bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering Knowledge-Based Variance-Reduction Simulation and G-Dominance for Structural Frame Robust Optimization
Authors: Greiner D. , Emperador J. M. , Galván B. , Méndez M. , Winter G.
Published: December 2013

This paper proposes the incorporation of engineering knowledge through both (a) advanced state-of-the-art preference handling decision-making tools integrated in multiobjective evolutionary algorithms and (b) engineering knowledge-based variance-reduction simulation as enhancing tools for the robust optimum design of structural frames taking uncertainties into consideration in the design variables. The simultaneous minimization of the constrained weight (adding structural weight and average distribution of constraint violations) on the one hand and the standard deviation of the distribution of constraint violation on the other are handled with multiobjective optimization-based evolutionary computation in two different multiobjective algorithms. The optimum design values of the deterministic structural problem in question are proposed as a reference point (the aspiration level) in reference-point-based evolutionary multiobjective algorithms (here g-dominance is used). Results including S-metric statistics in a structural frame test case with uncertain loads show considerable reductions in computational costs without harming the nondominated front quality, obtaining a design set that makes it possible to select minimum weight and maximum robustness optimum designs.
Effect of Coercive Voltage and Charge Injection on Performance of a Ferroelectric-Gate Thin-Film Transistor
Authors: Tue P. T. , Miyasako T. , Tokumitsu E. , Shimoda T.
Published: December 2013

We adopted a lanthanum oxide capping layer between semiconducting channel and insulator layers for fabrication of a ferroelectric-gate thin-film transistor memory (FGT) which uses solution-processed indium-tin-oxide (ITO) and lead-zirconium-titanate (PZT) film as a channel layer and a gate insulator, respectively. Good transistor characteristics such as a high “on/off” current ratio, high channel mobility, and a large memory window of 108, 15.0 cm2 V−1 s−1, and 3.5 V were obtained, respectively. Further, a correlation between effective coercive voltage, charge injection effect, and FGT’s memory window was investigated. It is found that the charge injection from the channel to the insulator layer, which occurs at a high electric field, dramatically influences the memory window. The memory window’s enhancement can be explained by a dual effect of the capping layer: (1) a reduction of the charge injection and (2) an increase of effective coercive voltage dropped on the insulator.
Antidiabetic and Antioxidant Properties ofTriticum aestivumin Streptozotocin-Induced Diabetic Rats
Authors: Mohan Yogesha , Jesuthankaraj Grace Nirmala , Ramasamy Thangavelu Narendhirakannan
Published: December 2013

The antidiabetic and antioxidant potential ofTriticum aestivumwere evaluated by usingin vivomethods in normal and streptozotocin-induced diabetic rats. Diabetes was induced in the Wistar strain albino rats by injecting streptozotocin at a dose of 55 mg/kg body weight. Ethanolic extracts ofTriticum aestivumat doses of 100 mg/kg body weight were administered orally for 30 days. Various parameters were studied and the treatment group with the extract showed a significant increase in the liver glycogen and a significant decrease in fasting blood glucose, glycosylated hemoglobin levels, and serum marker enzyme levels. The total cholesterol and serum triglycerides levels, low density lipoprotein, and very low density lipoprotein were also significantly reduced and the high density lipoprotein level was significantly increased upon treatment with theTriticum aestivumethanol extract. A significant decrease in the levels of lipid peroxides, superoxide dismutase, and glutathione peroxidise and increase in the levels of vitamin E, catalase, and reduced glutathione were observed inTriticum aestivumtreated diabetic rats. Thus, from this study we conclude that ethanolic extract ofTriticum aestivumexhibited significant antihyperglycemic, hypolipidemic, and antioxidant activities in streptozotocin-induced diabetic rats.
Pattern Recognition in Numerical Data Sets and Color Images through the Typicality Based on the GKPFCM Clustering Algorithm
Authors: Ojeda-Magaña B. , Ruelas R. , Corona Nakamura M. A. , Carr Finch D. W. , Gómez-Barba L.
Published: December 2013

We take the concept of typicality from the field of cognitive psychology, and we apply the meaning to the interpretation of numerical data sets and color images through fuzzy clustering algorithms, particularly the GKPFCM, looking to get better information from the processed data. The Gustafson Kessel Possibilistic Fuzzy c-means (GKPFCM) is a hybrid algorithm that is based on a relative typicality (membership degree, Fuzzy c-means) and an absolute typicality (typicality value, Possibilistic c-means). Thus, using both typicalities makes it possible to learn and analyze data as well as to relate the results with the theory of prototypes. In order to demonstrate these results we use a synthetic data set and a digitized image of a glass, in a first example, and images from the Berkley database, in a second example. The results clearly demonstrate the advantages of the information obtained about numerical data sets, taking into account the different meaning of typicalities and the availability of both values with the clustering algorithm used. This approach allows the identification of small homogeneous regions, which are difficult to find.
Power Management Strategy for Active Power Sharing in Hydro/PV/Battery Hybrid Energy System
Authors: Meshram Sweeka , Agnihotri Ganga , Gupta Sushma
Published: December 2013

