain-128, such as area and throughput, are improved as well.
Using Neural Networks to Forecast Available System Resources: An Approach and Empirical Investigation
Authors: Jia Yun-Fei , Zhou Zhi Quan , Xue Ke-Xian , Zhao Lei , Cai Kai-Yuan
Published: September 2015

Software aging refers to the phenomenon that software systems show progressive performance degradation or a sudden crash after longtime execution. It has been reported that this phenomenon is closely related to the exhaustion of system resources. This paper quantitatively studies available system resources under the real-world situation where workload changes dynamically over time. We propose a neural network approach to first investigate the relationship between available system resources and system workload and then to forecast future available system resources. Experimental results on data sets collected from real-world computer systems demonstrate that the proposed approach is effective.
Quantum state space dimension as a quantum resource
Authors: Plastino A. , Bellomo G. , Plastino A. R.
Published: September 2015

We argue that the dimensionality of the space of quantum systems’ states should be considered as a legitimate resource for quantum information tasks. The assertion is supported by the fact that quantum states with discord-like capacities can be obtained from classically-correlated states in spaces of dimension large enough. We illustrate things with some simple examples that justify our claim.
Early-Stage Adoption of Improved Banana “Matooke” Hybrids in Uganda: A Count Data Analysis Based on Farmers’ Perceptions
Authors: Akankwasa K. , Ortmann G. F. , Wale E. , Tushemereirwe W. K.
Published: September 2015

This paper analyzes farmers’ perceptions regarding the consumption and production attributes of new banana hybrids in Uganda. The data were collected from a sample of 454 farmers. Following descriptive statistics and a factor analysis, a zero-inflated poisson (ZIP) regression model was estimated to understand the effect of farmers’ perceptions and other factors on the likelihood of adopting the new hybrids. The results show that, compared to a local variety (Mbwazirume), four of the hybrids are preferred in terms of production attributes but regarded as inferior with respect to consumption characteristics. Resistance to nematodes, tolerance to weevils and high performance in good seasons in terms of bunch size mainly explain early-stage adoption of the hybrid banana varieties. Hybrid M9 is regarded as having a relatively good performance with respect to most of the production and consumption characteristics. In collaboration with extension agents, variety M9 could be disseminated to a wider farming community that targets larger households, younger farmers and farmers with relatively large sizes of land.
Multinational Firms, Internal Capital Markets, and the Value of Global Diversification
Authors: Sturgess Jason
Published: September 2015

Over the past 30 years, multinational firms’ investment grew four times faster than worldwide GDP. Yet the evidence on whether global diversification is valuable is inconclusive. This paper uses detailed foreign direct investment (FDI) data for 251 UK multinational firms and 4,676 subsidiaries for the period 1999–2005 to show that multinational firms exhibit, on average, a global diversification premium. I investigate this result and show that the premium is positively related to “winner-picking” transfers in internal capital markets, and more so for better-governed firms. The findings help explain why multinational firms’ investment and global diversification have significantly increased over the past three decades.
Visitors to ‘the northern playgrounds’: tourists and exploratory science in north Norway
Authors: Whalley W. Brian , Parkinson Anne F.
Published: September 2015

This paper outlines some significant visits made to north Norway by geologists and mountaineers from Britain and Ireland from the early to late nineteenth century. These visitors wrote up their travels and climbing experiences in a region in north Norway that was difficult to get to other than by sea: Øksfjordjøkelen and Lyngen. Early travellers revealed the sights of the fjord areas and thereby promoted the region for subsequent travellers. Leopold von Buch's
Travels though Norway and Lapland during the Years 1806, 1807, and 1808
probably prompted J. D. Forbes to visit and produce
Norway and Its Glaciers
and Archibald Geikie's
Geological Sketches at Home and Abroad
as part of the contemporary discussions about the ‘glacial theory’. In the latter years of the nineteenth century the British climbers William Cecil Slingsby and George Hastings, with local climber Josef Caspari, explored the Lyngen Peninsula. Elizabeth Main (Mrs Aubrey Le Blond) also climbed in Lyngen. As well as providing written summaries of their exploits, the early explorers included photographs in their books. Some of these images are helpful in the reconstruction of the glacierized landscapes at the end of the Little Ice Age. It is suggested that present-day travellers might leave their observations available, in digital media, for future investigators.
Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans
Authors: Sidhu Simranjit K. , Weavil Joshua C. , Venturelli Massimo , Rossman Matthew J. , Gmelch Benjamin S. , Bledsoe Amber D. , Richardson Russell S. , Amann Markus
Published: September 2015

