bluuebunny/crossref_metadata_2025 huggingface dataset:
A Solution to Reconstruct Cross-Cut Shredded Text Documents Based on Character Recognition and Genetic Algorithm
Authors: Xu Hedong , Zheng Jing , Zhuang Ziwei , Fan Suohai
Published: July 2014

The reconstruction of destroyed paper documents is of more interest during the last years. This topic is relevant to the fields of forensics, investigative sciences, and archeology. Previous research and analysis on the reconstruction of cross-cut shredded text document (RCCSTD) are mainly based on the likelihood and the traditional heuristic algorithm. In this paper, a feature-matching algorithm based on the character recognition via establishing the database of the letters is presented, reconstructing the shredded document by row clustering, intrarow splicing, and interrow splicing. Row clustering is executed through the clustering algorithm according to the clustering vectors of the fragments. Intrarow splicing regarded as the travelling salesman problem is solved by the improved genetic algorithm. Finally, the document is reconstructed by the interrow splicing according to the line spacing and the proximity of the fragments. Computational experiments suggest that the presented algorithm is of high precision and efficiency, and that the algorithm may be useful for the different size of cross-cut shredded text document.
Identifying Hierarchical and Overlapping Protein Complexes Based on Essential Protein-Protein Interactions and “Seed-Expanding” Method
Authors: Ren Jun , Zhou Wei , Wang Jianxin
Published: July 2014

Many evidences have demonstrated that protein complexes are overlapping and hierarchically organized in PPI networks. Meanwhile, the large size of PPI network wants complex detection methods have low time complexity. Up to now, few methods can identify overlapping and hierarchical protein complexes in a PPI network quickly. In this paper, a novel method, called MCSE, is proposed based onλ-module and “seed-expanding.” First, it chooses seeds as essential PPIs or edges with high edge clustering values. Then, it identifies protein complexes by expanding each seed to aλ-module. MCSE is suitable for large PPI networks because of its low time complexity. MCSE can identify overlapping protein complexes naturally because a protein can be visited by different seeds. MCSE uses the parameterλ_th to control the range of seed expanding and can detect a hierarchical organization of protein complexes by tuning the value ofλ_th. Experimental results ofS. cerevisiaeshow that this hierarchical organization is similar to that of known complexes in MIPS database. The experimental results also show that MCSE outperforms other previous competing algorithms, such as CPM, CMC, Core-Attachment, Dpclus, HC-PIN, MCL, and NFC, in terms of the functional enrichment and matching with known protein complexes.
Protective Effect of Polysaccharides from Inonotus obliquus on Streptozotocin‐Induced Diabetic Symptoms and Their Potential Mechanisms in Rats
Authors: Diao Bao-zhong , Jin Wei-rong , Yu Xue-jing
Published: July 2014

The present study aimed to evaluate the therapeutic effects of polysaccharides from Inonotus obliquus (PIO) on streptozotocin‐ (STZ‐) induced diabetic symptoms and their potential mechanisms. The effect of PIO on body weight, blood glucose, damaged pancreatic β‐cells, oxidative stresses, proinflammatory cytokines, and glucose metabolizing enzymes in liver was studied. The results show that administration of PIO can restore abnormal oxidative indices near normal levels. The STZ‐damaged pancreatic β‐cells of the rats were partly recovered gradually after the mice were administered with PIO 6 weeks later. Therefore, we may assume that PIO is effective in the protection of STZ‐induced diabetic rats and PIO may be of use as antihyperglycemic agent.
Emigration, Immigration, and Skill Formation: The Case of a Midstream Country
Authors: Kondoh Kenji
Published: July 2014

This study theoretically investigates the economy of a small country that exports skilled labor to higher developed countries and simultaneously imports unskilled labor from lower developed countries. Compared with the free immigration case, if this country adopts an optimally controlled immigration policy by imposing income tax on immigrants to maximize national income, skills formation is negatively affected and the number of domestic unskilled workers increases. Moreover, under certain conditions, we can assert the counter-intuitive possibility that the wage rate of domestic unskilled workers may decrease but that of skilled workers may increase owing to the restriction of foreign unskilled workers.
Local Sympathetic Denervation of Femoral Artery in a Rabbit Model by Using 6-HydroxydopamineIn Situ
Authors: Jin Yufei , Fan Junjun , Li Fuhang , Bi Long , Pei Guoxian
Published: July 2014

Both artery bundle and sympathetic nerve were involved with the metabolism of bone tissues. Whether the enhancing effects of artery bundle result from its accompanying sympathetic nerve or blood supply is still unknown. There is no ideal sympathetic nerve-inhibited method for thein situdenervation of artery bundle. Therefore, we dipped the femoral artery in the 6-hydroxydopamine (6-OHDA) locally and observed its effect. Compared with control group, thein situtreatment of 6-OHDA did not damage the normal structure of vascular bundle indicated by hematoxylin-eosin (HE) staining. However, the functions of sympathetic nerve was completely inhibited for more than 2 weeks, and only a few function of sympathetic nerve resumed 4 weeks later, evidenced by glyoxylic acid staining and the expression of tyrosine hydroxylase (TH) and nerve peptide Y (NPY). Thus, 6-OHDA is promising as an ideal reagent for the local denervation of sympathetic nerve from artery system.
Multiobjective Optimization of ELID Grinding Process Using Grey Relational Analysis Coupled with Principal Component Analysis
Authors: Prabhu S. , Vinayagam B. K.
Published: July 2014

