bluuebunny/crossref_metadata_2025 huggingface dataset:
Secernin-1 Contributes to Colon Cancer Progression through Enhancing Matrix Metalloproteinase-2/9 Exocytosis
Authors: Lin Shengtao , Jiang Tao , Yu Yang , Tang Huamei , Lu Su , Peng Zhihai , Fan Junwei
Published: February 2015

Emerging evidence shows that exocytosis plays a key role in tumor development and metastasis. Secernin-1 (SCRN1) is a novel regulator of exocytosis. Our previous work identified SCRN1 as a tumor-associated gene by bioinformatics analysis of transcriptomes. In this study, we demonstrated the aberrant overexpression of SCRN1 at mRNA and protein level in colon cancer. We also revealed that overexpression of SCRN1 was significantly associated with the tumor development and poor prognosis. Experimentsin vitrovalidated that SCRN1 may promote cancer cell proliferation and secretion of matrix metalloproteinase-2/9 (MMP-2/9) proteins to accelerate tumor progression.
Application of a Hybrid Method Combining Grey Model and Back Propagation Artificial Neural Networks to Forecast Hepatitis B in China
Authors: Gan Ruijing , Chen Xiaojun , Yan Yu , Huang Daizheng
Published: February 2015

Accurate incidence forecasting of infectious disease provides potentially valuable insights in its own right. It is critical for early prevention and may contribute to health services management and syndrome surveillance. This study investigates the use of a hybrid algorithm combining grey model (GM) and back propagation artificial neural networks (BP-ANN) to forecast hepatitis B in China based on the yearly numbers of hepatitis B and to evaluate the method’s feasibility. The results showed that the proposal method has advantages over GM (1, 1) and GM (2, 1) in all the evaluation indexes.
Effect of PAN Oxidation on the Electrochemical Lithium Insertion/Deinsertion Behavior of Resultant Carbons
Authors: Piotrowska Aleksandra , Kierzek Krzysztof , Machnikowski Jacek
Published: February 2015

The effect of polyacrylonitrile (PAN) oxidation on the properties and electrochemical lithium insertion/deinsertion behavior of carbons produced in the temperature range of 1000–1150°C has been assessed. Air-treatment at 220 and 240°C modifies essentially the carbonization behavior of polymer leading to materials with developed microporosity and enhanced oxygen content in contrast to practically nonporous pristine PAN-based carbon. The extent of the modification increases with the oxidation depth and decreases with HTT. Galvanostatic charge/discharge reveals typical hard carbons characteristics of all the materials. PAN-based carbon heat-treated at 1050°C represents most promising anodic performance. It gives reversible capacity (Crev) near 420 mAh g−1with a reasonable coulombic efficiency during cycling of ~99% and a moderate low voltage capacity of 100 mAh g−1. Extensive oxidation enhances overall 1st discharge cycle capacity to 870 mAh g−1andCrevto 560 mAh g−1; however, large irreversible capacity (Cirr) and poor cycleability are serious drawbacks of all carbons from oxidized PAN. Pyrolytic carbon coating using methane CVD at 830°C is effective in suppressingCirrby about 30% but the cycleability remains nonacceptable.
Adaptive Control of MEMS Gyroscope Based on T-S Fuzzy Model
Authors: Fang Yunmei , Wang Shitao , Fei Juntao , Hua Mingang
Published: February 2015

A multi-input multioutput (MIMO) Takagi-Sugeno (T-S) fuzzy model is built on the basis of a nonlinear model of MEMS gyroscope. A reference model is adjusted so that a local linear state feedback controller could be designed for each T-S fuzzy submodel based on a parallel distributed compensation (PDC) method. A parameter estimation scheme for updating the parameters of the T-S fuzzy models is designed and analyzed based on the Lyapunov theory. A new adaptive law can be selected to be the former adaptive law plus a nonnegative in variable to guarantee that the derivative of the Lyapunov function is smaller than zero. The controller output is implemented on the nonlinear model and T-S fuzzy model, respectively, for the purpose of comparison. Numerical simulations are investigated to verify the effectiveness of the proposed control scheme and the correctness of the T-S fuzzy model.
The Protective Effects ofAreca catechuExtract on Cognition and Social Interaction Deficits in a Cuprizone-Induced Demyelination Model
Authors: Adilijiang Abulimiti , Guan Teng , He Jue , Hartle Kelly , Wang Wenqiang , Li XinMin
Published: February 2015