Simulation and modeling of standalone DC linked hydro/PV/battery hybrid energy system (HES) and power management strategy (PMS) for identifying the active power sharing have been done. The performance analysis of the proposed HES and its power management strategy has been done using the simulink toolboxes of MATLAB software. The proposed system consists of 10 kW PV system, 7.5 kW hydro system, battery, and power condition unit. In some remote/rural areas, it is very difficult to satisfy the demand of electrical power throughout the year with the power grid. In such areas, the power requirement can be fulfilled by renewable energy system such as hydro or PV system. Either the hydro system or PV system is not capable of supplying power requirement throughout the year as both systems are intermittent. Hence, the judicious combination of hydro and PV system has been modeled for electrification. The power management strategy is modeled to manage the power flow of the energy systems and battery to fulfill the load demand. The presented results clearly show that the proposed HES and its control strategy are suitable for implementation in remote/rural areas.
Clinical Scoring for Diagnosis of Acute Lower Abdominal Pain in Female of Reproductive Age
Authors: Jearwattanakanok Kijja , Yamada Sirikan , Suntornlimsiri Watcharin , Smuthtai Waratsuda , Patumanond Jayanton
Published: December 2013

Background. Obstetrics and gynecological conditions (OB-GYNc) are difficult to be differentiated from appendicitis in young adult females presenting with acute lower abdominal pain. Timely and correct diagnosis is clinically challenging.Method. A retrospective data analysis was performed on 542 female patients who were admitted to a tertiary care hospital with a chief complaint of acute lower abdominal pain. Diagnostic indicators of appendicitis and OB-GYNc were identified by stepwise multivariable polytomous logistic regression. Diagnostic performances of the scores were tested.Result. The developed clinical score is comprised of (1) guarding or rebound tenderness, (2) pregnancy, (3) sites of abdominal tenderness, (4) leukocytosis, (5) peripheral neutrophils ≥75%, and (6) presence of diarrhea. For diagnosis of appendicitis, the area under the ROC curve was 0.8696, and the sensitivity and specificity were 89.25% and 70.00%. For OB-GYNc, the corresponding values were 0.8450, 66.67%, and 94.85%, respectively.Conclusion. The clinical scoring system can differentiate the diagnosis of acute lower abdominal pain in young adult females. Time spent for diagnosis at the emergency room may be shortened, and the patients would be admitted to the appropriate departments in less time.
Dendrimeric Systems and Their Applications in Ocular Drug Delivery
Authors: Yavuz Burçin , Bozdağ Pehlivan Sibel , Ünlü Nurşen
Published: December 2013

Ophthalmic drug delivery is one of the most attractive and challenging research area for pharmaceutical scientists and ophthalmologists. Absorption of an ophthalmic drug in conventional dosage forms is seriously limited by physiological conditions. The use of nonionic or ionic biodegradable polymers in aqueous solutions and colloidal dosage forms such as liposomes, nanoparticles, nanocapsules, microspheres, microcapsules, microemulsions, and dendrimers has been studied to overcome the problems mentioned above. Dendrimers are a new class of polymeric materials. The unique nanostructured architecture of dendrimers has been studied to examine their role in delivery of therapeutics and imaging agents. Dendrimers can enhance drug’s water solubility, bioavailability, and biocompatibility and can be applied for different routes of drug administration successfully. Permeability enhancer properties of dendrimers were also reported. The use of dendrimers can also reduce toxicity versus activity and following an appropriate application route they allow the delivery of the drug to the targeted site and provide desired pharmacokinetic parameters. Therefore, dendrimeric drug delivery systems are of interest in ocular drug delivery. In this review, the limitations related to eye’s unique structure, the advantages of dendrimers, and the potential applications of dendrimeric systems to ophthalmology including imaging, drug, peptide, and gene delivery will be discussed.
Secure e-Health System on Passive RFID: Outpatient Clinic and Emergency Care
Authors: Yeh Kou-Hui , Lo Nai-Wei , Wu Tzong-Chen , Wang Chieh
Published: December 2013

In recent years, many researches have demonstrated several RFID-based solutions to enhance patient medication safety and avoid human errors. Although RFID-based procedure is more efficient than traditional process, patient's information may be attacked (or stolen) during the data transmission period. This will cause inappropriate medication use and medical errors. In this paper, we introduce a robust RFID-based e-Health system which strengthens the system security and protects the patient's privacy as well. In addition, our e-Health system can provide better efficiency of outpatient clinic procedure and emergency care procedure in hospital environment.
Granulomatous Hepatitis Secondary toHistoplasmaInfection after Treatment with Infliximab
Authors: Barrera L. , Álvarez J. , Tapias M. , Idrovo V. , López R.
Published: December 2013