Carbon nanotube (CNT) mixed grinding wheel has been used in the electrolytic in-process dressing (ELID) grinding process to analyze the surface characteristics of AISI D2 Tool steel material. CNT grinding wheel is having an excellent thermal conductivity and good mechanical property which is used to improve the surface finish of the work piece. The multiobjective optimization of grey relational analysis coupled with principal component analysis has been used to optimize the process parameters of ELID grinding process. Based on the Taguchi design of experiments, an L9 orthogonal array table was chosen for the experiments. The confirmation experiment verifies the proposed that grey-based Taguchi method has the ability to find out the optimal process parameters with multiple quality characteristics of surface roughness and metal removal rate. Analysis of variance (ANOVA) has been used to verify and validate the model. Empirical model for the prediction of output parameters has been developed using regression analysis and the results were compared for with and without using CNT grinding wheel in ELID grinding process.
Improved Results on Robust Stability for Systems with Interval Time‐Varying Delays and Nonlinear Perturbations
Authors: Zhou Xin , Zhang Hexin , Hu Xiaoxiang , Hui Junjun , Li Tianmei
Published: July 2014

This paper investigated delay‐dependent robust stability criteria for systems with interval time‐varying delays and nonlinear perturbations. A delay‐partitioning approach is used in this paper, the delay‐interval is partitioned into multiple equidistant subintervals, a new Lyapunov‐Krasovskii (L‐K) functional contains some triple‐integral terms, and augment terms are introduced on these intervals. Then, by using integral inequalities method together with free‐weighting matrix approach, a new less conservative delay‐dependent stability criterion is formulated in terms of linear matrix inequalities (LMIs), which can be easily solved by optimization algorithms. Numerical examples are given to show the effectiveness and the benefits of the proposed method.
Programming of Fetal Insulin Resistance in Pregnancies with Maternal Obesity by ER Stress and Inflammation
Authors: Westermeier Francisco , Sáez Pablo J. , Villalobos-Labra Roberto , Sobrevia Luis , Farías-Jofré Marcelo
Published: July 2014

The global epidemics of obesity during pregnancy and excessive gestational weight gain (GWG) are major public health problems worldwide. Obesity and excessive GWG are related to several maternal and fetal complications, including diabetes (pregestational and gestational diabetes) and intrauterine programming of insulin resistance (IR). Maternal obesity (MO) and neonatal IR are associated with long-term development of obesity, diabetes mellitus, and increased global cardiovascular risk in the offspring. Multiple mechanisms of insulin signaling pathway impairment have been described in obese individuals, involving complex interactions of chronically elevated inflammatory mediators, adipokines, and the critical role of the endoplasmic reticulum (ER) stress-dependent unfolded protein response (UPR). However, the underlying cellular processes linking MO and IR in the offspring have not been fully elucidated. Here, we summarize the state-of-the-art evidence supporting the possibility that adverse metabolic postnatal outcomes such as IR in the offspring of pregnancies with MO and/or excessive GWG may be related to intrauterine activation of ER stress response.
Enhanced Efficacy of Bleomycin in Bladder Cancer Cells by Photochemical Internalization
Authors: Baglo Yan , Hagen Lars , Høgset Anders , Drabløs Finn , Otterlei Marit , Gederaas Odrun A.
Published: July 2014

Bleomycin is a cytotoxic chemotherapeutic agent widely used in cancer treatment. However, its efficacy in different cancers is low, possibly due to limited cellular internalization. In this study, a novel approach known as photochemical internalization (PCI) was explored to enhance bleomycin delivery in bladder cancer cells (human T24 and rat AY-27), as bladder cancer is a potential indication for use of PCI with bleomycin. The PCI technique was mediated by the amphiphilic photosensitizer disulfonated tetraphenyl chlorin (TPCS2a) and blue light (435 nm). Two additional strategies were explored to further enhance the cytotoxicity of bleomycin; a novel peptide drug ATX-101 which is known to impair DNA damage responses, and the protease inhibitor E-64 which may reduce bleomycin degradation by inhibition of bleomycin hydrolase. Our results demonstrate that the PCI technique enhances the bleomycin effect under appropriate conditions, and importantly we show that PCI-bleomycin treatment leads to increased levels of DNA damage supporting that the observed effect is due to increased bleomycin uptake. Impairing the DNA damage responses by ATX-101 further enhances the efficacy of the PCI-bleomycin treatment, while inhibiting the bleomycin hydrolase does not.
Positive Periodic Solutions of a Periodic Discrete Competitive System Subject to Feedback Controls
Authors: Tan Ronghua , Li Zuxiong , Wang Qinglong , Liu Zhijun
Published: July 2014

Species living in a fluctuating medium and human exploitation activities might result in the duration of continuous changes. Such changes can be well-approximated as feedback controls. In this contribution a periodic discrete competitive system subject to feedback controls is proposed. By using the methods of discrete inequality, fixed point theorem, and analysis techniques, a good understanding of the existence and global asymptotic stability of positive periodic solutions is obtained. Some numerical investigations are provided to verify our analytical results.
ATP Release through Lysosomal Exocytosis from Peripheral Nerves: The Effect of Lysosomal Exocytosis on Peripheral Nerve Degeneration and Regeneration after Nerve Injury
Authors: Jung Junyang , Jo Hyun Woo , Kwon Hyunseob , Jeong Na Young
Published: July 2014