Schizophrenia is a serious psychiatric illness with an unclear cause. One theory is that demyelination of white matter is one of the main pathological factors involved in the development of schizophrenia. The current study evaluated the protective effects ofAreca catechunut extract (ANE) on a cuprizone-induced demyelination mouse model. Two doses of ANE (1% and 2%) were administered orally in the diet for 8 weeks. Animals subjected to demyelination showed impaired spatial memory and less social activity. In addition, mice subjected to demyelination displayed significant myelin damage in cortex and demonstrated a higher expression of NG2 and PDGFRαand AMPK activation. ANE treatment not only significantly enhanced cognitive ability and social activity, but also protected myelin against cuprizone toxicity by promoting oligodendrocyte precursor cell (OPC) differentiation. In addition, ANE treatment demonstrated significant dephosphorylation of AMPKα, indicating a regulatory role for ANE in schizophrenia. This study showed that ANE treatment may enhance cognitive ability and social activity by facilitating OPC differentiation and protecting against myelin damage in cortex. Results also suggest the AMPK signaling pathway may be involved in this process.
Dynamics of an Earthquake under Magma Thrust Strength
Authors: Kagho L. Y. , Dongmo M. W. , Pelap F. B.
Published: February 2015

This paper deals with the study of the behaviour of a one spring-block model subjected to the strengths due to the motion of the tectonic plates and the upflow of magma during volcanism. Using the direct integration method, we show that the sound velocity decreases (or increases) with the amplitude of the block’s oscillation when the external frequency is zero (or not). It appears that this amplitude grows with the amplitude of the magma thrust strength. For the resonance case, where this external frequency equals the pseudofrequency of the block’s oscillation, we establish that the slip which occurs during the periodic movement of a block is a stick-slip motion instead of a creep motion as usually known; therefore, the transition does not occur. We also obtain that the event probability decreases with the amplitude of the magma thrust strength while the power of the earthquake increases with it.
The Anti-Porcine Parvovirus Activity of Nanometer Propolis Flavone and Propolis FlavoneIn VitroandIn Vivo
Authors: Ma Xia , Guo Zhenhuan , Shen Zhiqiang , Liu Yonglu , Wang Jinliang , Fan Yunpeng
Published: February 2015

Objectives. The present study was conducted to evaluate the activity of nanometer propolis flavone (NPF) on inhibiting porcine parvovirus (PPV)in vitroandin vivo.Methods.In vitro, the effect of NPF on cellular infectivity of PPV was carried out before and after adding drug and simultaneous adding and PPV after being mixed.In vivo, the anti-PPV effect of NPF in guinea pigs was performed.Results. The results showed that NPF could significantly inhibit PPV infecting porcine kidney- (PK-) 15 cells compared with propolis flavone (PF), and the activity of NPF was the best in preadding drug pattern. NPF at high and medium doses was able to observably restrain PPV copying in lung, gonad, blood, and spleen, decrease the impact of PPV on weight of guinea pigs, and improve hemagglutination inhibition (HI) of PPV in serum. In addition, it could also increase the contents of IL-2 and IL-6 in serum after PPV challenge.Conclusion. These results indicated that NPF could significantly improve the anti-PPV activity of PF, and its high concentration possessed the best efficacy. Therefore, NPF would be expected to be exploited into a new-style antiviral drug.
A Realizable Quantum Three-Pass Protocol Authentication Based on Hill-Cipher Algorithm
Authors: Abdullah Alharith A. , Khalaf Rifaat , Riza Mustafa
Published: February 2015

A realizable quantum three-pass protocol authentication based on Hill-cipher algorithm is presented by encoded and decoded plaintext using classical Hill-cipher algorithm. It is shown that the encoded message transferred to the particles called quantum state where we assumed that a photon is used as a qubit and after the encoded message is transferred into photons, the polarization of each photon is rotated by an angleθj, which is chosen randomly for each qubit. The sender and receiver agree over a Hill-cipher key, the encryption occurs by utilization of the quantum three-pass protocol (QTPP), the decryption will be illustrated, and an example shows how the algorithm will work. Finally, the security of this algorithm is analyzed in detail.
Effect of Luteolin and Apigenin on the Expression of Oct-4, Sox2, and c-Myc in Dental Pulp Cells withIn VitroCulture
Authors: Liu Lu , Peng Zhengjun , Xu Zezhen , Wei Xi
Published: February 2015

Introduction. Dental pulp cells (DPCs) are promising cell source for dental tissue regeneration. Recently, small molecules which optimize microenvironment or activate the reprogramming network provide a new way to enhance the pluripotency. Two promising bioflavonoids luteolin and apigenin were reported to enhance reprogramming efficiency in mouse embryonic fibroblast (MEF). However, their effect and underlying mechanism in cell fate determination of human DPCs remain unclear.Methods. To elucidate the effect of luteolin and apigenin on the cell fate determination of DPCs, we explored the cell proliferation, cell cycle, senescence, apoptosis, expression of pluripotency markers Oct-4, Sox2, and c-Myc, and multilineage differentiation capability of DPCs with luteolin or apigenin treatment.Results. We demonstrated that luteolin and apigenin inhibited cell proliferation, arrested DPCs in G2/M and S phase, and upregulated PI value and apoptosis. Moreover, luteolin and apigenin increased telomerase activity, maintained DPCs in a presenescent state, and activated the expression of Oct-4, Sox2, and c-Myc at a dose- and time-dependent pattern in DPCs even at late passages, albeit repressed lineage-specific differentiation.Conclusions. Addition of luteolin and apigenin in the culture medium might provide an effective way to maintain DPCs in an undifferentiated stage and inhibit lineage-specific differentiation.
Fourier Transform Infrared Spectroscopic Imaging of Fracture Healing in the Normal Mouse
Authors: Gollwitzer Hans , Yang Xu , Spevak Lyudmila , Lukashova Lyudmila , Nocon Allina , Fields Kara , Pleshko Nancy , Courtland Hayden William , Bostrom Mathias P. , Boskey Adele L.
Published: February 2015