We investigated the influence of aging on the group III/IV muscle afferents in the exercise pressor reflex-mediated cardiovascular response to rhythmic exercise. Nine old (OLD; 68 ± 2 yr) and nine young (YNG; 24 ± 2 yr) males performed single-leg knee extensor exercise (15 W, 30 W, 80% max) under control conditions and with lumbar intrathecal fentanyl impairing feedback from group III/IV leg muscle afferents. Mean arterial pressure (MAP), cardiac output, leg blood flow (QL), systemic (SVC) and leg vascular conductance (LVC) were continuously determined. With no hemodynamic effect at rest, fentanyl blockade during exercise attenuated both cardiac output and QL ∼17% in YNG, while the decrease in cardiac output in OLD (∼5%) was significantly smaller with no impact on QL ( P = 0.8). Therefore, in the face of similar significant ∼7% reduction in MAP during exercise with fentanyl blockade in both groups, LVC significantly increased ∼11% in OLD, but decreased ∼8% in YNG. The opposing direction of change was reflected in SVC with a significant ∼5% increase in OLD and a ∼12% decrease in YNG. Thus while cardiac output seems to account for the majority of group III/IV-mediated MAP responses in YNG, the impact of neural feedback on the heart may decrease with age and alterations in SVC become more prominent in mediating the similar exercise pressor reflex in OLD. Interestingly, in terms of peripheral hemodynamics, while group III/IV-mediated feedback plays a clear role in increasing LVC during exercise in the YNG, these afferents seem to actually reduce LVC in OLD. These peripheral findings may help explain the limited exercise-induced peripheral vasodilation often associated with aging.
Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism
Authors: Moran Timothy P. , Nakano Keiko , Whitehead Gregory S. , Thomas Seddon Y. , Cook Donald N. , Nakano Hideki
Published: September 2015

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.
DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease
Authors: Birch Jodie , Anderson Rhys K. , Correia-Melo Clara , Jurk Diana , Hewitt Graeme , Marques Francisco Madeira , Green Nicola J. , Moisey Elizabeth , Birrell Mark A. , Belvisi Maria G. , Black Fiona , Taylor John J. , Fisher Andrew J. , De Soyza Anthony , Passos João F.
Published: September 2015

Cellular senescence has been associated with the structural and functional decline observed during physiological lung aging and in chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the first line of defense in the lungs and are important to COPD pathogenesis. However, the mechanisms underlying airway epithelial cell senescence, and particularly the role of telomere dysfunction in this process, are poorly understood. We aimed to investigate telomere dysfunction in airway epithelial cells from patients with COPD, in the aging murine lung and following cigarette smoke exposure. We evaluated colocalization of γ-histone protein 2A.X and telomeres and telomere length in small airway epithelial cells from patients with COPD, during murine lung aging, and following cigarette smoke exposure in vivo and in vitro. We found that telomere-associated DNA damage foci increase in small airway epithelial cells from patients with COPD, without significant telomere shortening detected. With age, telomere-associated foci increase in small airway epithelial cells of the murine lung, which is accelerated by cigarette smoke exposure. Moreover, telomere-associated foci predict age-dependent emphysema, and late-generation Terc null mice, which harbor dysfunctional telomeres, show early-onset emphysema. We found that cigarette smoke accelerates telomere dysfunction via reactive oxygen species in vitro and may be associated with ataxia telangiectasia mutated-dependent secretion of inflammatory cytokines interleukin-6 and -8. We propose that telomeres are highly sensitive to cigarette smoke-induced damage, and telomere dysfunction may underlie decline of lung function observed during aging and in COPD.
Repeated exposure to heat stress results in a diaphragm phenotype that resists ventilator-induced diaphragm dysfunction
Authors: Yoshihara Toshinori , Ichinoseki-Sekine Noriko , Kakigi Ryo , Tsuzuki Takamasa , Sugiura Takao , Powers Scott K. , Naito Hisashi
Published: September 2015

Controlled mechanical ventilation (CMV) is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged mechanical ventilation (MV) results in diaphragmatic atrophy and contractile dysfunction, both of which are predicted to contribute to problems in weaning patients from the ventilator. Therefore, developing a strategy to protect the diaphragm against ventilator-induced weakness is important. We tested the hypothesis that repeated bouts of heat stress result in diaphragm resistance against CMV-induced atrophy and contractile dysfunction. Male Wistar rats were randomly divided into six experimental groups: 1) control; 2) single bout of whole body heat stress; 3) repeated bouts of whole body heat stress; 4) 12 h CMV; 5) single bout of whole body heat stress 24 h before CMV; and 6) repeated bouts of whole body heat stress 1, 3, and 5 days before 12 h of CMV. Our results revealed that repeated bouts of heat stress resulted in increased levels of heat shock protein 72 in the diaphragm and protection against both CMV-induced diaphragmatic atrophy and contractile dysfunction at submaximal stimulation frequencies. The specific mechanisms responsible for this protection remain unclear: this heat stress-induced protection against CMV-induced diaphragmatic atrophy and weakness may be partially due to reduced diaphragmatic oxidative stress, diminished activation of signal transducer/transcriptional activator-3, lower caspase-3 activation, and decreased autophagy in the diaphragm.
Angiogenesis-related ultrastructural changes to capillaries in human skeletal muscle in response to endurance exercise
Authors: Baum Oliver , Gübeli Jennifer , Frese Sebastian , Torchetti Eleonora , Malik Corinna , Odriozola Adolfo , Graber Franziska , Hoppeler Hans , Tschanz Stefan A.
Published: September 2015