Studies have shown that lysosomal activation increases in Schwann cells after nerve injury. Lysosomal activation is thought to promote the engulfment of myelin debris or fragments of injured axons in Schwann cells during Wallerian degeneration. However, a recent interpretation of lysosomal activation proposes a different view of the phenomenon. During Wallerian degeneration, lysosomes become secretory vesicles and are activated for lysosomal exocytosis. The lysosomal exocytosis triggers adenosine 5′-triphosphate (ATP) release from peripheral neurons and Schwann cells during Wallerian degeneration. Exocytosis is involved in demyelination and axonal degradation, which facilitate nerve regeneration following nerve degeneration. At this time, released ATP may affect the communication between cells in peripheral nerves. In this review, our description of the relationship between lysosomal exocytosis and Wallerian degeneration has implications for the understanding of peripheral nerve degenerative diseases and peripheral neuropathies, such as Charcot-Marie-Tooth disease or Guillain-Barré syndrome.
Convenience Yield Value of International Emission Allowance Based on Call Options
Authors: Chang Kai
Published: July 2014

Convenience yield is call options; spot holders attain excess investment revenues through holding spot assets instituted futures assets. Based on the hypothesis of convenience yields, our empirical results show that monthly convenience yield of emission allowance has significant options feature; convenience yield has strong correlation with price spread between spot and futures and their price volatility. The market information set is helpful to adjust portfolio policy and improve portfolio investment revenues of emission allowances.
Reversal of Ampicillin Resistance in MRSA via Inhibition of Penicillin-Binding Protein 2a byAcalypha wilkesiana
Authors: Santiago Carolina , Pang Ee Leen , Lim Kuan-Hon , Loh Hwei-San , Ting Kang Nee
Published: July 2014

The inhibitory activity of a semipure fraction from the plant,Acalypha wilkesianaassigned as 9EA-FC-B, alone and in combination with ampicillin, was studied against methicillin-resistantStaphylococcus aureus(MRSA). In addition, effects of the combination treatment on PBP2a expression were investigated. Microdilution assay was used to determine the minimal inhibitory concentrations (MIC). Synergistic effects of 9EA-FC-B with ampicillin were determined using the fractional inhibitory concentration (FIC) index and kinetic growth curve assay. Western blot experiments were carried out to study the PBP2a expression in treated MRSA cultures. The results showed a synergistic effect between ampicillin and 9EA-FC-B treatment with the lowest FIC index of 0.19 (synergism≤0.5). The presence of 9EA-FC-B reduced the MIC of ampicillin from 50 to 1.56 μg mL−1. When ampicillin and 9EA-FC-B were combined at subinhibitory level, the kinetic growth curves were suppressed. The antibacterial effect of 9EA-FC-B and ampicillin was shown to be synergistic. The synergism is due the ability of 9EA-FC-B to suppress the activity of PBP2a, thus restoring the susceptibility of MRSA to ampicillin. Corilagin was postulated to be the constituent responsible for the synergistic activity showed by 9EA-FC-B.
Naja naja atra Venom Protects against Manifestations of Systemic Lupus Erythematosus in MRL/lpr Mice
Authors: Zhu Jiali , Cui Kui , Kou Jianqun , Wang Shuzhi , Xu Yinli , Ding Zhihui , Han Rong , Qin Zhenghong
Published: July 2014

Systemic lupus erythematosus (SLE) is an autoimmune disease and effective therapy for this pathology is currently unavailable. We previously reported that oral administration of Naja naja atra venom (NNAV) had anti‐inflammatory and immune regulatory actions. We speculated that NNAV may have therapeutic effects in MRL/lpr SLE mice. Twelve‐week‐old MRL/lpr mice received oral administration of NNAV (20, 40, and 80 μg/kg) or Tripterygium wilfordii polyglycosidium (10 mg/kg) daily for 16 weeks. The effects of NNAV on SLE manifestations, including skin erythema, proteinuria, and anxiety‐like behaviors, were assessed with visual inspection and Multistix 8 SG strips and open field test, respectively. The pathology of spleen and kidney was examined with H&E staining. The changes in autoimmune antibodies and cytokines were determined with ELISA kits. The results showed that NNAV protected against the manifestation of SLE, including skin erythema and proteinuria. In addition, although no apparent histological change was found in liver and heart in MRL/lpr SLE mice, NNAV reduced the levels of glutamate pyruvate transaminase and creatine kinase. Furthermore, NNAV increased serum C3 and reduced concentrations of circulating globulin, anti‐dsDNA antibody, and inflammatory cytokines IL‐6 and TNF‐α. NNAV also reduced lymphadenopathy and renal injury. These results suggest that NNAV may have therapeutic values in the treatment of SLE by inhibiting autoimmune responses.
A Vehicle Haptic Steering by Wire System Based on High Gain GPI Observers
Authors: Rodriguez-Angeles A. , Sira-Ramirez H. , Garcia-Antonio J. A.
Published: July 2014

A vehicle steering by wire (SBW) haptic system based on high gain generalized proportional integral (GPI) observers is introduced. The observers are considered for the estimation of dynamic perturbations that are present at the tire and steering wheel. To ensure efficient tracking between the commanded steering wheel angle and the tire orientation angle, the estimated perturbations are on line canceled. As to provide a haptic interface with the driver, the estimated dynamic effects at the steering rack are fed back to the steering wheel, yielding a master‐slave haptic system with bilateral communication. For implementation purposes few sensors and minimum knowledge of the dynamic model are required, which is a major advantage compared to other approaches. Only position tracking errors are fed back, while all other signals are estimated by the high gain GPI observers. The scheme is robust to uncertainty on the input gain and cancels dynamic perturbation effects such as friction and aligning forces on the tire. Experimental results are presented on a prototype platform.
Usefulness of Combining Galectin-3 and BIVA Assessments in Predicting Short- and Long-Term Events in Patients Admitted for Acute Heart Failure
Authors: De Berardinis Benedetta , Magrini Laura , Zampini Giorgio , Zancla Benedetta , Salerno Gerardo , Cardelli Patrizia , Di Stasio Enrico , Gaggin Hanna K. , Belcher Arianna , Parry Blair A. , Nagurney John T. , Januzzi James L. , Di Somma Salvatore
Published: July 2014