Fourier transform infrared spectroscopic imaging (FTIRI) was used to study bone healing with spatial analysis of various callus tissues in wild type mice. Femoral fractures were produced in 28 male C57BL mice by osteotomy. Animals were sacrificed at 1, 2, 4, and 8 weeks to obtain callus tissue at well-defined healing stages. Following microcomputerized tomography, bone samples were cut in consecutive sections for FTIRI and histology, allowing for spatial correlation of both imaging methods in different callus areas (early calcified cartilage, woven bone, areas of intramembranous and endochondral bone formation). Based on FTIRI, mineral/matrix ratio increased significantly during the first 4 weeks of fracture healing in all callus areas and correlated with bone mineral density measured by micro-CT. Carbonate/phosphate ratio was elevated in newly formed calcified tissue and at week 2 attained values comparable to cortical bone. Collagen maturity and mineral crystallinity increased during weeks 1–8 in most tissues while acid phosphate substitution decreased. Temporal and callus area dependent changes were detected throughout the healing period. These data assert the usefulness of FTIRI for evaluation of fracture healing in the mouse and its potential to evaluate pathologic fracture healing and the effects of therapeutic interventions.
Real-Life Report on Chemoembolization Using DEBIRI for Liver Metastases from Colorectal Cancer
Authors: Stutz M. , Mamo A. , Valenti D. , Hausvater A. , Cabrera T. , Metrakos P. , Chaudhury P. , Steacy G. , Garoufalis E. , Kavan P.
Published: February 2015

Background. Transarterial chemoembolization (TACE) has been investigated in patients with liver metastases from colorectal cancer (LMCRC). Limited experience and available data suggest that TACE can achieve disease stabilization or improvement, even in heavily pretreated patients.Methods. Patients with LMCRC, ECOG 0–2, who failed at least 1 line of systemic chemotherapy, received embolizations with 2 mL of microspheres preloaded with 100 mg of irinotecan. Beads were delivered selectively into hepatic arteries. Primary endpoint was overall survival (OS), analyzed using the Kaplan-Meier method. Secondary endpoint was safety, assessed using CTCAE version 4.0.Results. 27 patients were treated using DEBIRI. Patient median age was 57 years (range was 45–82 years). The median number of total embolizations was 1.3 (range 1–3). The median OS was 5.4 months (95% CI; 1.1–22.7 months). The most reported postembolization events were nausea (8/27), vomiting (6/27), right upper quadrant pain (16/27), fatigue (9/27), and the development of ascites (6/27). 5/26 patients required hospitalization after TACE for severe pain. Hospitalization was also required for 1 case of allergic reaction and 1 case of infection.Conclusion. Our data suggest that TACE with DEBIRI could be efficacious in a palliative setting for patients with LMCRC, but they do not necessarily support routine use in clinical practice.
Dynamic Rendezvous Based Routing Algorithm on Sparse Opportunistic Network Environment
Authors: Kerdsri Jiradett , Wipusitwarakun Komwut
Published: February 2015

An opportunistic network is a network where the nodes need to communicate with each other even if existing routes between them may not permanently exist due to the nodes’ random movement. Most routing algorithms employ a paradigm by which a node can keep the receiving messages, carrying the messages with them when moving and then forwarding the messages to the opportunistic meeting nodes when possible. This routing model works well in the networks with high-to-moderate node density in which the opportunity that the moving nodes can meet with each other is rather high. On the other hand, the delivery ratio becomes remarkably low in the sparse network environment especially when there is a strict constraint on message delivery deadline. In this paper, we introduce the novel concept of rendezvous place where the passing nodes can announce, deposit, or pick up their own messages without having to meet the other nodes carrying the desired message. The rendezvous place can be detected automatically and its area's shape is dynamically changed according to the interaction among nodes. The results from extensive simulations show that our routing algorithm can achieve higher delivery ratio and utilize lower energy consumption than traditional opportunistic routing algorithms especially in sparse network environment.
Evolution of Action Potential Alternans in Rabbit Heart during Acute Regional Ischemia
Authors: Martišienė Irma , Jurevičius Jonas , Vosyliūtė Rūta , Navalinskas Antanas , Treinys Rimantas , Mačianskienė Regina , Benetis Rimantas , Matiukas Arvydas , Pertsov Arkady M.
Published: February 2015