Classical presentation ofHistoplasmainfection includes fever and respiratory symptoms. Opportunistic microorganisms must be suspected on immunocompromised patients who develop bizarre symptoms. We present a case of a female patient with rheumatoid arthritis who received treatment with Infliximab during one and a half year; she developed granulomatous hepatitis secondary toHistoplasmainfection. The patient was admitted with acute hepatitis and thrombocytopenic coagulopathy. A liver biopsy was performed revealing granulomatous hepatitis, microvesicular steatosis, isolated apoptotic cells, and parenchyma microabscesses. PAS and Gömöri stains revealed areas with mycotic microorganisms morphologically compatible withHistoplasmaspp. and confirmed by culture.
Circuit Implementation, Operation, and Simulation of Multivalued Nonvolatile Static Random Access Memory Using a Resistivity Change Device
Authors: Nakayama Kazuya , Kitagawa Akio
Published: December 2013

We proposed and computationally analyzed a multivalued, nonvolatile SRAM using a ReRAM. Two reference resistors and a programmable resistor are connected to the storage nodes of a standard SRAM cell. The proposed 9T3R MNV-SRAM cell can store 2 bits of memory. In the storing operation, the recall operation and the successive decision operation of whether or not write pulse is required can be performed simultaneously. Therefore, the duration of the decision operation and the circuit are not required when using the proposed scheme. In order to realize a stable recall operation, a certain current (or voltage) is applied to the cell before the power supply is turned on. To investigate the process variation tolerance and the accuracy of programmed resistance, we simulated the effect of variations in the width of the transistor of the proposed MNV-SRAM cell, the resistance of the programmable resistor, and the power supply voltage with 180 nm 3.3 V CMOS HSPICE device models.
The Thermal Conductivity of Carbon Nanotubes with Defects and Intramolecular Junctions
Authors: Zhou Qiaoli , Meng Fanyan , Liu Zhuhong , Shi Sanqiang
Published: December 2013

The thermal conductivity of various carbon nanotubes with defects or intramolecular junctions was studied using nonequilibrium molecular dynamics approach. The results show that the thermal conductivity of both armchair and zigzag carbon nanotubes increased with the decrease of the radius of the tube. The thermal conductivity of armchair tube is higher than that of zigzag tube when the radii of the two tubes are kept almost same. Discontinuities appear on the temperature profile along the tube axial at the region of IMJ, resulting in the large temperature gradient and thus lower thermal conductivity of (n, n)/(m, 0) tube with one IMJ and (m, 0)/(n, n)/(m, 0) tube with two IMJs. For the (m, 0)/(n, n)/(m, 0) tube with two IMJs, phonon mean free path of the middle (n, n) tube is much smaller than that of the isolate (n, n) tube.
Effects of Mass Transfer, Radiation, Joule Heating, and Viscous
Dissipation on Steady MHD Marangoni Convection Flow over a Flat Surface with Suction and Injection
Authors: Ibrahim S. Mohammed
Published: December 2013

The combined effects of radiation and mass transfer on a steady MHD two-dimensional Marangoni convection flow over a flat surface in presence of Joule heating and viscous dissipation under influence of suction and injection is studied numerically. The general governing partial differential equations are transformed into a set of nonlinear ordinary differential equations by using unique similarity transformation. Numerical solutions of the similarity equations are obtained using the Runge-Kutta method along with shooting technique. The effects of governing parameters on velocity, temperature, and concentration as well as interface velocity, the surface temperature gradient, and the surface concentration gradient were presented in graphical and tabular forms. Comparisons with previously published work are performed and the results are found to be in excellent agreement.
Distal Humerus as Delayed Site of Metastasis from Small Cell Carcinoma of Gallbladder
Authors: Tunio Mutahir A. , AlAsiri Mushabbab , Ali Asma Mohammed F. , AlSaeed Eyad Fawzi , Shuja Muhammad , Fatani Hanadi
Published: December 2013

Background. Small cell carcinoma (SCC) of the gallbladder is a rare entity and is often seen in elderly women. SCC of gallbladder is typically a nonsecretory carcinoid tumor without overt clinical symptoms and is often discovered at advanced stages. SCC of gallbladder carries a dismal prognosis as compared to SCC of lung and adenocarcinoma of gallbladder. To date, only 73 case reports have been published in the world literature.Case Presentation. Herein, we report a case of a 73-year-old Saudi woman who presented with one week history of right upper quadrant abdominal pain and obstructive jaundice and was found to be a case of locally advanced, metastatic SCC of gallbladder cT4N1M1 (liver, para-aortic lymph nodes, and bone). The patient was treated with neoadjuvant etoposide and cisplatin (EP) chemotherapy three cycles after biliary stenting followed by radical cholecystectomy, lymphadenectomy, and adjuvant EP chemotherapy and then one year later developed distal humerus osseous metastasis.Conclusion. SCC of the gallbladder is very rare entity and is often seen at advanced stages. Osseous metastases of peripheral skeleton from SCC gallbladder are rarely reported. Surgery is curative option but only for early stage tumors. Incorporation of chemotherapy along with radical resection increases the survival.
Robust Monitoring of Contaminated Multivariate Data
Authors: Howington Eric B.
Published: December 2013