The ultrastructure of capillaries in skeletal muscle was morphometrically assessed in vastus lateralis muscle (VL) biopsies taken before and after exercise from 22 participants of two training studies. In study 1 (8 wk of ergometer training), light microscopy revealed capillary-fiber (C/F) ratio (+27%) and capillary density (+16%) to be higher ( P ≤ 0.05) in postexercise biopsies than in preexercise biopsies from all 10 participants. In study 2 (6 mo of moderate running), C/F ratio and capillary density were increased (+23% and +20%; respectively, P ≤ 0.05) in VL biopsies from 6 angiogenesis responders (AR) after training, whereas 6 nonangiogenesis responders (NR) showed nonsignificant changes in these structural indicators (−4%/−4%, respectively). Forty capillary profiles per participant were evaluated by point and intersection counting on cross sections after transmission electron microscopy. In study 1, volume density (Vv) and mean arithmetic thickness (T) of endothelial cells (ECs; +19%/+17%, respectively) and pericytes (PCs; +20%/+21%, respectively) were higher ( P ≤ 0.05), whereas Vv and T of the pericapillary basement membrane (BM) were −23%/−22% lower ( P ≤ 0.05), respectively, in posttraining biopsies. In study 2, exercise-related differences between AR and NR-groups were found for Vv and T of PCs (AR, +26%/+22%, respectively, both P ≤ 0.05; NR, +1%/−3%, respectively, both P > 0.05) and BM (AR, −14%/−13%, respectively, both P ≤ 0.05; NR, −9%/−11%, respectively, P = 0.07/0.10). Vv and T of ECs were higher (AR, +16%/+18%, respectively; NR, +6% /+6%, respectively; all P ≤ 0.05) in both groups. The PC coverage was higher (+13%, P ≤ 0.05) in VL biopsies of individuals in the AR group but nonsignificantly altered (+3%, P > 0.05) in those of the NR group after training. Our study suggests that intensified PC mobilization and BM thinning are related to exercise-induced angiogenesis in human skeletal muscle, whereas training per se induces EC-thickening.
Developing a Robust Strategy Map in Balanced Scorecard Model Using Scenario Planning
Authors: Jafari Mostafa , Shahanaghi Kamran , Tootooni Majid
Published: September 2015

The key to successful strategy implementation in an organization is for people in the organization to understand it, which requires the establishment of complicated but vital processes whereby the intangible assets are converted into tangible outputs. In this regard, a strategy map is a useful tool that helps execute this difficult task. However, such maps are typically developed based on ambiguous cause-effect relationships that result from the extrapolation of past data and flawed links with possible futures. However, if the strategy map is a mere reflection of the status quo but not future conditions and does not embrace real-world uncertainties, it will endanger the organization since it posits that the current situation will continue. In order to compensate for this deficiency, the environmental scenarios affecting an organization were identified in the present study. Then the strategy map was developed in the form of a scenario-based balanced scorecard. Besides, the effect of environmental changes on the components of the strategy map was investigated using the strategy maps illustrated over time together with the corresponding cash flow vectors. Subsequently, a method was proposed to calculate the degree of robustness of every component of the strategy map for the contingency of every scenario. Finally, the results were applied to a post office.
Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma
Authors: Tian Yuan , Wong Vincent W.S. , Wong Grace L.H. , Yang Weiqin , Sun Hanyong , Shen Jiayun , Tong Joanna H.M. , Go Minnie Y.Y. , Cheung Yue S. , Lai Paul B.S. , Zhou Mingyan , Xu Gang , Huang Tim H.M. , Yu Jun , To Ka F. , Cheng Alfred S.L. , Chan Henry L.Y.
Published: September 2015

The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesity-promoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLD-associated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G2–M phase cell-cycle arrest and stimulated β-catenin–dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active β-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients. Cancer Res; 75(22); 4803–16. ©2015 AACR.
Early Prediction of Cancer Progression by Depth-Resolved Nanoscale Mapping of Nuclear Architecture from Unstained Tissue Specimens
Authors: Uttam Shikhar , Pham Hoa V. , LaFace Justin , Leibowitz Brian , Yu Jian , Brand Randall E. , Hartman Douglas J. , Liu Yang
Published: September 2015

Early cancer detection currently relies on screening the entire at-risk population, as with colonoscopy and mammography. Therefore, frequent, invasive surveillance of patients at risk for developing cancer carries financial, physical, and emotional burdens because clinicians lack tools to accurately predict which patients will actually progress into malignancy. Here, we present a new method to predict cancer progression risk via nanoscale nuclear architecture mapping (nanoNAM) of unstained tissue sections based on the intrinsic density alteration of nuclear structure rather than the amount of stain uptake. We demonstrate that nanoNAM detects a gradual increase in the density alteration of nuclear architecture during malignant transformation in animal models of colon carcinogenesis and in human patients with ulcerative colitis, even in tissue that appears histologically normal according to pathologists. We evaluated the ability of nanoNAM to predict “future” cancer progression in patients with ulcerative colitis who did and did not develop colon cancer up to 13 years after their initial colonoscopy. NanoNAM of the initial biopsies correctly classified 12 of 15 patients who eventually developed colon cancer and 15 of 18 who did not, with an overall accuracy of 85%. Taken together, our findings demonstrate great potential for nanoNAM in predicting cancer progression risk and suggest that further validation in a multicenter study with larger cohorts may eventually advance this method to become a routine clinical test. Cancer Res; 75(22); 4718–27. ©2015 AACR.
Predictive Value of Cytokines and Immune Activation Biomarkers in AIDS-Related Non-Hodgkin Lymphoma Treated with Rituximab plus Infusional EPOCH (AMC-034 trial)
Authors: Epeldegui Marta , Lee Jeannette Y. , Martínez Anna C. , Widney Daniel P. , Magpantay Larry I. , Regidor Deborah , Mitsuyasu Ronald , Sparano Joseph A. , Ambinder Richard F. , Martínez-Maza Otoniel
Published: September 2015