Introduction. Acute heart failure (AHF) is associated with a higher risk for the occurrence of rehospitalization and death. Galectin-3 (GAL3) is elevated in AHF patients and is an indicator in predicting short-term mortality. The total body water using bioimpedance vector analysis (BIVA) is able to identify mortality within AHF patients. The aim of this study was to evaluate the short- and long-term predictive value of GAL3, BIVA, and the combination of both in AHF patients in Emergency Department (ED).Methods. 205 ED patients with AHF were evaluated by testing for B type natriuretic peptide (BNP) and GAL3. The primary endpoint was death and rehospitalization at 30, 60, 90, and 180 days and 12 and 18 months. AHF patients were evaluated at the moment of ED arrival with clinical judgment and GAL3 and BIVA measurement.Results. GAL3 level was significantly higher in patients >71 years old, and witheGFR<30 cc/min. The area under the curve (AUC) ofGAL3+BIVA, GAL3 and BIVA for death and rehospitalization both when considered in total and when considered serially for the follow-up period showed that the combination has a better prognostic value. Kaplan-Meier survival curve for GAL3 values >17.8 ng/mL shows significant survival difference. At multivariate Cox regression analysis GAL3 is an independent variable to predict death + rehospitalization with a value of 32.24 ng/mL at 30 days (P<0.005).Conclusion. In patients admitted for AHF an early assessment of GAL3 and BIVA seems to be useful in identifying patients at high risk for death and rehospitalization at short and long term. Combining the biomarker and the device could be of great utility since they monitor the severity of two pathophysiological different mechanisms: heart fibrosis and fluid overload.
A Novel Pseudorandom Bit Generator Based on Chirikov Standard Map Filtered with Shrinking Rule
Authors: Stoyanov Borislav , Kordov Krasimir
Published: July 2014

This communication proposes a simplified model of pseudorandom bit generator, based on two Chirikov standard maps filtered with shrinking rule. The study also demonstrates that the generated keystreams have excellent properties of randomness and resistance to statistical attacks, which is proven by using the NIST, ENT, and DIEHARD testing suites.
Cancer Affects microRNA Expression, Release, and Function in Cardiac and Skeletal Muscle
Authors: Chen Daohong , Goswami Chirayu P. , Burnett Riesa M. , Anjanappa Manjushree , Bhat-Nakshatri Poornima , Muller William , Nakshatri Harikrishna
Published: July 2014

Circulating microRNAs (miRNA) are emerging as important biomarkers of various diseases, including cancer. Intriguingly, circulating levels of several miRNAs are lower in patients with cancer compared with healthy individuals. In this study, we tested the hypothesis that a circulating miRNA might serve as a surrogate of the effects of cancer on miRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR486 is lower in patients with breast cancer compared with healthy individuals and that this difference is replicated faithfully in MMTV-PyMT and MMTV-Her2 transgenic mouse models of breast cancer. In tumor-bearing mice, levels of miR486 were relatively reduced in muscle, where there was elevated expression of the miR486 target genes PTEN and FOXO1A and dampened signaling through the PI3K/AKT pathway. Skeletal muscle expressed lower levels of the transcription factor MyoD, which controls miR486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro were sufficient to elicit reduced levels of miR486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated tumor necrosis factor α (TNFα) and four additional cytokines as mediators of miR486 expression in CM-treated cells. Because miR486 is a potent modulator of PI3K/AKT signaling and the muscle-enriched transcription factor network in cardiac/skeletal muscle, our findings implicated TNFα-dependent miRNA circuitry in muscle differentiation and survival pathways in cancer. Cancer Res; 74(16); 4270–81. ©2014 AACR.
miR-21 Induces Myofibroblast Differentiation and Promotes the Malignant Progression of Breast Phyllodes Tumors
Authors: Gong Chang , Nie Yan , Qu Shaohua , Liao Jian-You , Cui Xiuying , Yao Herui , Zeng Yunjie , Su Fengxi , Song Erwei , Liu Qiang
Published: July 2014

Phyllodes tumors of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of phyllodes tumors. It remains unknown what drives the malignant progression of phyllodes tumors. We found that the expression of myofibroblast markers, α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), and stromal cell–derived factor-1 (SDF-1), is progressively increased in the malignant progression of phyllodes tumors. Microarray showed that miR-21 was one of the most significantly upregulated microRNAs in malignant phyllodes tumors compared with benign phyllodes tumors. In addition, increased miR-21 expression was primarily localized to α-SMA–positive myofibroblasts. More importantly, α-SMA and miR-21 are independent predictors of recurrence and metastasis, with their predictive value of recurrence better than histologic grading. Furthermore, miR-21 mimics promoted, whereas miR-21 antisense oligos inhibited, the expression of α-SMA, FAP, and SDF-1, as well as the proliferation and invasion of primary stromal cells of phyllodes tumors. The ability of miR-21 to induce myofibroblast differentiation was mediated by its regulation on Smad7 and PTEN, which regulate the migration and proliferation, respectively. In breast phyllodes tumor xenografts, miR-21 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. This study suggests an important role of myofibroblast differentiation in the malignant progression of phyllodes tumors that is driven by increased miR-21. Cancer Res; 74(16); 4341–52. ©2014 AACR.
EpCAM-Selective Elimination of Carcinoma Cells by a Novel MAP-Based Cytolytic Fusion Protein
Authors: Hristodorov Dmitrij , Amoury Manal , Mladenov Radoslav , Niesen Judith , Arens Katharina , Berges Nina , Hein Lea , Di Fiore Stefano , Pham Anh-Tuan , Huhn Michael , Helfrich Wijnand , Fischer Rainer , Thepen Theo , Barth Stefan
Published: July 2014