This study investigates the development of the spatiotemporal pattern of action potential alternans during acute regional ischemia. Experiments were carried out in isolated Langendorff-perfused rabbit heart using a combination of optical mapping and microelectrode recordings. The alternans pattern significantly changed over time and had a biphasic character reaching maximum at 6–9 min after occlusion. Phase I (3–11 minutes of ischemia) is characterized by rapid increase in the alternans magnitude and expansion of the alternans territory. Phase I is followed by gradual decline of alternans (Phase II) in both magnitude and territory. During both phases we observed significant beat-to-beat variations of the optical action potential amplitude (OAPA) alternans. Simultaneous microelectrode recordings from subepicardial and subendocardial layers showed that OAPA alternans coincided with intramural 2 : 1 conduction blocks. Our findings are consistent with the modeling studies predicting that during acute regional ischemia alternans can be driven by 2 : 1 conduction blocks in the ischemic region.
FOXP3 Controls an miR-146/NF-κB Negative Feedback Loop That Inhibits Apoptosis in Breast Cancer Cells
Authors: Liu Runhua , Liu Cong , Chen Dongquan , Yang Wei-Hsiung , Liu Xiuping , Liu Chang-Gong , Dugas Courtney M. , Tang Fei , Zheng Pan , Liu Yang , Wang Lizhong
Published: February 2015

FOXP3 functions not only as the master regulator in regulatory T cells, but also as an X-linked tumor suppressor. The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, but its role during tumor progression remains controversial. Moreover, the mechanism of FOXP3-mediated tumor-suppressive activity remains largely unknown. Using chromatin immunoprecipitation (ChIP) sequencing, we identified a series of potential FOXP3-targeted miRNAs in MCF7 cells. Notably, FOXP3 significantly induced the expression of miR-146a/b. In vitro, FOXP3-induced miR-146a/b prevented tumor cell proliferation and enhanced apoptosis. Functional analyses in vitro and in vivo revealed that FOXP3-induced miR-146a/b negatively regulates NF-κB activation by inhibiting the expression of IRAK1 and TRAF6. In ChIP assays, FOXP3 directly bound the promoter region of miR-146a but not of miR-146b, and FOXP3 interacted directly with NF-κB p65 to regulate an miR-146–NF-κB negative feedback regulation loop in normal breast epithelial and tumor cells, as demonstrated with luciferase reporter assays. Although FOXP3 significantly inhibited breast tumor growth and migration in vitro and metastasis in vivo, FOXP3-induced miR-146a/b contributed only to the inhibition of breast tumor growth. These data suggest that miR-146a/b contributes to FOXP3-mediated tumor suppression during tumor growth by triggering apoptosis. The identification of a FOXP3–miR-146–NF-κB axis provides an underlying mechanism for disruption of miR-146 family member expression and constitutive NF-κB activation in breast cancer cells. Linking the tumor suppressor function of FOXP3 to NF-κB activation reveals a potential therapeutic approach for cancers with FOXP3 defects. Cancer Res; 75(8); 1703–13. ©2015 AACR.
Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling
Authors: Man Jianghong , Shoemake Jocelyn D. , Ma Tuopu , Rizzo Anthony E. , Godley Andrew R. , Wu Qiulian , Mohammadi Alireza M. , Bao Shideng , Rich Jeremy N. , Yu Jennifer S.
Published: February 2015

Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment. Cancer Res; 75(8); 1760–9. ©2015 AACR.
Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case–Control Study
Authors: Wibom Carl , Späth Florentin , Dahlin Anna M. , Langseth Hilde , Hovig Eivind , Rajaraman Preetha , Johannesen Tom Børge , Andersson Ulrika , Melin Beatrice
Published: February 2015

Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case–control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included.

Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research.

Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study.

Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis.

Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology. Cancer Epidemiol Biomarkers Prev; 24(5); 810–6. ©2015 AACR.
Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3β
Authors: Chen Xiangmei , Zhang Ling , Zheng Sujun , Zhang Ting , Li Meng , Zhang Xiaolei , Zeng Zhenzhen , McCrae Malcolm A. , Zhao Jingmin , Zhuang Hui , Lu Fengmin
Published: February 2015