Monitoring a process that suffers from data contamination using a traditional multivariate T2 chart can lead to an excessive number of false alarms. A diagnostic statistic can be used to distinguish between real control chart signals due to assignable causes and signals due to contamination from a single outlier. In phase II analysis, a traditional T2 control chart augmented by a diagnostic statistic improves the work stoppage rates for multivariate processes suffering from contaminated data and maintains the ability to detect process shifts.
A Mechanism of Hypoxia-Mediated Escape from Adaptive Immunity in Cancer Cells
Authors: Barsoum Ivraym B. , Smallwood Chelsea A. , Siemens D. Robert , Graham Charles H.
Published: December 2013

Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1α (HIF-1α). In vivo studies also demonstrated cellular colocalization of HIF-1α and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1α accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics. Cancer Res; 74(3); 665–74. ©2013 AACR.
miRNA-491-5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis
Authors: Huang Wei-Chieh , Chan Shih-Hsuan , Jang Te-Hsuan , Chang Jer-Wei , Ko Ying-Chin , Yen Tzu-Chen , Chiang Shang-Lun , Chiang Wei-Fan , Shieh Tien-Yu , Liao Chun-Ta , Juang Jyh-Lyh , Wang Hsueh-Chun , Cheng Ann-Joy , Lu Ya-Ching , Wang Lu-Hai
Published: December 2013

MicroRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells, established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression analysis to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of patients with OSCCs. miR-491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G-protein—coupled receptor kinase-interacting protein 1 (GIT1)—as a direct target gene for miR-491-5p control. GIT1 overexpression was sufficient to rescue miR-491-5p–mediated inhibition of migration/invasion and lung metastasis. Conversely, GIT1 silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GIT1 attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated extracellular signal–regulated kinase (ERK1/2) activation, and MMP2/9 levels and activities. In clinical specimens of OSCCs, GIT1 levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GIT1 correlated inversely in OSCCs, where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GIT1 as biomarkers for prognosis in this cancer. Cancer Res; 74(3); 751–64. ©2013 AACR.
Gambogic Acid Induces Apoptosis in Imatinib-Resistant Chronic Myeloid Leukemia Cells via Inducing Proteasome Inhibition and Caspase-Dependent Bcr-Abl Downregulation
Authors: Shi Xianping , Chen Xin , Li Xiaofen , Lan Xiaoying , Zhao Chong , Liu Shouting , Huang Hongbiao , Liu Ningning , Liao Siyan , Song Wenbin , Zhou Ping , Wang Shunqing , Xu Li , Wang Xuejun , Dou Q. Ping , Liu Jinbao
Published: December 2013

Purpose: Chronic myelogenous leukemia (CML) is characterized by the constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl-T315I is the predominant mutation that causes resistance to imatinib, cytotoxic drugs, and the second-generation tyrosine kinase inhibitors. The emergence of imatinib resistance in patients with CML leads to searching for novel approaches to the treatment of CML. Gambogic acid, a small molecule derived from Chinese herb gamboges, has been approved for phase II clinical trial for cancer therapy by the Chinese Food and Drug Administration (FDA). In this study, we investigated the effect of gambogic acid on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl.

Experimental Design: CML cell lines (KBM5, KBM5-T315I, and K562), primary cells from patients with CML with clinical resistance to imatinib, and normal monocytes from healthy volunteers were treated with gambogic acid, imatinib, or their combination, followed by measuring the effects on cell growth, apoptosis, and signal pathways. The in vivo antitumor activity of gambogic acid and its combination with imatinib was also assessed with nude xenografts.

Results: Gambogic acid induced apoptosis and cell proliferation inhibition in CML cells and inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Our data suggest that GA-induced proteasome inhibition is required for caspase activation in both imatinib-resistant and -sensitive CML cells, and caspase activation is required for gambogic acid–induced Bcr-Abl downregulation and apoptotic cell death.

Conclusions: These findings suggest an alternative strategy to overcome imatinib resistance by enhancing Bcr-Abl downregulation with the medicinal compound gambogic acid, which may have great clinical significance in imatinib-resistant cancer therapy. Clin Cancer Res; 20(1); 151–63. ©2013 AACR.
T Lymphocytes Redirected against the Chondroitin Sulfate Proteoglycan-4 Control the Growth of Multiple Solid Tumors both In Vitro and In Vivo
Authors: Geldres Claudia , Savoldo Barbara , Hoyos Valentina , Caruana Ignazio , Zhang Ming , Yvon Eric , Del Vecchio Michele , Creighton Chad J. , Ittmann Michael , Ferrone Soldano , Dotti Gianpietro
Published: December 2013

Purpose: Because of its high expression on various types of tumors and its restricted distribution in normal tissues, chondroitin sulfate proteoglycan-4 (CSPG4) represents an attractive target for the antibody-based therapy of several solid tumors. We tested whether T cells transduced with a CSPG4-specific chimeric antigen receptor (CAR) inhibited the growth of CSPG4-expressing tumor cells both in vitro and in vivo.