In normal epithelia, the epithelial cell adhesion molecule (EpCAM) expression is relatively low and only present at the basolateral cell surface. In contrast, EpCAM is aberrantly overexpressed in various human carcinomas. Therefore, EpCAM is considered to be a highly promising target for antibody-based cancer immunotherapy. Here, we present a new and fully human cytolytic fusion protein (CFP), designated “anti–EpCAM(scFv)-MAP,” that is comprised of an EpCAM-specific antibody fragment (scFv) genetically fused to the microtubule-associated protein tau (MAP). Anti–EpCAM(scFv)-MAP shows potent EpCAM-restricted proapoptotic activity toward rapidly proliferating carcinoma cells. In vitro assays confirmed that treatment with anti–EpCAM(scFv)-MAP resulted in the colocalization and stabilization of microtubules, suggesting that this could be the potential mode of action. Dose-finding experiments indicated that anti–EpCAM(scFv)-MAP is well tolerated in mice. Using noninvasive far-red in vivo imaging in a tumor xenograft mouse model, we further demonstrated that anti–EpCAM(scFv)-MAP inhibited tumor growth in vivo. In conclusion, our data suggest that anti–EpCAM(scFv)-MAP may be of therapeutic value for the targeted elimination of EpCAM+ carcinomas. Mol Cancer Ther; 13(9); 2194–202. ©2014 AACR.
Translational Exposure–Efficacy Modeling to Optimize the Dose and Schedule of Taxanes Combined with the Investigational Aurora A Kinase Inhibitor MLN8237 (Alisertib)
Authors: Huck Jessica J. , Zhang Mengkun , Mettetal Jerome , Chakravarty Arijit , Venkatakrishnan Karthik , Zhou Xiaofei , Kleinfield Rob , Hyer Marc L. , Kannan Karuppiah , Shinde Vaishali , Dorner Andy , Manfredi Mark G. , Shyu Wen Chyi , Ecsedy Jeffrey A.
Published: July 2014

Aurora A kinase orchestrates multiple key activities, allowing cells to transit successfully into and through mitosis. MLN8237 (alisertib) is a selective Aurora A inhibitor that is being evaluated as an anticancer agent in multiple solid tumors and heme-lymphatic malignancies. The antitumor activity of MLN8237 when combined with docetaxel or paclitaxel was evaluated in in vivo models of triple-negative breast cancer grown in immunocompromised mice. Additive and synergistic antitumor activity occurred at multiple doses of MLN8237 and taxanes. Moreover, significant tumor growth delay relative to the single agents was achieved after discontinuing treatment; notably, durable complete responses were observed in some mice. The tumor growth inhibition data generated with multiple dose levels of MLN8237 and paclitaxel were used to generate an exposure–efficacy model. Exposures of MLN8237 and paclitaxel achieved in patients were mapped onto the model after correcting for mouse-to-human variation in plasma protein binding and maximum tolerated exposures. This allowed rank ordering of various combination doses of MLN8237 and paclitaxel to predict which pair would lead to the greatest antitumor activity in clinical studies. The model predicted that 60 and 80 mg/m2 of paclitaxel (every week) in patients lead to similar levels of efficacy, consistent with clinical observations in some cancer indications. The model also supported using the highest dose of MLN8237 that can be achieved, regardless of whether it is combined with 60 or 80 mg/m2 of paciltaxel. The modeling approaches applied in these studies can be used to guide dose-schedule optimization for combination therapies using other therapeutic agents. Mol Cancer Ther; 13(9); 2170–83. ©2014 AACR.
Oral versus Short-Term Intratympanic Prednisolone Therapy for Idiopathic Sudden Hearing Loss
Authors: Filipo Roberto , Attanasio Giuseppe , Russo Francesca Y. , Cartocci Giulia , Musacchio Angela , De Carlo Andrea , Roukos Raymond , De Seta Elio , Di Tillo Giacinto , Viccaro Marika , Sarnacchiaro Pasquale , Covelli Edoardo
Published: July 2014

Objectives: To assess the therapeutic effectiveness of an intratympanic (IT) steroid protocol compared to a systemic steroid protocol. Methods: A total of 265 consecutive patients presenting unilateral idiopathic sudden sensorineural hearing loss were divided into 2 groups. One group comprised 131 patients enrolled between May 2009 and May 2010, and the other consisted of 134 patients enrolled between June 2010 and June 2011; a total of 48 patients were excluded among the 2 groups. The first group received oral prednisone for 8 days in tapering doses; the second group had IT prednisolone at a dose of 62.5 mg/ml once a day for 3 consecutive days. Audiological examinations were performed at study entry and 30 days after the beginning of therapy. Mean pure tone audiometry (PTA) of both groups and hearing outcomes following the criteria of Furuhashi et al. [Clin Otolaryngol 2002;27:458-463] and Siegel [Otolaryngol Clin North Am 1975;8:467-473] were investigated. Results: The strong efficacy of steroid therapy was evident in both groups, observing both PTA and hearing threshold improvement. The evaluation of the hearing outcomes shows a significantly better result for the short-term IT protocol; this result is ascribable to two types of audiometric curves: down- and up-sloping. Conclusion: The results show a significant efficacy of both steroid therapeutic approaches. There was no significant difference in PTA improvement between the 2 study groups; the short-term IT protocol led to better results in the evaluation of the hearing outcomes (following the criteria of Siegel and Furuhashi et al.) for up- and down-sloping audiometric curves.
Competing Risk Model in Screening for Preeclampsia by Mean Arterial Pressure and Uterine Artery Pulsatility Index at 30-33 Weeks' Gestation
Authors: Tayyar Ahmet , Garcia-Tizon Larroca Santiago , Poon Leona C. , Wright David , Nicolaides Kypros H.
Published: July 2014