Purpose: The aims of this study were to determine whether pretreatment plasma levels of cytokines and immune activation-associated molecules changed following treatment for AIDS-NHL with rituximab plus infusional EPOCH, and to determine whether pretreatment levels of these molecules were associated with response to treatment and/or survival.

Experimental Design: We quantified plasma levels of B-cell activation-associated molecules (sCD27, sCD30, and sCD23) and cytokines (IL6, IL10, and CXCL13) before and after the initiation of treatment in persons with AIDS-NHL (n = 69) in the AIDS Malignancies Consortium (AMC) 034 study, which evaluated treatment of AIDS-NHL with EPOCH chemotherapy and rituximab.

Results: Treatment resulted in decreased plasma levels of some of these molecules (CXCL13, sCD27, and sCD30), with decreased levels persisting for one year following the completion of treatment. Lower levels of CXCL13 before treatment were associated with complete responses following lymphoma therapy. Elevated levels of IL6 pretreatment were associated with decreased overall survival, whereas higher IL10 levels were associated with shorter progression-free survival (PFS), in multivariate analyses. Furthermore, patients with CXCL13 or IL6 levels higher than the median levels for the NHL group, as well as those who had detectable IL10, had lower overall survival and PFS, in Kaplan–Meier analyses.

Conclusions: These results indicate that CXCL13, IL6, and IL10 have significant potential as prognostic biomarkers for AIDS-NHL. Clin Cancer Res; 22(2); 328–36. ©2015 AACR.
MYC, Metabolism, and Cancer
Authors: Stine Zachary E. , Walton Zandra E. , Altman Brian J. , Hsieh Annie L. , Dang Chi V.
Published: September 2015

The MYC oncogene encodes a transcription factor, MYC, whose broad effects make its precise oncogenic role enigmatically elusive. The evidence to date suggests that MYC triggers selective gene expression amplification to promote cell growth and proliferation. Through its targets, MYC coordinates nutrient acquisition to produce ATP and key cellular building blocks that increase cell mass and trigger DNA replication and cell division. In cancer, genetic and epigenetic derangements silence checkpoints and unleash MYC's cell growth– and proliferation-promoting metabolic activities. Unbridled growth in response to deregulated MYC expression creates dependence on MYC-driven metabolic pathways, such that reliance on specific metabolic enzymes provides novel targets for cancer therapy.

Significance: MYC's expression and activity are tightly regulated in normal cells by multiple mechanisms, including a dependence upon growth factor stimulation and replete nutrient status. In cancer, genetic deregulation of MYC expression and loss of checkpoint components, such as TP53, permit MYC to drive malignant transformation. However, because of the reliance of MYC-driven cancers on specific metabolic pathways, synthetic lethal interactions between MYC overexpression and specific enzyme inhibitors provide novel cancer therapeutic opportunities. Cancer Discov; 5(10); 1024–39. ©2015 AACR.
Combination of Ginsenoside Rg1 and Bone Marrow Mesenchymal Stem Cell Transplantation in the Treatment of Cerebral Ischemia Reperfusion Injury in Rats
Authors: Bao Cuifen , Wang Yan , Min Heming , Zhang Miaomiao , Du Xiaowei , Han Ruiyi , Liu Xia
Published: September 2015

Background/Aims: The present study aims to explore the protective role and mechanism of ginsenoside Rg1 combined with bone marrow mesenchymal stem cell (BMSC) transplantation for cerebral ischemia reperfusion injury (CIRI) in rat brain. Methods: One hundred twenty male SD rats were randomly divided into a sham group, an Ischemia Reperfusion (IR) group, an IR group treated with BMSC transplantation (IR+BMSCs), an IR group treated with Rg1 (IR+Rg1), and an IR group treated with BMSC transplantation and Rg1 (IR+Rg1+BMSCs). To establish a CIRI model, right middle cerebral artery embolization was used. The neurological score, 2,3,5-triphenyltet-razolium chloride monohydrate (TTC) staining and brain water content were detected to assess the treatment efficiency. HE staining and TUNEL were used to explore the pathologic changes and apoptosis. To explore the protein levels of neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP), immunofluoresence was utilized. Western blotting was used to explore apoptosis-related proteins such as Bcl-2 and Bax. Results: Compared with the sham group, the IR group demonstrated obvious ischemic changes, such as significant neurologic defects and enhanced brain water content. The Rg1 treatment resulted in an obvious decrease in cell apoptosis and improved ischemic conditions. By BMSC transplantation, the transplanted cells could be differentiated into neurons and glial cells, which also improved cerebral ischemia. More importantly, the IR+Rg1+BMSCs group showed the best treatment efficiency with reduced cell apoptosis and better cerebral recovery. Conclusions: The Rg1 treatment resulted in an obvious decrease in cell apoptosis, while the transplanted cells could be differentiated into neurons and glial cells, which also improved cerebral ischemia.
Combinatorial MicroRNAs Suppress Hypoxia-Induced Cardiomyocytes Apoptosis
Authors: Xu Yingqi , Zhu Wenliang , Wang Zhe , Yuan Wei , Sun Yong , Liu Huibin , Du Zhimin
Published: September 2015