The Hepatitis B virus X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). It has been suggested that the transcriptional activation of cyclin D1 by HBx is implicated in the development of HCC. However, numerous studies have shown that overexpression of cyclin D1 alone is not sufficient to drive oncogenic transformation. Herein, we investigated whether HBx can stabilize cyclin D1 and induce cyclin D1 protein nuclear accumulation, and thereby accelerate hepatocarcinogenesis. The effects of HBx on cyclin D1 stabilization were assessed in cell-based transfection, Western blot, immunoprecipitation, immunocytofluorescence staining, and flow-cytometric assays. The results demonstrated that ectopic expression of HBx in HCC cells could extend the half-life of cyclin D1 protein from 40–60 minutes to 80–110 minutes. HBx stabilized cyclin D1 primarily in the S phase of the cell cycle, in a manner dependent on the inactivation of GSK-3β, which was mediated by ERK activation. HBx also prompted the nuclear accumulation of cyclin D1, and cotransfection of the constitutively active mutant of GSK-3β along with HBx could reverse the nuclear accumulation and subsequent cell proliferation induced by HBx. Further, a positive correlation between HBx and nuclear cyclin D1 level was established in HCC specimens detected by an immunohistochemical assay. Taken together, our results indicated that HBx could stabilize and increase cyclin D1 nuclear accumulation through ERK-mediated inactivation of GSK-3β. This HBx-induced cyclin D1 upregulation might play an important role in HCC development and progression. Cancer Prev Res; 8(5); 455–63. ©2015 AACR.
A Novel Target for Oral Cancer Chemoprevention? Notch Quite, Yet…
Authors: William William N. , El-Naggar Adel K.
Published: February 2015

The two major goals of oral cancer chemoprevention efforts are the ability to segregate the high-risk patients and the identification of an effective pharmacologic agent that halts progression to invasive cancer. Considerable progress has recently been achieved in profiling invasive head and neck squamous cell carcinomas, particularly with the use of high-throughput technologies. A similar molecular characterization of potentially malignant oral epithelial lesions (OPML; leukoplakia and erythroplakia) is yet to be accomplished. It is postulated, though, that molecular profiling could lead to the discovery of novel markers of cancer risk that could also serve as potential targets for chemoprevention. In this perspective, we comment on the work by Izumchenko and colleagues that reports a high prevalence of NOTCH1 gain-of-function mutations in Chinese patients with OPMLs. Although additional studies are needed to validate the findings, the study is the first to link alterations in this gene in oral premalignancy. These findings could serve as a first prototype of a single gene mutation as a potential target in clinical chemoprevention setting. Cancer Prev Res; 8(4); 262–5. ©2015 AACR.

See related article by Izumchenko et al., p. 277
Human Leukocyte Antigen (HLA) A*1101-Restricted Epstein-Barr Virus–Specific T-cell Receptor Gene Transfer to Target Nasopharyngeal Carcinoma
Authors: Zheng Yong , Parsonage Greg , Zhuang Xiaodong , Machado Lee R. , James Christine H. , Salman Asmaa , Searle Peter F. , Hui Edwin P. , Chan Anthony T.C. , Lee Steven P.
Published: February 2015

Infusing virus-specific T cells is effective treatment for rare Epstein-Barr virus (EBV)–associated posttransplant lymphomas, and more limited success has been reported using this approach to treat a far more common EBV-associated malignancy, nasopharyngeal carcinoma (NPC). However, current approaches using EBV-transformed lymphoblastoid cell lines to reactivate EBV-specific T cells for infusion take 2 to 3 months of in vitro culture and favor outgrowth of T cells targeting viral antigens expressed within EBV+ lymphomas, but not in NPC. Here, we explore T-cell receptor (TCR) gene transfer to rapidly and reliably generate T cells specific for the NPC-associated viral protein LMP2. We cloned a human leukocyte antigen (HLA) A*1101-restricted TCR, which would be widely applicable because 40% of NPC patients carry this HLA allele. Studying both the wild-type and modified forms, we have optimized expression of the TCR and demonstrated high-avidity antigen-specific function (proliferation, cytotoxicity, and cytokine release) in both CD8+ and CD4+ T cells. The engineered T cells also inhibited LMP2+ epithelial tumor growth in a mouse model. Furthermore, transduced T cells from patients with advanced NPC lysed LMP2-expressing NPC cell lines. Using this approach, within a few days large numbers of high-avidity LMP2-specific T cells can be generated reliably to treat NPC, thus providing an ideal clinical setting to test TCR gene transfer without the risk of autoimmunity through targeting self-antigens. Cancer Immunol Res; 3(10); 1138–47. ©2015 AACR.
Clinical Value of Maternal Bile Acid Quantification in Intrahepatic Cholestasis of Pregnancy as an Adverse Perinatal Outcome Predictor
Authors: Garcia-Flores Jose , Cañamares Marina , Cruceyra Mireia , Garicano Ainhoa , Espada Mercedes , Lopez Ana , Tamarit Ines
Published: February 2015