Objective: To assess risk for preeclampsia (PE) based on maternal characteristics, mean arterial pressure (MAP) and uterine artery pulsatility index (Ut-PI) at 30-33 weeks' gestation. Methods: Screening study in singleton pregnancies including 2,140 that subsequently developed PE and 83,615 that were unaffected by PE, gestational hypertension or delivery of small-for-gestational-age neonates (normal group). We developed a survival time model for the time of delivery for PE by combination of maternal characteristics and history with MAP and Ut-PI multiple of the median (MoM) values (biophysical test). Data on third-trimester MAP and Ut-PI were available in 350 cases of PE and 13,878 of the normal group. The detection rate of PE requiring delivery within 4, 6 and 8 weeks of the visit was estimated. Results: In pregnancies with PE the log10 MoM values of MAP and Ut-PI were inversely related to gestational age at delivery. Biophysical testing detected 90, 65 and 53% of PE with delivery within 4, 6 and 8 weeks of the visit, at a fixed false-positive rate of 5%. Interpretation: Testing by maternal characteristics, Ut-PI and MAP at 30-33 weeks could identify 90% of pregnancies developing PE and requiring delivery within the subsequent 4 weeks.
Structural Brain Imaging in Children and Adolescents following Prenatal Cocaine Exposure: Preliminary Longitudinal Findings
Authors: Akyuz Nurunisa , Kekatpure Minal V. , Liu Jie , Sheinkopf Stephen J. , Quinn Brian T. , Lala Meenakshi D. , Kennedy David , Makris Nikos , Lester Barry M. , Kosofsky Barry E.
Published: July 2014

The brain morphometry of 21 children, who were followed from birth and underwent structural brain magnetic resonance imaging at 8-10 years, was studied. This cohort included 11 children with prenatal cocaine exposure (CE) and 10 noncocaine-exposed children (NCE). We compared the CE versus NCE groups using FreeSurfer to automatically segment and quantify the volume of individual brain structures. In addition, we created a pediatric atlas specifically for this population and demonstrate the enhanced accuracy of this approach. We found an overall trend towards smaller brain volumes among CE children. The volume differences were significant for cortical gray matter, the thalamus and the putamen. Here, reductions in thalamic and putaminal volumes showed a robust inverse correlation with exposure levels, thus highlighting effects on dopamine-rich brain regions that form key components of brain circuitry known to play important roles in behavior and attention. Interestingly, head circumferences (HCs) at birth as well as at the time of imaging showed a tendency for smaller size among CE children. HCs at the time of imaging correlated well with the cortical volumes for all subjects. In contrast, HCs at birth were predictive of the cortical volume only for the CE group. A subgroup of these subjects (6 CE, 4 NCE) was also scanned at 13-15 years of age. In subjects who were scanned twice, we found that the trend for smaller structures continued into teenage years. We found that the differences in structural volumes between the CE and NCE groups are largely diminished when the HCs are controlled for or matched by study design. Participants in this study were drawn from a unique longitudinal cohort and, while the small sample size precludes strong conclusions regarding the longitudinal findings reported, the results point to reductions in HCs and in specific brain structures that persist through teenage years in children who were exposed to cocaine in utero.
Age Effects on Cortical Thickness in Cognitively Normal Elderly Individuals
Authors: Hurtz Sona , Woo Ellen , Kebets Valeria , Green Amity E. , Zoumalan Charleen , Wang Benjamin , Ringman John M. , Thompson Paul M. , Apostolova Liana G.
Published: July 2014

Background/Aims: Atrophy in both grey and white matter is found in normal aging. The prefrontal cortex and the frontal lobe white matter are thought to be the most affected regions. Our aim was to examine the effects of normal aging on cortical grey matter using a 3D quantitative cortical mapping method. Methods: We analyzed 1.5-tesla brain magnetic resonance imaging data from 44 cognitively normal elderly subjects using cortical pattern matching and cortical thickness analyses. Linear regression analysis was used to study the effect of age on cortical thickness. 3D map-wide correction for multiple comparisons was conducted with permutation analyses using a threshold of p < 0.01. Results: We found a significant negative association between age and cortical thickness in the right hemisphere (pcorrected = 0.009) and a trend level association in the left hemisphere (pcorrected = 0.081). Age-related changes were greatest in the sensorimotor, bilateral dorsal anterior cingulate and supplementary motor cortices, and the right posterior middle and inferior frontal gyri. Age effects greater in the medial than lateral visual association cortices were also seen bilaterally. Conclusion: Our novel method further validates that normal aging results in diffuse cortical thinning that is most pronounced in the frontal and visual association cortices.
Behavior and Neural Correlates of Empathy in Adolescents
Authors: Overgaauw Sandy , Güroğlu Berna , Rieffe Carolien , Crone Eveline A.
Published: July 2014

This study examined neural correlates of empathy in adolescence while observing harmful acts. A total of 32 participants (aged 12-19 years) viewed pictures depicting negative (offenders inflicting intentional harm) and positive (friends socializing) social situations. After viewing each picture, participants could allocate hypothetical points to either the offender or the victim in a dictator game. Behaviorally, participants of all ages acted prosocially towards victims, fairly towards positive individuals and punishingly towards offenders. Brain imaging analyses showed that viewing negative situations was associated with more activation in the bilateral intraparietal lobule and the superior temporal sulcus (STS), whereas viewing positive situations was associated with more medial prefrontal cortex and left temporal parietal junction activity. Analyses testing for associations between brain activity and self-reported empathy showed that the STS was correlated negatively with reports of understanding others' distress and the willingness to help others. Together, the findings suggest that adolescents show similar prosocial behavior, as previously reported in adults with greater STS activity, when observing negative social acts that is modulated by an individual's empathy for others.
Renal Arteriolar Injury by Salt Intake Contributes to Salt Memory for the Development of Hypertension
Authors: Oguchi Hideyo , Sasamura Hiroyuki , Shinoda Kazunobu , Morita Shinya , Kono Hidaka , Nakagawa Ken , Ishiguro Kimiko , Hayashi Kaori , Nakamura Mari , Azegami Tatsuhiko , Oya Mototsugu , Itoh Hiroshi
Published: July 2014

The role of salt intake in the development of hypertension is prominent, but its mechanism has not been fully elucidated. Our aim was to examine the effect of transient salt intake during the prehypertensive period in hypertensive model animals. Dahl salt-sensitive rats and spontaneously hypertensive rats were fed from 6 to 14 weeks with low-salt (0.12% NaCl), normal-salt (0.8% NaCl), high-salt (7% NaCl), or high-sodium/normal-chloride diet and returned to normal-salt diet for 3 months. Rats in the high-salt group saw elevations in blood pressure (BP) not only during the treatment period but also for the 3 months after returning to normal-salt diet. We named this phenomenon salt memory. Renal arteriolar injury was found in the high-salt group at the end of experiment. Dahl salt-sensitive rats were fed from 6 to 14 weeks with high-salt diet with angiotensin receptor blocker, vasodilator, calcium channel blocker, and calcium channel blocker+angiotensin receptor blocker and returned to normal-salt diet. Although BP was suppressed to control levels by vasodilator or calcium channel blocker, elevated renal angiotensin II and renal arteriolar injury were observed, and salt memory did not disappear because of sustained renal arteriolar injury. Calcium channel blocker+angiotensin receptor blocker suppressed renal arteriolar injury, resulting in the disappearance of salt memory. Cross-transplantation of kidneys from Dahl salt-sensitive rats on high salt to control rats caused increase of BP, whereas control kidneys caused reduction in BP of hypertensive rats, inducing the central role of the kidney. These results suggest that renal arteriolar injury through BP and renal angiotensin II elevation plays important roles in the development of salt memory for hypertension.
Effects of the Once-Weekly Glucagon-Like Peptide-1 Receptor Agonist Dulaglutide on Ambulatory Blood Pressure and Heart Rate in Patients With Type 2 Diabetes Mellitus
Authors: Ferdinand Keith C. , White William B. , Calhoun David A. , Lonn Eva M. , Sager Philip T. , Brunelle Rocco , Jiang Honghua H. , Threlkeld Rebecca J. , Robertson Kenneth E. , Geiger Mary Jane
Published: July 2014

Glucagon-like peptide-1 receptor agonists, used to treat type 2 diabetes mellitus, are associated with small reductions in systolic blood pressure (SBP) and increases in heart rate. However, findings based on clinic measurements do not adequately assess a drug’s 24-hour pharmacodynamic profile. The effects of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, on BP and heart rate were investigated using ambulatory BP monitoring. Patients (n=755; 56±10 years; 81% white; 48% women), with type 2 diabetes mellitus, taking ≥1 oral antihyperglycemic medication, with a clinic BP between 90/60 and 140/90 mm Hg were randomized to dulaglutide (1.5 or 0.75 mg) or placebo subcutaneously for 26 weeks. Ambulatory BP monitoring was performed at baseline and at 4, 16, and 26 weeks. The primary end point was change from baseline to week 16 in mean 24-hour SBP, a tree gatekeeping strategy compared the effects of dulaglutide to placebo. Both doses of dulaglutide were noninferior to placebo for changes in 24-hour SBP and diastolic blood pressure, and dulaglutide 1.5 mg significantly reduced SBP (least squares mean difference [95% confidence interval]), −2.8 mm Hg [−4.6, −1.0];
P
≤0.001). Dulaglutide 0.75 mg was noninferior to placebo (1.6 bpm; [0.3, 2.9];
P
≤0.02) for 24-hour heart rate (least squares mean difference [95% confidence interval]), but dulaglutide 1.5 mg was not (2.8 bpm [1.5, 4.2]). Dulaglutide 1.5 mg was associated with a reduction in 24-hour SBP and an increase in 24-hour heart rate. The mechanisms responsible for the observed effects remain to be clarified.
β2‐Microglobulin, Cystatin C, and Creatinine and Risk of Symptomatic Peripheral Artery Disease
Authors: Joosten Michel M. , Pai Jennifer K. , Bertoia Monica L. , Gansevoort Ron T. , Bakker Stephan J. L. , Cooke John P. , Rimm Eric B. , Mukamal Kenneth J.
Published: July 2014

Background

β
2
‐Microglobulin and cystatin C may have advantages over creatinine in assessing risk associated with kidney function. We therefore investigated whether emerging filtration markers, β
2
‐microglobulin and cystatin C, are prospectively associated with risk of the development of peripheral artery disease (
PAD
).

Methods and Results

We conducted nested case‐control studies among women within the Nurses’ Health Study (1990–2010) and among men within the Health Professionals Follow‐up Study (1994–2008) with the use of archived blood samples collected before
PAD
diagnosis. During follow‐up, symptomatic
PAD
was confirmed in 144 women and 143 men. Controls were matched 3:1 based on age, race, smoking status, fasting status, and date of blood sampling. Conditional logistic regression models were used to estimate relative risks (
RRs
) and were adjusted for plasma creatinine and cardiovascular risk factors. In women, the
RR
s (95% CI) per 1‐SD) increment were 1.16 (0.85 to 1.58) for β
2
‐microglobulin and 0.94 (0.69 to 1.28) for cystatin C. Corresponding
RR
s in men were 1.50 (1.08 to 2.09) for β
2
‐microglobulin and 1.54 (1.07 to 2.22) for cystatin C. There was no association between creatinine and
PAD
risk in women, whereas the association in men (
RR
1.41, 95%
CI
1.10 to 1.81) disappeared after adjustment for either β
2
‐microglobulin or cystatin C. In pooled analyses of men and women, only β
2
‐microglobulin was associated with
PAD
risk (
RR
1.31, 95%
CI
1.04 to 1.64).

Conclusions

In pooled analyses, β
2
‐microglobulin was associated with an increased risk of symptomatic
PAD
; a similar association with cystatin C was observed only in men. The findings suggest that β
2
‐microglobulin may capture the atherosclerosis‐promoting or atherosclerosis‐related elements of kidney dysfunction better than creatinine.
Pistachio Nut Consumption Modifies Systemic Hemodynamics, Increases Heart Rate Variability, and Reduces Ambulatory Blood Pressure in Well‐Controlled Type 2 Diabetes: a Randomized Trial
Authors: Sauder Katherine A. , McCrea Cindy E. , Ulbrecht Jan S. , Kris‐Etherton Penny M. , West Sheila G.
Published: July 2014

Background

Managing cardiovascular risk factors is important for reducing vascular complications in type 2 diabetes, even in individuals who have achieved glycemic control. Nut consumption is associated with reduced cardiovascular risk; however, there is mixed evidence about the effect of nuts on blood pressure (
BP
), and limited research on the underlying hemodynamics. This study assessed the effect of pistachio consumption on
BP
, systemic hemodynamics, and heart rate variability in adults with well‐controlled type 2 diabetes.

Methods and Results

We enrolled 30 adults (40 to 74 years) with type 2 diabetes in a randomized, crossover, controlled feeding study. After a 2‐week run‐in period, participants consumed a low‐fat control diet (27% fat) containing low‐fat/high‐carbohydrate snacks and a moderate‐fat diet (33% fat) containing pistachios (20% of total energy) for 4 weeks each, separated by a 2‐week washout. Following each diet period, we assessed
BP
, systemic hemodynamics, and heart rate variability at rest and during acute mental stress, and, in a subset of participants (n=21), 24‐hour ambulatory
BP
.
BP
at rest and during stress did not differ between treatments. The pistachio diet significantly reduced total peripheral resistance (−3.7±2.9%,
P
=0.004), increased cardiac output (3.1±2.3%,
P
=0.002), and improved some measures of heart rate variability (all
P
<0.05). Systolic ambulatory
BP
was significantly reduced by 3.5±2.2 mm Hg (
P
=0.046) following the pistachio diet, with the greatest reduction observed during sleep (−5.7±2.6 mm Hg,
P
=0.052).

Conclusions

A moderate‐fat diet containing pistachios modestly improves some cardiovascular risk factors in adults with well‐controlled type 2 diabetes.

Clinical Trial Registration

URL:
www.clinicaltrials.gov
. Unique identifier: NCT00956735.
Reconstructing Archival Practices in Abbasid Baghdad
Authors: van Berkel Maaike
Published: July 2014

The Abbasid administration relied extensively on the use of written documents. The central administrative apparatus in Baghdad, with its numerous specialised bureaus, seems to have been one of the main producers of documents and it must have possessed some of the largest archives of its era. However, only few documents issued by and written for the central administration have survived in their original form. Through an analysis of references found in narrative sources, this article seeks to provide a reconstruction of the functioning of the archives of the central administration in Baghdad during the caliphate of al-Muqtadir (r. 295/908-320/932).
Two new fringe-limbed frogs of the genus Ecnomiohyla (Anura: Hylidae) from Panama
Authors: BATISTA ABEL , HERTZ ANDREAS , MEBERT KONRAD , KÖHLER GUNTHER , LOTZKAT SEBASTIAN , PONCE MARCOS , VESELY MILAN
Published: July 2014

Forest canopy-dwelling frogs are usually among the rarest anuran species observed in the neotropical forest, mainly because they fall outside of the scope of the standard search methods used by herpetologists. During field explorations undertaken in western and eastern Panama in recent years, we discovered two species belonging to the genus Ecnomiohyla, which showed significant differences in genetic distances (16S mtDNA gene) and morphological characteristics different from any known Ecnomiohyla species. The first specimen originates from the Serranía de Jingurudó, Darién province, southeastern Panamá, and is described herein as E. bailarina sp. nov., and the second specimen was found at Santa Fe National Park, Veraguas province, central-western Panama, and is described as E. veraguensis sp. nov. We provide a detailed description of both new species, including comparisons of morphological and molecular characters of almost all members of the genus in lower Central America, as well as an identification key for the entire genus.
A new species of Neoliomera Odhner, 1925, from the western Pacific, and the first record of N. demani Forest & Guinot, 1961, from Taiwan (Crustacea: Decapoda: Brachyura: Xanthidae)
Authors: HO P.-H. , NG PETER K. L.
Published: July 2014

A new species of a strikingly coloured xanthid crab of the genus Neoliomera Odhner, 1925, is described from coral reefs in Guam, Taiwan, and the Hawaiian Islands. The new species is allied to N. pubescens (H. Milne Edwards, 1834), and N. demani Forest & Guinot, 1961, but differs in the form of the carapace armature, frontal margin, structure of the chela, proportions of the ambulatory merus and the form of the male first gonopod. Neoliomera demani is also recorded from Taiwan for the first time and aspects of its taxonomy are discussed.