Experimental Design: We first independently validated by immunohistochemistry (IHC) the expression of CSPG4 in an extensive panel of tumor arrays and normal tissues as well as queried public gene expression profiling datasets of human tumors. We constructed a second-generation CSPG4-specific CAR also encoding the CD28 costimulatory endodomain (CAR.CSPG4). We then evaluated human T lymphocytes expressing this CAR for their ex vivo and in vivo antitumor activity against a broad panel of solid tumors.

Results: IHC showed that CSPG4 is highly expressed in melanoma, breast cancer, head and neck squamous cell carcinoma (HNSCC), and mesothelioma. In addition, in silico analysis of microarray expression data identified other important potential tumors expressing this target, including glioblastoma, clear cell renal carcinoma, and sarcomas. T lymphocytes genetically modified with a CSPG4-CAR controlled tumor growth in vitro and in vivo in NSG mice engrafted with human melanoma, HNSCC, and breast carcinoma cell lines.

Conclusions: CAR.CSPG4-redirected T cells should provide an effective treatment modality for a variety of solid tumors. Clin Cancer Res; 20(4); 962–71. ©2013 AACR.
Comparative microRNA Profiling of Prostate Carcinomas with Increasing Tumor Stage by Deep Sequencing
Authors: Hart Martin , Nolte Elke , Wach Sven , Szczyrba Jaroslaw , Taubert Helge , Rau Tilman T. , Hartmann Arndt , Grässer Friedrich A. , Wullich Bernd
Published: December 2013

MicroRNAs (miRNA) posttranscriptionally regulate gene expression and are important in tumorigenesis. Previous deep sequencing identified the miRNA profile of prostate carcinoma versus nonmalignant prostate tissue. Here, we generated miRNA expression profiles of prostate carcinoma by deep sequencing, with increasing tumor stage relative to corresponding nonmalignant and healthy prostate tissue, and detected clearly changed miRNA expression patterns. The miRNA profiles of the healthy and nonmalignant tissues were consistent with our previous findings, indicating a high fidelity of the method employed. In the tumors, quantitative real-time PCR (qRT-PCR) analysis of 40 paired samples of prostate carcinoma versus normal tissue revealed significant upregulation of miR-20a, miR-148a, miR-200b, and miR-375 and downregulation of miR-143 and miR-145. Hereby, miR-375 increased from normal to organ-confined tumors (pT2 pN0), slightly decreased in tumors with extracapsular growth (pT3 pN0), but was then expressed again at higher levels in lymph node metastasizing (pN1) tumors. The sequencing data for miR-375 were confirmed by Northern blotting and qRT-PCR. The regulation for other selected miRNAs could, however, not be confirmed by qRT-PCR in individual tumor stages. MiR-200b, in addition to miR-200c and miR-375 reduced the expression of SEC23A. Interestingly, miR-375, found by sequencing in pT2 upregulated by us and others in tumor versus normal tissue, and miR-15a, found by sequencing in pT2 and pT3 and in the metastasizing tumors, target the phosphatases PHLPP1 and PHLPP2, respectively. PHLPP1 and PHLPP2 dephosphorylate members of the AKT family of signal transducers, thereby inhibiting cell growth. Coexpression of miR-15a and miR-375 resulted in downregulation of PHLPP1/2 and strongly increased prostate carcinoma cell growth.

Implications: These genomic data reveal relevant miRNAs in prostate cancer that may have biomarker and therapeutic potential. Mol Cancer Res; 12(2); 250–63. ©2013 AACR.
RETRACTED: miRNA-302b Suppresses Human Hepatocellular Carcinoma by Targeting AKT2
Authors: Wang Lumin , Yao Jiayi , Zhang Xiaogang , Guo Bo , Le Xiaofeng , Cubberly Mark , Li Zongfang , Nan Kejun , Song Tusheng , Huang Chen
Published: December 2013

miRNAs (miR) play a critical role in human cancers, including hepatocellular carcinoma. Although miR-302b has been suggested to function as a tumor repressor in other cancers, its role in hepatocellular carcinoma is unknown. This study investigated the expression and functional role of miR-302b in human hepatocellular carcinoma. The expression level of miR-302b is dramatically decreased in clinical hepatocellular carcinoma specimens, as compared with their respective nonneoplastic counterparts, and in hepatocellular carcinoma cell lines. Overexpression of miR-302b suppressed hepatocellular carcinoma cell proliferation and G1–S transition in vitro, whereas inhibition of miR-302b promoted hepatocellular carcinoma cell proliferation and G1–S transition. Using a luciferase reporter assay, AKT2 was determined to be a direct target of miR-302b. Subsequent investigation revealed that miR-302b expression was inversely correlated with AKT2 expression in hepatocellular carcinoma tissue samples. Importantly, silencing AKT2 recapitulated the cellular and molecular effects seen upon miR-302b overexpression, which included inhibiting hepatocellular carcinoma cell proliferation, suppressing G1 regulators (Cyclin A, Cyclin D1, CDK2) and increasing p27Kip1 phosphorylation at Ser10. Restoration of AKT2 counteracted the effects of miR-302b expression. Moreover, miR-302b was able to repress tumor growth of hepatocellular carcinoma cells in vivo.