Aims: To evaluate the correlation between perinatal outcome and bile acid levels in intrahepatic cholestasis of pregnancy (ICP), and to evaluate variations in the mean bile acid level when stratifying by maternal and perinatal factors. A comparison between mild and severe ICP was made. Methods: A prospective observational study was performed in pregnant patients who underwent blood tests for bile acids due to persistent pruritus. Based on bile acid levels, maternal and neonatal data were obtained and were compared between patients presenting with ICP and gestational pruritus (normal bile acid level). Results: A total of 145 patients were included, 47 of whom were diagnosed as ICP (52 newborns) and 98 as gestational pruritus (102 newborns). The ICP group had a higher rate of NICU admission (14/42 vs. 6/98, p < 0.001) and global neonatal morbidity (13/42 vs. 9/98, p = 0.002), but these differences were no longer seen after adjusting for gestational age, singleton pregnancies and induction of labour. Patients presenting with severe ICP (maximum bile acids levels above 40 µmol/l) showed a higher rate of meconium-stained amniotic fluid (0/28 vs. 4/14, p = 0.009), NICU admission (9/34 vs. 11/17, p = 0.01) and neonatal global morbidity (5/32 vs. 8/17, p = 0.02). Conclusions: ICP patients have higher rates of adverse neonatal outcomes when compared to those with gestational pruritus. Some of this neonatal morbidity may be secondary to late spontaneous preterm deliveries, multiple gestation and a policy of elective induction of labour after 37 weeks of gestation. A comparison of outcomes among patients with mild and severe ICP shows that the severely affected group has higher rates of meconium-stained amniotic fluid and neonatal morbidity.
Novel Transparent Urinary Tract Simulator Improves Teaching of Urological Operation Skills at a Single Institution
Authors: Zhong Xiao , Wang Pingxian , Feng Jiayu , Hu Wengang , Huang Chibing
Published: February 2015

Objective: This randomized controlled study compared a novel transparent urinary tract simulator with the traditional opaque urinary tract simulator as an aid for efficiently teaching urological surgical procedures. Methods: Senior medical students were tested on their understanding of urological theory before and after lectures concerning urinary system disease. The students received operative training using the transparent urinary tract simulator (experimental group, n = 80) or the J3311 opaque plastic urinary tract simulator (control, n = 80), specifically in catheterization and retrograde double-J stent implantation. The operative training was followed by a skills test and student satisfaction survey. Results: The test scores for theory were similar between the two groups, before and after training. Students in the experimental group performed significantly better than those in the control group on the procedural skills test, and also had significantly better self-directed learning skills, analytical skills, and greater motivation to learn. Conclusion: During the initial step of training, the novel transparent urinary tract simulator significantly improved the efficiency of teaching urological procedural skills compared with the traditional opaque device.
Prevalence of Patent Foramen Ovale in Ischaemic Stroke in Italy: Results of SISIFO Study
Authors: Consoli Domenico , Paciaroni Maurizio , Galati Franco , Aguggia Marco , Melis Maurizio , Malferrari Giovanni , Consoli Arturo , Vidale Simone , Bosco Domenico , Cerrato Paolo , Sacco Simona , Gandolfo Carlo , Bovi Paolo , Serrati Carlo , Del Sette Massimo , Cavallini Anna , Diomedi Marina , Postorino Paolo , Reboldi Paolo , Ricci Stefano ,   on behalf of SISIFO group
Published: February 2015

Background: Although several authors have studied the association between patent foramen ovale (PFO) and ischaemic stroke, the matter is still controversial; few have suggested an association between cryptogenetic stroke and PFO, while others have denied this association. The aim of this study was to evaluate PFO prevalence in the whole ischaemic stroke population, independently from age and stroke subtypes and to identify the characteristics associated with the presence of PFO. Methods: SISIFO study was a multicenter, prospective, single-wave, cross-sectional survey conducted on consecutive patients with acute ischemic stroke admitted to selected clinical centres. Data regarding vascular risk factors were registered for each patient; all patients underwent computed tomography scan and/or magnetic resonance imaging of the brain; an electrocardiogram and standard laboratory blood tests were performed. A Doppler ultrasound study of extra-cranial arteries was performed too. The cases were classified according to TOAST and OCSP criteria. Each patient underwent transcranial Doppler or transcranial color-coded duplex sonography with bubble test as diagnostic tool for right-to-left-shunt. Where right-to-left shunt was detected, PFO presence was confirmed by echocardiography. Findings: 1,130 consecutive patients were included. We found a PFO in 247 (21.9%; 95% CI, 19.5-24.3%) patients; PFO was present in 23.5% of patients with cryptogenic stroke and in 21.3% of patients with stroke of known causes; this difference was not statistically significant. At the univariate analysis, decreasing age, hypertension, diabetes mellitus, and atrial fibrillation, and stroke characteristics such as NIHSS, OCSP and TOAST were predictors of PFO presence. At the multivariate analysis, we found a significant interaction between age and OCSP syndrome. Being LACI the reference category, the prevalence of PFO in PACI and POCI decreased significantly along with age, whereas there was no change in TACI. Conclusion: If any relationship exists between stroke and PFO, this is more likely in PACI and POCI at a younger age. Our results are consistent with recent findings that underline PFO alone must not be considered a significant independent predictor for stroke; so the presence of PFO alone doesn't permit rushed causal correlations or ‘therapeutic aggressiveness'.
The Cost Effectiveness of Erythropoietin-Stimulating Agents for Treating Anemia in Patients on Dialysis: A Systematic Review
Authors: Ferguson Thomas , Xu Yang , Gunasekara Ravindi , Lerner Blake , Macdonald Kerry , Rigatto Claudio , Tangri Navdeep , Komenda Paul
Published: February 2015