Background/Aims: Our previous in silico analysis revealed potential synergy in the activities of micro(mi)RNAs in myocardial infarction. The present study investigated whether miR-1 and -21 act synergistically to protect against cardiomyocytes apoptosis. Methods: Cell survival was analyzed with cell viability assay; apoptosis was detected by flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling, and the caspase-3 activity assay; and protein expression level was determined by western blotting. Results: MiR-1:miR-21 and several other miRNA pairs were evaluated for their potentially synergistic effects against myocardial hypoxia in neonatal rat ventricular cardiomyocytes. Lower combination indices suggested that miRNA pairs acted synergistically to inhibit apoptosis; miR-1 and -21 jointly blocked hypoxia-induced cardiomyocytes apoptosis. Moreover, combined application of miR-1 and -21 activated Akt and blocked hypoxia-induced upregulation of p53 in these cells. Conclusion: MiR-1 and -21 exert synergistic effects against hypoxia-induced cardiomyocytes apoptosis. These results provide a basis for the development of combined miRNA-based therapeutics to treat cardiovascular diseases.
Expanding Endovascular Therapy of Very Small Ruptured Aneurysms with the 1.5-mm Coil
Authors: Nguyen Thanh N. , Masoud Hesham , Tarlov Nicholas , Holsapple James , Chin Lawrence S. , Norbash Alexander M.
Published: September 2015

Background: Very small ruptured aneurysms (≤3 mm) demonstrate a significant risk for procedural rupture with endovascular therapy. Since 2007, 1.5-mm-diameter coils have been available (Micrus, Microvention, and ev3), allowing neurointerventionalists the opportunity to offer patients with very small aneurysms endovascular treatment. In this study, we review the clinical and angiographic outcome of patients with very small ruptured aneurysms treated with the 1.5-mm coil. Methods: This is a retrospective cohort study in which we examined consecutive ruptured very small aneurysms treated with coil embolization at a single institution. The longest linear aneurysm was recorded, even if the first coil was sized to a smaller transverse diameter. Very small aneurysms were defined as ≤3 mm. Descriptive results are presented. Results: From July 2007 to March 2015, 81 aneurysms were treated acutely with coils in 78 patients presenting with subarachnoid hemorrhage. There were 5 patients with 3-mm aneurysms, of which the transverse diameter was ≤2 mm in 3 patients. In all 5 patients, a balloon was placed for hemostatic prophylaxis in case of rupture, and a single 1.5-mm coil was inserted for aneurysm treatment without complication. Complete aneurysm occlusion was achieved in 1 patient, residual neck in 2, and residual aneurysm in 2 patients. Aneurysm recanalization was present in 2 patients with an anterior communicating artery aneurysm; a recoiling attempt was unsuccessful in 1 of these 2 patients due to inadvertent displacement and distal coil embolization, but subsequent surgical clipping was successful. Another patient was retreated by surgical clipping for a residual wide-neck carotid terminus aneurysm. One patient died of ventriculitis 3 weeks after presentation; all 4 other patients had an excellent outcome with no rebleed at follow-up (mean 21 months, range 1-62). Conclusion: The advent of the 1.5-mm coil may be used in the endovascular treatment of patients with very small ruptured aneurysms, providing a temporary protection to the site of rupture in the acute phase. If necessary, bridging with elective clipping may provide definitive aneurysm treatment.
Duplication of the Posterior Cerebral Artery and the ‘True Fetal' Variant
Authors: Masoud Hesham , Nguyen Thanh N. , Thatcher Joshua , Barest Glenn , Norbash Alexander M.
Published: September 2015

We present a rare case of bilateral posterior cerebral artery variant anatomy seen in a patient presenting with acute ischemic stroke. An embryological explanation of the variant configuration is discussed along with demonstrative radiologic images and a display of the vascular territory supplied.
Endovascular Therapy in Strokes with ASPECTS 5-7 May Result in Smaller Infarcts and Better Outcomes as Compared to Medical Treatment Alone
Authors: Noorian Ali Reza , Rangaraju Srikant , Sun Chung-Huan , Owada Kumiko , Nahab Fadi , Belagaje Samir R. , Anderson Aaron M. , Frankel Michael R. , Nogueira Raul G.
Published: September 2015