Implications: Taken together, miR-302b inhibits HCC cell proliferation and growth in vitro and in vivo by targeting AKT2. Mol Cancer Res; 12(2); 190–202. ©2013 AACR.
Actin-Binding Protein, Espin: A Novel Metastatic Regulator for Melanoma
Authors: Yanagishita Takeshi , Yajima Ichiro , Kumasaka Mayuko , Kawamoto Yoshiyuki , Tsuzuki Toyonori , Matsumoto Yoshinari , Watanabe Daisuke , Kato Masashi
Published: December 2013

Espin is a multifunctional actin-bundling protein with multiple isoforms, and has special connections to hair cell stereocilia and microvillar specializations of sensory cells in the inner ear. However, there have been no reports showing the expression and function of Espin in cancers, including melanoma. Here, it is demonstrated that Espin expression is significantly increased in melanomas that spontaneously developed in RET-transgenic mice (RET-mice). Importantly, the invasion capacity of Espin-depleted Mel-ret melanoma cells derived from a tumor of the RET-mouse was dramatically less than that of control melanoma cells with reductions of lamellipodia, focal adhesion kinase (FAK), and GTP-Rac1 activities. Correspondingly, the ratio of metastatic foci in Espin-depleted Mel-ret melanoma cells was significantly less than that of control melanoma cells in an in vivo melanoma metastasis model. Moreover, Espin could be a novel biomarker of melanoma in humans, because our immunohistochemical analysis data reveal that percentages of Espin-positive cells in human primary and metastatic melanomas were significantly higher than that of cells in melanocytic nevi. Together, these results indicate that Espin is not only a metastatic regulator for melanoma but also a potential biomarker of disease progression.

Implications: Actin-binding protein Espin is expressed in melanoma, affects metastasis, and is a potential target for melanoma therapy. Mol Cancer Res; 12(3); 440–6. ©2013 AACR.
Gemcitabine plus Cisplatin versus Capecitabine plus Cisplatin as First-Line Chemotherapy for Advanced Biliary Tract Cancer: A Retrospective Cohort Study
Authors: Woo Sang Myung , Lee Woo Jin , Kim Ji Hun , Kim Dong Hwan , Han Sung-Sik , Park Sang-Jae , Kim Tae Hyun , Lee Ju Hee , Koh Young Hwan , Hong Eun Kyung
Published: December 2013

Background and Aim: Gemcitabine plus cisplatin (GP) is a standard chemotherapy option for patients with advanced biliary tract cancer (BTC). We compared the efficacy and safety of capecitabine plus cisplatin (XP) versus GP in advanced BTC. Methods: The records of all patients treated with GP or XP chemotherapy for unresectable, metastatic, or recurrent BTC at the National Cancer Center between December 2001 and August 2012 were reviewed retrospectively. Patients with histologically confirmed intrahepatic cholangiocarcinoma, gallbladder cancer, or extrahepatic cholangiocarcinoma were enrolled. Results: Of the 344 patients enrolled, 127 received GP and 217 received XP. At a median follow-up time of 8.9 months, the median time to progression was longer in the GP group than in the XP group (5.6 vs. 4.7 months), but the difference was not statistically significant (p = 0.081). The median overall survival (OS) was 8.4 months (95% CI 6.2-10.7) in the GP group and 7.6 months (95% CI 6.8-8.7) in the XP group (p = 0.024), with statistical significance retained following multivariate analysis (HR 0.72; 95% CI 0.527-0.987; p = 0.004). Grade 3/4 toxicities were significantly more frequent in the GP group than in the XP group (40.9 vs. 24.9%, p = 0.002). Conclusions: GP was superior to XP in prolonging OS, despite increasing the rate of grade 3/4 adverse events.
A New Temporal Bone and Cadaver Head Holder for Temporal Bone Surgical Technique Training
Authors: Feng Guodong , Lv Wei , Tian Xu , Wu Haiyan , Gao Zhiqiang
Published: December 2013