Background: Anemia is a common complication associated with kidney failure and is marked by poor health and increased risk of morbidity and mortality. There are ongoing concerns with the use of Erythropoietin Stimulating Agents (ESAs) to treat anemia in patients with kidney failure on dialysis. Questions as to their benefits, harms and overall effect on quality of life are still relevant today. Our objective was to systematically review studies evaluating the cost-effectiveness of ESAs in patients with kidney failure on dialysis. Methods: We performed a systematic review of studies determining the cost-effectiveness of ESAs in adult patients on dialysis. Databases, including PubMed, EMBASE, and Cochrane Database of Systematic Reviews, were searched from their establishment until June 2013. Studies that reported an incremental cost-effectiveness ratio of hemoglobin correction strategies based on ESA treatments in comparison to red blood cell transfusions, lower hemoglobin targets, or no ESA treatment were included. Results: Seven studies met inclusion criteria. Reported cost/quality-adjusted life-year (QALY) ratios ranged from USD 931-677,749/QALY across five studies comparing ESAs to red blood cell transfusions. There was heterogeneity in results when considering higher hemoglobin targets, with studies finding higher targets to be both dominant and dominated. Mortality, hospitalization, and utility estimates were major drivers. Conclusions: There is substantial variability in the estimates of the cost-effectiveness of using ESAs in the dialysis population. New models incorporating recent meta-analyses for estimates of utility, mortality, and hospitalization changes would allow for a more comprehensive answer to this question.
Novel Mutation in the α-Myosin Heavy Chain Gene Is Associated With Sick Sinus Syndrome
Authors: Ishikawa Taisuke , Jou Chuanchau J. , Nogami Akihiko , Kowase Shinya , Arrington Cammon B. , Barnett Spencer M. , Harrell Daniel T. , Arimura Takuro , Tsuji Yukiomi , Kimura Akinori , Makita Naomasa
Published: February 2015

Background—

Recent genome-wide association studies have demonstrated an association between
MYH6
, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. Moreover, a rare
MYH6
variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing
MYH6
mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown.

Methods and Results—

We screened 9 genotype-negative probands with sick sinus syndrome families for mutations in
MYH6
and identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C in one patient. Co-immunoprecipitation analysis revealed enhanced binding of delE933 α-MHC to myosin-binding protein C. Irregular fluorescent speckles retained in the cytoplasm with substantially disrupted sarcomere striation were observed in neonatal rat cardiomyocytes transfected with α-MHC mutants carrying delE933 or R721W. In addition to the sarcomere impairments, delE933 α-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 α-MHC showed a significantly slower conduction velocity on multielectrode array than those of wild-type α-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knockdown of
MYH6
in zebrafish significantly reduced the heart rate, which was rescued by coexpressed wild-type human α-MHC but not by delE933 α-MHC.

Conclusions—

The novel
MYH6
mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of
MYH6
for sinus node function and identifies a novel pathophysiology underlying familial sick sinus syndrome.
Interactions of Lipid Genetic Risk Scores With Estimates of Metabolic Health in a Danish Population
Authors: Justesen Johanne M. , Allin Kristine H. , Sandholt Camilla H. , Borglykke Anders , Krarup Nikolaj T. , Grarup Niels , Linneberg Allan , Jørgensen Torben , Hansen Torben , Pedersen Oluf
Published: February 2015

Background—

There are several well-established lifestyle factors influencing dyslipidemia and currently; 157 genetic susceptibility loci have been reported to be associated with serum lipid levels at genome-wide statistical significance. However, the interplay between lifestyle risk factors and these susceptibility loci has not been fully elucidated. We tested whether genetic risk scores (GRS) of lipid-associated single nucleotide polymorphisms associate with fasting serum lipid traits and whether the effects are modulated by lifestyle factors or estimates of metabolic health.

Methods and Results—

The single nucleotide polymorphisms were genotyped in 2 Danish cohorts: inter99 (n=5961) for discovery analyses and Health2006 (n=2565) for replication. On the basis of published effect sizes of single nucleotide polymorphisms associated with circulating fasting levels of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, or triglyceride, 4 weighted GRS were constructed. In a cross-sectional design, we investigated whether the effect of these weighted GRSs on lipid levels were modulated by diet, alcohol consumption, physical activity, and smoking or the individual metabolic health status as estimated from body mass index, waist circumference, and insulin resistance assessed using homeostasis model assessment of insulin resistance. All 4 lipid weighted GRSs associated strongly with their respective trait (from
P
=3.3×10
–69
to
P
=1.1×10
–123
). We found interactions between the triglyceride weighted GRS and body mass index and waist circumference on fasting triglyceride levels in Inter99 and replicated these findings in Health2006 (
P
interaction
=9.8×10
–5
and 2.0×10
–5
, respectively, in combined analysis).