Introduction: Intra-arterial therapy (IAT) for large vessel occlusion strokes (LVOS) has been increasingly utilized. The benefit of IAT in patients with midrange Alberta Stroke Program Early Computed Tomography Score (ASPECTS) remains to be established. Materials and Methods: This was a retrospective analysis of LVOS with ASPECTS 5-7 treated with IAT (n = 86) or medical therapy alone (intravenous tissue plasminogen activator; n = 15) at two centers from 2009 to 2012. Definitions were as follows: symptomatic intracranial hemorrhage = any parenchymal hematoma; successful reperfusion = mTICI ≥2b; good and acceptable outcomes = 90-day mRS 0-2 and 0-3, respectively. Final infarct volumes (FIV) were calculated based on 24-hour CT/MRI scans. Results: Mean age (67 ± 14 vs. 67 ± 19 years) and baseline NIHSS (20 ± 5 vs. 20 ± 6) were similar in the two groups. Successful reperfusion was achieved in 58 (67%) IAT patients. Symptomatic and asymptomatic intracranial hemorrhage occurred in 9 (10%) and 31 (36%) IAT patients, respectively. The proportion of 90-day good and acceptable outcomes was 20 (17/86) and 33% (28/86), respectively. Successful IAT reperfusion was associated with smaller FIV (p = 0.015) and higher rates of good (p = 0.01) and acceptable (p = 0.014) outcomes. There was a strong trend towards a higher hemicraniectomy requirement in medically as compared to endovascularly treated patients (20 vs. 6%; p = 0.06) despite similar in-hospital mortality. The median FIV was significantly lower with IAT versus medical therapy [80 ml (interquartile range, 38-122) vs. 190 ml (121-267); p = 0.015]. Conclusions: Despite a relatively low probability of achieving functional independence, IAT in LVOS patients with ASPECTS 5-7 appears to result in lower degrees of disability and may lessen the need for hemicraniectomy. Therefore, it may be a reasonable option for patients and families who favor a shift from severe to moderate disability.
Silencing of ATPase Inhibitory Factor 1 Inhibits Cell Growth via Cell Cycle Arrest in Bladder Cancer
Authors: Wei Shihu , Fukuhara Hideo , Kawada Chiaki , Kurabayashi Atsushi , Furihata Mutsuo , Ogura Shun-ichiro , Inoue Keiji , Shuin Taro
Published: September 2015

Objective: The role of the ATPase inhibitory factor 1 (IF1) is inhibit the hydrolase activity of F1Fo-ATPase when oxidative phosphorylation is impaired. It has been demonstrated that IF1 is overexpressed in various carcinomas and mediates tumor cell activities, but the detailed mechanisms of IF1-mediated tumor progression and the link between IF1 and cell cycle progression remain unclear. Herein, we aimed to investigate the potential role of IF1 in cell cycle progression of human bladder cancer (BCa). Methods: The expression of IF1 was analyzed by immunohistochemistry in tumor tissues. Western blot was used to detect protein expression in the cells. Cell proliferation was determined by MTT and colony formation assays. The cell cycle was analyzed using flow cytometry. Results: We firstly showed IF1 was overexpressed in BCa. Silencing of IF1 by small interfering RNA led to a significant decrease in cell proliferation and migration in T24 and UM-UC-3 cells. Importantly, IF1 knockdown caused cell cycle arrest at G₀/G1 stage and decreased the protein level of cyclin E/cyclin-dependent kinases (cdk) 2 and/or cyclin D/cdk4/cdk6. Conclusion: These results suggest the inhibitory effect of IF1 knockdown on BCa cell proliferation is via the suppression of cyclins and cdks related to G1/S transition and then induction of G₀/G1 arrest, and firstly indicate IF1 mediates the tumor cell cycle. We concluded that IF1 may be a novel therapeutic target for BCa.
Renalase and Biomarkers of Contrast-Induced Acute Kidney Injury
Authors: Wybraniec Maciej T. , Mizia-Stec Katarzyna
Published: September 2015

Background: Contrast-induced acute kidney injury (CI-AKI) remains one of the crucial issues related to the development of invasive cardiology. The massive use of contrast media exposes patients to a great risk of contrast-induced nephropathy and chronic kidney disease development, and increases morbidity and mortality rates. The serum creatinine concentration does not allow for a timely and accurate CI-AKI diagnosis; hence numerous other biomarkers of renal injury have been proposed. Renalase, a novel catecholamine-metabolizing amine oxidase, is synthesized mainly in proximal tubular cells and secreted into urine and blood. It is primarily engaged in the degradation of circulating catecholamines. Notwithstanding its key role in blood pressure regulation, renalase remains a potential CI-AKI biomarker, which was shown to be markedly downregulated in the aftermath of renal injury. In this sense, renalase appears to be the first CI-AKI marker revealing an actual loss of renal function and indicating disease severity. Summary: The purpose of this review is to summarize the contemporary knowledge about the application of novel biomarkers of CI-AKI and to highlight the potential role of renalase as a functional marker of contrast-induced renal injury. Key Messages: Renalase may constitute a missing biochemical link in the mutual interplay between kidney and cardiac pathology known as the cardiorenal syndrome.
Morphological Changes in the Overall Mycobacterium tuberculosis H37Ra Cell Shape and Cytoplasm Homogeneity due to Mutellina purpurea L. Essential Oil and Its Main Constituents
Authors: Sieniawska Elwira , Swatko-Ossor Marta , Sawicki Rafał , Ginalska Grażyna
Published: September 2015

Objective: The aim of this study was to evaluate the antimycobacterial activity of the essential oil (EO) of Mutellina purpurea L. and its main constituents against the M. tuberculosis H37Ra strain. Materials and Methods: The M. purpurea EO was obtained by hydrodistillation, while its main constituents were purchased. The minimal inhibitory concentration values were determined by the log2 dilution method. Visualization of the effects of the tested substances on M. tuberculosis was performed using a transmission electron microscope (TEM). Mathematical shape descriptors such as area, circularity, aspect ratio and roundness were calculated to describe morphological changes in bacterial cell shape. Results: The EO of M.purpurea and all substances tested in this experiment showed a significant antimycobacterial activity. The most active was α-pinene followed by bisabolol and myrcene (8, 16 and 32 µg/ml, respectively). The EO and limonene exhibited the same antimicrobial activity (64 µg/ml). The TEM images and shape descriptors showed significant changes in the overall tuberculosis cell shape and cytoplasm homogeneity (uniformity and consistency) Conclusions: In this study, the low molecular weight compounds of mono- and sesquiterpenes penetrated/destabilized the complex mycobacterial cell wall and decreased its viability. There is a need for further experiments to explain the mechanism of action of these small particles.
Effect of Chondroitin Sulphate on Pro-Inflammatory Mediators and Disease Activity in Patients with Inflammatory Bowel Disease
Authors: Linares P.M. , Chaparro M. , Algaba A. , Román M. , Moreno Arza I. , Abad Santos F. , Ochoa D. , Guerra I. , Bermejo F. , Gisbert J.P.
Published: September 2015

Background/Aims: To evaluate the incidence rate of relapse in patients with inflammatory bowel disease (IBD) undergoing chondroitin sulphate (CS) treatment and its effect on the concentrations of several pro-inflammatory proteins. Methods: Prospective, observational, 12-month follow-up study in patients with IBD in remission, starting CS (Condrosan®, Bioiberica S.A.) treatment for osteoarthritis (OA). Crohn's Disease Activity Index and modified Truelove-Witts severity index were calculated for Crohn's disease and ulcerative colitis (UC) respectively. Levels of vascular endothelial growth factor (VEGFA), -C, fibroblast growth factor 2, hepatocyte growth factor, angiopoietin (Ang)-1, Ang-2, transforming growth factor beta, tumour necrosis factor alpha, interleukin (IL)-1β, IL-6, IL-12, IL-17, IL-23, intracellular adhesion molecule-1, vascular adhesion molecule-1, matrix metalloproteinase-3 and PGE2 were quantified by ELISA. OA joint pain was evaluated using a visual analogue scale. Results: A total of 37 patients (19 UC and 18 Crohn's disease) were included. The mean values for OA joint pain decreased after 12 months from 5.9 ± 2.8 to 3.0 ± 2.3 (p < 0.05). Only 1 patient (with UC) flared during follow-up. The incidence rate of relapse was 3.4% per patient-year of follow-up. Mean serum VEGFA levels increased between baseline (492 pg/ml) and 12-month treatment (799 pg/ml; p < 0.05). Conclusion: The incidence of IBD relapse in patients under CS treatment was lower than that generally reported. This treatment might modulate VEGFA. CS decreases OA-related pain in patients with IBD.
Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine
Authors: Yin Kai , You Yong , Swier Vicki , Tang Lin , Radwan Mohamed M. , Pandya Amit N. , Agrawal Devendra K.
Published: September 2015

Objective—

Prevalence of vitamin D (VD) deficiency and its association with the risk of cardiovascular disease prompted us to evaluate the effect of VD status on lipid metabolism and atherosclerosis in hypercholesterolemic microswine.

Approach and Results—

Yucatan microswine were fed with VD-deficient (0 IU/d), VD-sufficient (1000 IU/d), or VD-supplemented (3000 IU/d) high-cholesterol diet for 48 weeks. Serum lipids and 25(OH)-cholecalciferol levels were measured biweekly. Histology and biochemical parameters of liver and arteries were analyzed. Effect of 1,25(OH)
2
D
3
on cholesterol metabolism was examined in human hepatocyte carcinoma cell line (HepG2) and human monocytic cell line (THP-1) macrophage-derived foam cells. VD deficiency decreased plasma high-density lipoprotein levels, expression of liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 and promoted cholesterol accumulation and atherosclerosis in hypercholesterolemic microswine. VD promoted nascent high-density lipoprotein formation in HepG2 cells via ATP-binding membrane cassette transporter A1–mediated cholesterol efflux. Cytochrome P450 (CYP)27B1 and VD receptor were predominantly present in the CD206
+
M2 macrophage foam cell–accumulated cores in coronary artery plaques. 1,25(OH)
2
D
3
increased the expression of liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 and promoted cholesterol efflux in THP-1 macrophage–derived foam cells. 1,25(OH)
2
D
3
decreased intracellular free cholesterol and polarized macrophages to M2 phenotype with decreased expression of tumor necrosis factor-α, interleukin-1β, interleukin-6 under lipopolysaccharide stimulation. 1,25(OH)
2
D
3
markedly induced CYP27A1 expression via a VD receptor–dependent c-Jun N-terminal kinase (JNK) 1/2 signaling pathway and increased 27-hydroxycholesterol levels, which induced liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 expression and stimulated cholesterol efflux that was inhibited by VD receptor antagonist and JNK1/2 signaling inhibitor in THP-1 macrophage–derived foam cell.

Conclusions—

VD protects against atherosclerosis in hypercholesterolemic swine via controlling cholesterol efflux and macrophage polarization via increased CYP27A1 activation.
Therapeutic Angiogenesis by Ultrasound-Mediated MicroRNA-126-3p Delivery
Authors: Cao Wei J. , Rosenblat Joshua D. , Roth Nathan C. , Kuliszewski Michael A. , Matkar Pratiek N. , Rudenko Dmitriy , Liao Christine , Lee Paul J.H. , Leong-Poi Howard
Published: September 2015

Objective—

MicroRNAs are involved in many critical functions, including angiogenesis. Ultrasound-targeted microbubble destruction (UTMD) is a noninvasive technique for targeted vascular transfection of plasmid DNA and may be well suited for proangiogenic microRNA delivery. We aimed to investigate UTMD of miR-126-3p for therapeutic angiogenesis in chronic ischemia.

Approach and Results—

The angiogenic potential of miR-126-3p was tested in human umbilical vein endothelial cells in vitro. UTMD of miR-126-3p was tested in vivo in Fischer-344 rats before and after chronic left femoral artery ligation, evaluating target knockdown, miR-126-3p and miR-126-5p expression, phosphorylated Tie2 levels, microvascular perfusion, and vessel density. In vitro, miR-126-3p–transfected human umbilical vein endothelial cells showed repression of sprouty-related protein-1 and phosphatidylinositol-3-kinase regulatory subunit 2, negative regulators of vascular endothelial growth factor and angiopoietin-1 signaling, increased phosphorylated Tie2 mediated by knockdown of phosphatidylinositol-3-kinase regulatory subunit 2 and greater angiogenic potential mediated by both vascular endothelial growth factor/vascular endothelial growth factor R2 and angiopoietin-1 /Tie2 effects. UTMD of miR-126-3p resulted in targeted vascular transfection, peaking early after delivery and lasting for >3 days, and resulting in inhibition of sprouty-related protein-1 and phosphatidylinositol-3-kinase regulatory subunit 2, with minimal uptake in remote organs. Finally, UTMD of miR-126-3p to chronic ischemic hindlimb muscle resulted in improved perfusion, vessel density, enhanced arteriolar formation, pericyte coverage, and phosphorylated Tie2 levels, without affecting miR-126-5p or delta-like 1 homolog levels.

Conclusions—

UTMD of miR-126 results in improved tissue perfusion and vascular density in the setting of chronic ischemia by repressing sprouty-related protein-1 and phosphatidylinositol-3-kinase regulatory subunit 2 and enhancing vascular endothelial growth factor and angiopoietin-1 signaling, with no effect on miR-126-5p. UTMD is a promising platform for microRNA delivery, with applications for therapeutic angiogenesis.
Rate-Control Treatment and Mortality in Atrial Fibrillation
Authors: Chao Tze-Fan , Liu Chia-Jen , Tuan Ta-Chuan , Chen Su-Jung , Wang Kang-Ling , Lin Yenn-Jiang , Chang Shih-Lin , Lo Li-Wei , Hu Yu-Feng , Chen Tzeng-Ji , Chiang Chern-En , Chen Shih-Ann
Published: September 2015

Background—

Current American and European guidelines emphasize the importance of rate-control treatments in treating atrial fibrillation with a Class I recommendation, although data on the survival benefits of rate control are lacking. The goal of the present study was to investigate whether patients receiving rate-control drugs had a better prognosis compared with those without rate-control treatment.

Methods and Results—

This study used the National Health Insurance Research Database in Taiwan. There were 43 879, 18 466, and 38 898 patients with atrial fibrillation enrolled in the groups receiving β-blockers, calcium channel blockers, and digoxin, respectively. The reference group consisted of 168 678 subjects who did not receive any rate-control drug. The clinical end point was all-cause mortality. During a follow-up of 4.9±3.7 years, mortality occurred in 88 263 patients (32.7%). After adjustment for baseline differences, the risk of mortality was lower in patients receiving β-blockers (adjusted hazard ratio=0.76; 95% confidence interval=0.74–0.78) and calcium channel blockers (adjusted hazard ratio=0.93; 95% confidence interval=0.90–0.96) compared with those who did not receive rate-control medications. On the contrary, the digoxin group had a higher risk of mortality with an adjusted hazard ratio of 1.12 (95% confidence interval=1.10–1.14). The results were observed consistently in subgroup analyses and among the cohorts after propensity matching.

Conclusions—

In this nationwide atrial fibrillation cohort, the risk of mortality was lower for patients receiving rate-control treatment with β-blockers or calcium channel blockers, and the use of β-blockers was associated with the largest risk reduction. Digoxin use was associated with greater mortality. Prospective, randomized trials are necessary to confirm these findings.