Objective: To design a new temporal bone and cadaver head holder, overcoming the drawbacks of the bowl-type holder and other existing holders for dissection, and thereby benefiting training and research on temporal bone surgery. Materials and Methods: We designed and fabricated a novel holder with a horizontal arm that can be connected with an object holder specific for the temporal bone or a three-pin fixture specific for cadaver heads. A separate hand support helps to stabilize the hand during examinations on the temporal bone and skull base. Results: The use of the temporal bone and cadaver head holder by 30 trainees during our temporal bone surgical technique courses held by the Department of Otolaryngology, Peking Union Medical College Hospital (PUMCH) worked better than other holders and saved laboratory time. It has become the standard equipment of the Temporal Bone Laboratory of PUMCH. Conclusions: The temporal bone and cadaver head holder we describe is compact, stable and easily adjustable. It offers considerable advantages to trainees.
Emotions and Memory in Borderline Personality Disorder
Authors: Winter Dorina , Elzinga Bernet , Schmahl Christian
Published: December 2013

Memory processes such as encoding, storage, and retrieval of information are influenced by emotional content. Because patients with borderline personality disorder (BPD) are particularly susceptible to emotional information, it is relevant to understand whether such memory processes are altered in this patient group. This systematic literature review collects current evidence on this issue. Research suggests that emotional information interferes more strongly with information processing and learning in BPD patients than in healthy controls. In general, BPD patients do not seem to differ from healthy control subjects in their ability to memorize emotional information, but they tend to have specific difficulties forgetting negative information. Also, BPD patients seem to recall autobiographical, particularly negative events with stronger arousal than healthy controls, while BPD patients also show specific temporo-prefrontal alterations in neural correlates. No substantial evidence was found that the current affective state influences learning and memory in BPD patients any differently than in healthy control subjects. In general, a depressive mood seems to both deteriorate and negatively bias information processing and memories, while there is evidence that dissociative symptoms impair learning and memory independently of stimulus valence. This review discusses methodological challenges of studies on memory and emotions in BPD and makes suggestions for future research and clinical implications.
A Regulator of Secretory Vesicle Size, Kelch-Like Protein 12, Facilitates the Secretion of Apolipoprotein B100 and Very-Low-Density Lipoproteins—Brief Report
Authors: Butkinaree Chutikarn , Guo Liang , Ramkhelawon Bhama , Wanschel Amarylis , Brodsky Jeffrey L. , Moore Kathryn J. , Fisher Edward A.
Published: December 2013

Objective—

One of the major risk factors for atherosclerosis is the plasma level of low-density lipoprotein (LDL), which is a product of very-low-density lipoprotein (VLDL). Hepatic apolipoprotein B100 (apoB100) is the essential component that provides structural stability to VLDL particles. Newly translated apoB100 is partially lipidated in the endoplasmic reticulum (ER), forming nascent apoB100-VLDL particles. These particles are further modified to form fully mature VLDLs in the Golgi apparatus. Therefore, the transport of nascent VLDL from the ER to the Golgi represents a critical step during VLDL maturation and secretion and in regulating serum LDL cholesterol levels. Our previous studies showed that apoB100 exits the ER in coat complex II vesicles (COPII), but the cohort of related factors that control trafficking is poorly defined.

Approach and Results—

Expression levels of Kelch-like protein 12 (KLHL12), an adaptor protein known to assist COPII–dependent transport of procollagen, were manipulated by using a KLHL12-specific small interfering RNA and a KLHL12 expression plasmid in the rat hepatoma cell line, McArdle RH7777. KLHL12 knockdown decreased the secreted and intracellular pools of apoB100, an effect that was attenuated in the presence of an autophagy inhibitor. KLHL12 knockdown also significantly reduced secretion of the most lipidated apoB100-VLDL species and led to the accumulation of apoB100 in the ER. Consistent with these data, KLHL12 overexpression increased apoB100 recovery and apoB100-VLDL secretion. Images obtained from confocal microscopy revealed colocalization of apoB100 and KLHL12, further supporting a direct link between KLHL12 function and VLDL trafficking from the ER.

Conclusions—

KLHL12 plays a critical role in facilitating the ER exit and secretion of apoB100-VLDL particles, suggesting that KLHL12 modulation would influence plasma lipid levels.
Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension
Authors: George Peter M. , Oliver Eduardo , Dorfmuller Peter , Dubois Olivier D. , Reed Daniel M. , Kirkby Nicholas S. , Mohamed Nura A. , Perros Frederic , Antigny Fabrice , Fadel Elie , Schreiber Benjamin E. , Holmes Alan M. , Southwood Mark , Hagan Guy , Wort Stephen J. , Bartlett Nathan , Morrell Nicholas W. , Coghlan John G. , Humbert Marc , Zhao Lan , Mitchell Jane A.
Published: December 2013

Rationale
:

Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted.

Objective
:

To explore the role of type I IFN in PAH.

Methods and Results
:

Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1
−/−
) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon γ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1
−/−
mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels.

Conclusions
:

These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.
β-Arrestin1–Biased β
1
-Adrenergic Receptor Signaling Regulates MicroRNA Processing
Authors: Kim Il-man , Wang Yongchao , Park Kyoung-mi , Tang Yaoping , Teoh Jian-peng , Vinson Joseph , Traynham Christopher J. , Pironti Gianluigi , Mao Lan , Su Huabo , Johnson John A. , Koch Walter J. , Rockman Howard A.
Published: December 2013

Rationale:

MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin intermediate miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes after activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-arrestins are now appreciated to transduce multiple effector pathways independent of G-protein–mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the β-arrestin–biased βAR agonist, carvedilol, activates cellular pathways in the heart.

Objective:

Here, we tested whether carvedilol could activate β-arrestin–mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects.

Methods and Results:

In human cells and mouse hearts, carvedilol upregulates a subset of mature and pre-miRs, but not their pri-miRs, in β
1
AR-, G-protein–coupled receptor kinase 5/6–, and β-arrestin1–dependent manner. Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs.

Conclusions:

Our findings indicate a novel function for β
1
AR-mediated β-arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.
Visible Age-Related Signs and Risk of Ischemic Heart Disease in the General Population
Authors: Christoffersen Mette , Frikke-Schmidt Ruth , Schnohr Peter , Jensen Gorm B. , Nordestgaard Børge G. , Tybjærg-Hansen Anne
Published: December 2013

Background—

Cardiovascular disease is 1 of the most common age-related diseases, and also 1 of the most common causes of death in the general population. We tested the hypothesis that visible age-related signs associate with risk of ischemic heart disease (IHD), myocardial infarction (MI), and death in the general population, independent of chronological age.

Methods and Results—

10,885 individuals aged 20 to 93 years free of IHD were followed from 1976 through 1978 until June 2011 with 100% complete follow-up. During these 35 years of follow-up, 3401 participants developed IHD and 1708 developed MI. Presence of frontoparietal baldness, crown top baldness, earlobe crease, and xanthelasmata was associated with increased risk of IHD or MI after multifactorial adjustment for chronological age and well-known cardiovascular risk factors. The risk of IHD and MI increased stepwise with increasing number of age-related signs with multifactorially adjusted hazard ratios up to 1.40 (95% confidence interval, 1.20–1.62) for IHD and 1.57 (1.28–1.93) for MI, in individuals with 3 to 4 versus no age-related signs at baseline (
P
for trend <0.001). In all age groups in both women and men, absolute 10-year risk of IHD and MI increased with increasing number of visible age-related signs.

Conclusions—

Male pattern baldness, earlobe crease, and xanthelasmata—alone or in combination—associate with increased risk of ischemic heart disease and myocardial infarction independent of chronological age and other well-known cardiovascular risk factors. This is the first prospective study to show that looking old for your age is a marker of poor cardiovascular health.
Renal Hemodynamic Effect of Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus
Authors: Cherney David Z.I. , Perkins Bruce A. , Soleymanlou Nima , Maione Maria , Lai Vesta , Lee Alana , Fagan Nora M. , Woerle Hans J. , Johansen Odd Erik , Broedl Uli C. , von Eynatten Maximilian
Published: December 2013

Background—

The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks’ sodium glucose cotransporter 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D).

Methods and Results—

Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR ≥ 135 mL/min/1.73m
2
, n=27) or normal GFR (T1D-N, GFR 90–134 mL/min/1.73m
2
, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4–6 mmol/L) and hyperglycemic (9–11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 mL/min/1.73m
2
with empagliflozin in T1D-H, (GFR 172±23–139±25 mL/min/1.73 m
2
,
P
<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all
P
<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (
P
≤0.04).

Conclusions—

In conclusion, short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01392560.
First record of the genus Limonium (Plumbaginaceae) from the Malesian region
Authors: Nakamura Koh , Rubite Rosalio Rivera , Kokubugata Goro , Yoshiko Kono , Yokota Masatsugu , Peng Ching-I
Published: December 2013

The absence of the cosmopolitan genus Limonium Miller (1754: no pagination) (Plumbaginaceae) in the mega-diverse flora of the Malesian region (comprising Brunei Darussalam, Indonesia, Malaysia, Papua New Guinea, the Philippines, and Singapore; Merrill 1923, Ridley 1923, Steenis 1949, Backer & Bakhuizen van den Brink Jr. 1965, Balgooy 1993, Coode et al. 1996, Balgooy 2001, Conn et al. 2004, Chong et al. 2009, Pelser et al. 2011) has intrigued taxonomists and biogeographers since Steenis (1949) noted this. During a field survey as part of the project on floristic and phylogenetic biogeography in the island chain of the Philippines, Taiwan, and southern Japan, we found a population of Limonium in the northern Philippines (Batan Islands) that represents the first record of the genus in the Malesian region. Batan Islands, comprising 10 small (≤ 83.1 km2) oceanic islands, is the northernmost tip of the Malesian region, being ca. 190 km north of Luzon Island of the Philippines and ca. 140 km southeast of Taiwan Island. From the geological location, the present finding suggests that a more extensive survey in Batan Islands may add some more East Asian temperate genera to the flora of the Malesian region, although two enumerations of the early and mid 20th century provide us baseline knowledge of the flora of Batan Islands (Merrill 1908, Hatusima 1966).