Conclusions—

Our findings suggest that individuals who are obese may be more susceptible to the cumulative genetic burden of triglyceride single nucleotide polymorphisms. Therefore, it is suggested that especially these genetically at-risk individuals may benefit more from targeted interventions aiming at obesity prevention.
Use of Coronary Artery Calcium Scanning Beyond Coronary Computed Tomographic Angiography in the Emergency Department Evaluation for Acute Chest Pain
Authors: Pursnani Amit , Chou Eric T. , Zakroysky Pearl , Deaño Roderick C. , Mamuya Wilfred S. , Woodard Pamela K. , Nagurney John T. , Fleg Jerome L. , Lee Hang , Schoenfeld David , Udelson James E. , Hoffmann Udo , Truong Quynh A.
Published: February 2015

Background—

Whether a coronary artery calcium (CAC) scan provides added value to coronary computed tomographic angiography (CCTA) in emergency department patients with acute chest pain remains unsettled. We sought to determine the value of CAC scan in patients with acute chest pain undergoing CCTA.

Methods and Results—

In the multicenter Rule Out Myocardial Infarction using Computer-Assisted Tomography (ROMICAT) II trial, we enrolled low-intermediate risk emergency department patients with symptoms suggesting acute coronary syndrome (ACS). In this prespecified subanalysis of 473 patients (54±8 years, 53% men) who underwent both CAC scanning and CCTA, the ACS rate was 8%. Overall, 53% of patients had CAC=0 of whom 2 (0.8%) developed ACS, whereas 7% had CAC>400 with 49% whom developed ACS. C-statistic of CAC>0 was 0.76, whereas that using the optimal cut point of CAC≥22 was 0.81. Continuous CAC score had lower discriminatory capacity than CCTA (c-statistic, 0.86 versus 0.92;
P
=0.03). Compared with CCTA alone, there was no benefit combining CAC score with CCTA (c-statistic, 0.93;
P
=0.88) or with selective CCTA strategies after initial CAC>0 or optimal cut point CAC≥22 (
P
≥0.09). Mean radiation dose from CAC acquisition was 1.4±0.7 mSv. Higher CAC scores resulted in more nondiagnostic CCTA studies although the majority remained interpretable.

Conclusions—

In emergency department patients with acute chest pain, CAC score does not provide incremental value beyond CCTA for ACS diagnosis. CAC=0 does not exclude ACS, nor a high CAC score preclude interpretation of CCTA in most patients. Thus, CAC results should not influence the decision to proceed with CCTA, and the decision to perform a CAC scan should be balanced with the additional radiation exposure required.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01084239.
Invasive Evaluation of Patients With Angina in the Absence of Obstructive Coronary Artery Disease
Authors: Lee Bong-Ki , Lim Hong-Seok , Fearon William F. , Yong Andy S. , Yamada Ryotaro , Tanaka Shigemitsu , Lee David P. , Yeung Alan C. , Tremmel Jennifer A.
Published: February 2015

Background—

More than 20% of patients presenting to the cardiac catheterization laboratory with angina have no angiographic evidence of coronary artery disease. Despite a “normal” angiogram, these patients often have persistent symptoms, recurrent hospitalizations, a poor functional status, and adverse cardiovascular outcomes, without a clear diagnosis.

Methods and Results—

In 139 patients with angina in the absence of obstructive coronary artery disease (no diameter stenosis >50%), endothelial function was assessed; the index of microcirculatory resistance, coronary flow reserve, and fractional flow reserve were measured; and intravascular ultrasound was performed. There were no complications. The average age was 54.0±11.4 years, and 107 (77%) were women. All patients had at least some evidence of atherosclerosis based on an intravascular ultrasound examination of the left anterior descending artery. Endothelial dysfunction (a decrease in luminal diameter of >20% after intracoronary acetylcholine) was present in 61 patients (44%). Microvascular impairment (an index of microcirculatory resistance ≥25) was present in 29 patients (21%). Seven patients (5%) had a fractional flow reserve ≤0.80. A myocardial bridge was present in 70 patients (58%). Overall, only 32 patients (23%) had no coronary explanation for their angina, with normal endothelial function, normal coronary physiological assessment, and no myocardial bridging.

Conclusions—

The majority of patients with angina in the absence of obstructive coronary artery disease have occult coronary abnormalities. A comprehensive invasive assessment of these patients at the time of coronary angiography can be performed safely and provides important diagnostic information that may affect treatment and outcomes.
Mineralocorticoid Receptor Antagonism Treats Obesity-Associated Cardiac Diastolic Dysfunction
Authors: Bender Shawn B. , DeMarco Vincent G. , Padilla Jaume , Jenkins Nathan T. , Habibi Javad , Garro Mona , Pulakat Lakshmi , Aroor Annayya R. , Jaffe Iris Z. , Sowers James R.
Published: February 2015

Patients with obesity and diabetes mellitus exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin-aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure–independent low-dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide–independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling, with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. In addition, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure–independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance.