bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of nonspecific HIF1α inhibitors on development of castrate resistance and metastases in prostate cancer
Authors: Ranasinghe Weranja K. B. , Sengupta Shomik , Williams Scott , Chang Mike , Shulkes Arthur , Bolton Damien M. , Baldwin Graham , Patel Oneel
Published: January 2014

Expression of hypoxia‐inducible factor (HIF)1α increases the risk of castrate‐resistant prostate cancer (CRPC) and metastases in patients on androgen deprivation therapy (ADT) for prostate cancer (PC). We aimed to investigate the effects of nonspecific HIF1α inhibitors (Digoxin, metformin, and angiotensin‐2 receptor blockers) on development of CRPC and metastases while on ADT. A retrospective review of prospectively collected medical records was conducted of all men who had continuous ADT as first‐line therapy for CRPC at the Austin Hospital from 1983 to 2011. Association between HIF1α inhibitor medications and time to develop CRPC was investigated using actuarial statistics. Ninety‐eight patients meeting the criteria were identified. Eighteen patients (21.4%) were treated with the nonspecific HIF1α inhibitors. Both groups had similar characteristics, apart from patients on HIF1α inhibitors being older (70 years vs. 63.9 years). The median CRPC‐free survival was longer in men using HIF1α inhibitors compared to those not on inhibitors (6.7 years vs. 2.7 years, P = 0.01) and there was a 71% reduction in the risk of developing CRPC (HR 0.29 [95% CI 0.10–0.78] P = 0.02) after adjustment for Gleason score, age, and prostate‐specific antigen (PSA). The median metastasis‐free survival in men on HIF1α inhibitors was also significantly longer compared to those on no inhibitors (5.1 years vs. 2.6 years, P = 0.01) with an 81% reduction in the risk of developing metastases (HR 0.19 [CI 0.05–0.76] P = 0.02) after adjustment for Gleason score, age, and PSA. Nonspecific HIF1α inhibitors appear to increase the progression‐free survival and reduce the risk of developing CRPC and metastases in patients on continuous ADT.
Impact of Sludge Floc Size and Water Composition on Dewaterability
Authors: Fitria Dewi , Scholz Miklas , Swift Gareth M. , Hutchinson Simon M.
Published: January 2014

In order to observe the impact of different water compositions on sludge dewaterability, assessments of floc sizes using a particle size analyzer and of sludge dewaterability based on the capillary suction time (CST) test were carried out. Synthetic raw water had small floc sizes, and synthetic domestic wastewater had both larger median floc sizes and a better correlation between sludge dewaterability and median floc sizes. The floc size distribution results showed that synthetic raw water is associated with a narrow particle size distribution. In comparison, synthetic domestic wastewater produced a wider distribution. However, the CST values were similar for both waters. Compared to synthetic wastewater, natural wastewater had the largest distribution with generally larger particle sizes.
Seeding Molecular Rotators on a Passivated Silicon Surface
Authors: Guillermet Oliver , Mahmood Ather , Yang Jianshu , Echeverria Jorge , Jeannoutot Judicael , Gauthier Sebastien , Joachim Christian , Chérioux Frederic , Palmino Frank
Published: January 2014

Thermally activated rotation of single molecules adsorbed on a silicon‐based surface between 77 and 150 K has been successfully achieved. This remarkable phenomenon relies on a nanoporous supramolecular network, which acts as a template to seed periodic molecule rotors on the surface. Thermal activation of rotation has been demonstrated by STM experiments and confirmed by theoretical calculations.
Orthogonal Orientation of Chromonic Liquid Crystals by Rubbed Polyamide Films
Authors: Mcguire Aya , Yi Youngwoo , Clark Noel A.
Published: January 2014

Chromonic liquid crystals (CLCs) have drawn attention for applications to organic electronics and optical films as well as biological materials. Understanding the alignment mechanism of CLCs is important for those applications. Using a polarized transmission optical microscope, we observe the optical texture, dichroism, and birefringence of CLC films of sunset yellow (SSY) confined by polyamide (nylon) films that are rubbed with a brush. The films align with the stacks of SSY molecules oriented, surprisingly, perpendicular to the rubbing direction. We propose that this alignment is stabilized by molecular interaction between the stretched nylon chains and molecular grooves of the SSY stacks rather than elastic energy of the CLCs due to surface topography induced by the rubbing.
An analysis of performance factors on Esper‐based stream big data processing in a virtualized environment
Authors: Ku Mino , Choi Eunmi , Min Dugki
Published: January 2014

To process big data in a cloud computing environment, a large scale of stream big data is one of the challenging issues. In particular, complex event processing is an emerging technology to handle massive events from multiple sources and process them in a near real time. In this paper, we analyze four performance‐influencing factors on a virtualized event processing system: the number of query statements, garbage collection intervals, the quantity of virtual machine resources, and virtual CPU assignment types. In our experiments, we observe the performance effects of these performance parameters, by implementing and running an Esper‐based event processing application on top of a Xen‐based virtualized system. With experimental results, we analyze the memory consumption problem, and apply periodic garbage collection, to reduce unexpected memory consumption of JVM. Also, we analyze performance effects of the number of cores in a virtual machine (VM) and resource sharing among VMs. Under the virtualized environment in cloud computing infrastructure, one of the critical issues is the management of virtualized computing resources. Accordingly, we present the event processing performance on VMs as a function of virtual CPU assignment types and the number of VMs that share virtual CPUs. Copyright © 2014 John Wiley & Sons, Ltd.
Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer's disease: studies in animal models
Authors: Calvo‐Ochoa Erika , Arias Clorinda
Published: January 2014

A growing body of animal and epidemiological studies suggest that metabolic diseases such as obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus are associated with the development of cognitive impairment, dementia and Alzheimer's disease, particularly in aging. Several lines of evidence suggest that insulin signalling dysfunction produces these metabolic alterations and underlie the development of these neurodegenerative diseases. In this article, we address normal insulin function in the synapse; we review and discuss the physiopathological hallmarks of synaptic insulin signalling dysfunction associated with metabolic alterations. Additionally, we describe and review the major animal models of obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus. The comprehensive knowledge of the molecular mechanisms behind the association of metabolic alterations and cognitive impairment could facilitate the early detection of neurodegenerative diseases in patients with metabolic alterations, with treatment that focus on neuroprotection. It could also help in the development of metabolic‐based therapies and drugs for using in dementia and Alzheimer's disease patients to alleviate their symptoms in a more efficient and comprehensive way. Copyright © 2014 John Wiley & Sons, Ltd.
Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for “inflamm‐aging”
Authors: Pinti Marcello , Cevenini Elisa , Nasi Milena , De Biasi Sara , Salvioli Stefano , Monti Daniela , Benatti Stefania , Gibellini Lara , Cotichini Rodolfo , Stazi Maria Antonietta , Trenti Tommaso , Franceschi Claudio , Cossarizza Andrea
Published: January 2014

Mitochondrial components, including mitochondrial DNA (mtDNA), when released extracellularly, can act as “damage‐associated molecular pattern” (DAMP) agents and cause inflammation. As many elderly people are characterized by a low‐grade, chronic inflammatory status defined “inflamm‐aging,” we evaluated if circulating mtDNA can contribute to this phenomenon. Eight hundred and thirty‐one Caucasian subjects were enrolled in the study, including 429 siblings aged 90–104 (90+ siblings). mtDNA plasma levels increased gradually after the fifth decade of life. In 90+ subjects, mtDNA values of two members of the same sibling relationship were directly correlated, suggesting a role for familiar/genetic background in controlling the levels of circulating mtDNA. The subjects with the highest mtDNA plasma levels had the highest amounts of TNF‐α, IL‐6, RANTES, and IL‐1ra; the subjects with the lowest mtDNA levels had the lowest levels of the same cytokines. In vitro stimulation of monocytes with mtDNA concentrations similar to the highest levels observed in vivo resulted in an increased production of TNF‐α, suggesting that mtDNA can modulate the production of proinflammatory cytokines. Our findings therefore show that circulating mtDNA increases with age, and can significantly contribute to the maintenance of the low‐grade, chronic inflammation observed in elderly people.
Toll‐like receptors expressed on embryonic macrophages couple inflammatory signals to iron metabolism during early ontogenesis
Authors: Balounová Jana , Vavrochová Tereza , Benešová Martina , Ballek Ondřej , Kolář Michal , Filipp Dominik
Published: January 2014

Mammalian TLRs in adult animals serve indispensable functions in establishing innate and adaptive immunity and contributing to the homeostasis of surrounding tissues. However, the expression and function of TLRs during mammalian embryonic development has not been studied so far. Here, we show that CD45+ CD11b+ F4/80+ macrophages from 10.5‐day embryo (E10.5) co‐express TLRs and CD14. These macrophages, which have the capability to engulf both apoptotic cells and bacteria, secrete a broad spectrum of proinflammatory cytokines and chemokines upon TLR stimulation, demonstrating that their TLRs are functional. Comparative microarray analysis revealed an additional set of genes that were significantly upregulated in E10.5 TLR2+ CD11b+ macrophages. This analysis, together with our genetic, microscopic, and biochemical evidence, showed that embryonic phagocytes express protein machinery that is essential for the recycling of cellular iron and that this expression can be regulated by TLR engagement in a MyD88‐dependent manner, leading to typical inflammatory M1 responses. These results characterize the utility of TLRs as suitable markers for early embryonic phagocytes as well as molecular triggers of cellular responses, the latter being demonstrated by the involvement of TLRs in an inflammation‐mediated regulation of embryonic homeostasis via iron metabolism.
Expansion of CD16 positive and negative human NK cells in response to tumor stimulation
Authors: Tsukerman Pinchas , Stern‐Ginossar Noam , Yamin Rachel , Ophir Yael , Stanietsky Anna Miller, Noa , Mandelboim Ofer
Published: January 2014

NK cells are innate immune lymphocytes that express a vast repertoire of germ‐line encoded receptors for target recognition. These receptors include inhibitory and activating proteins, among the latter of which is CD16, a low affinity binding Fc receptor. Here, we show that human NK cells expand in response to stimulation with various tumor cell lines. We further demonstrate that the tumor‐derived expansion of NK cells is accompanied by rapid, cell‐dependent, changes in CD16 expression levels. We show that in NK cells expanded in response to the EBV‐transformed cell line 721.221, CD16 is shed and therefore approximately half of the expanded 721.221‐derived NK‐cell population does not express CD16. We also show, in contrast, that in response to 1106mel cells, CD16 expression is maintained on the cell surface of the expanded NK cells due to an antibody‐dependent mechanism. Our results may provide a basis for the selective expansion of NK cells that may be used for tumor immunotherapy.
Binding of Zn(II) ions to chitosan–PVA blend in aqueous environment: Adsorption kinetics and equilibrium studies
Authors: Anitha T. , Senthil Kumar P. , Sathish Kumar K.
Published: January 2014

Zinc ion [Zn(II)] is the one of the most toxic and common among the heavy metal pollutants of industrial effluents. The present investigation has been aimed at describing the synthesis and characterization of biodegradable nanoparticle based on chitosan, then blending with biodegradable synthetic polymer (polyvinyl alcohol, PVA) and which was applied for the removal of Zn(II) ions from the aqueous system. The prepared nanoparticle and the chitosan blended polymers were characterized using transmission electron microscope (TEM), scanning electron microscope (SEM), and X‐ray diffraction (XRD) analyses. The adsorption behaviour of chitosan blended polymer for Zn(II) ions has been studied as a function of solution pH, adsorbent dose, contact time, and adsorbate concentration in a batch system. The maximum adsorption was observed as 99.45% for an initial Zn(II) ions concentration of 10 mg/L for the solution pH of 5.0 and contact time of 30 min and at 5 g/L of adsorbent dose. The adsorption kinetics was investigated by fitting the experimental data to the pseudo‐first order, pseudo‐second order kinetic models, Weber and Morris intraparticle diffusion and Boyd kinetic models. Adsorption equilibrium data were analyzed by the Langmuir and Freundlich adsorption isotherm models and it was found that the Langmuir isotherm model fits best with the experimental data. The desorption of Zn(II) ions from the spent chitosan/PVA blend was carried out by HCl solution. The results of the present study showed the polymer blends may act as an effective adsorbent for the removal of Zn(II) ions from the aqueous solution. © 2014 American Institute of Chemical Engineers Environ Prog, 34: 15–22, 2015
Stability and aggregation of silver and titanium dioxide nanoparticles in seawater: Role of salinity and dissolved organic carbon
Authors: Wang Huanhua , Burgess Robert M. , Cantwell Mark G. , Portis Lisa M. , Perron Monique M. , Wu Fengchang , Ho Kay T.
Published: January 2014

The behavior and fate of nanoparticles (NPs) in the marine environment are largely unknown and potentially have important environmental and human health implications. The aggregation and fate of NPs in the marine environment are greatly influenced by their interactions with seawater and dissolved organic carbon (DOC). In the present study, the stability and aggregation of 30-nm–diameter silver nanoparticles (AgNPs) capped with citrate and polyvinylpyrrolidone (PVP; AgNP-citrate and AgNP-PVP) and 21-nm-diameter titanium dioxide (TiO2) NPs as affected by seawater salinity and DOC were investigated by measuring hydrodynamic diameters and zeta potentials. The added DOC (in humic acid form) stabilized the 3 types of NPs when the seawater salinities were ≤5 parts per thousand (ppt), but the stabilizing effect of DOC was reduced by a higher salinity (e.g., 30 ppt). In addition, AgNP-PVP was more stable than AgNP-citrate in seawater, indicating that surface capping agents and stabilization mechanisms govern the stability and aggregation of NPs. Statistical analysis showed that salinity is the most dominant influence on the stability and aggregation of AgNPs and TiO2NPs, followed by DOC. These findings expand our knowledge on the behavior of AgNPs and TiO2NPs in seawater and indicate that the fate of these NPs will be primarily to aggregate in the water column, precipitate, and accumulate in sediments following release into the marine environment. Environ Toxicol Chem 2014;33:1023–1029. © 2014 SETAC
Statistical analysis of histopathological endpoints
Authors: Green John W. , Springer Timothy A. , Saulnier Amy N. , Swintek Joe
Published: January 2014

Histopathological assessments of fish from aquatic ecotoxicology studies are being performed with increasing frequency. Aquatic ecotoxicology studies performed for submission to regulatory agencies are usually conducted with multiple subjects (e.g., fish) in each of multiple vessels (replicates) within a water control and within each of several concentrations of a test substance. A number of histopathological endpoints are evaluated in each fish, and a severity score is generally recorded for each endpoint. The severity scores are often recorded using a nonquantitative scale of 0 to 4, with 0 indicating no effect, 1 indicating minimal effect, through 4 for severe effect. Statistical methods often used to analyze these scores suffer from several shortcomings: computing average scores as though scores were quantitative values, considering only the frequency of abnormality while ignoring severity, ignoring any concentration–response trend, and ignoring the possible correlation between responses of individuals within test vessels. A new test, the Rao-Scott Cochran-Armitage by Slices (RSCABS), is proposed that incorporates the replicate vessel experimental design and the biological expectation that the severity of the effect tends to increase with increasing doses or concentrations, while retaining the individual subject scores and taking into account the severity as well as frequency of scores. A power simulation and examples demonstrate the performance of the test. R-based software has been developed to carry out this test and is available free of charge at www.epa.gov/med/Prods_Pubs/rscabs.htm. The SAS-based RSCABS software is available from the first and third authors. Environ Toxicol Chem 2014;33:1108–1116. © 2014 SETAC
The naturally occurring carcinogen ptaquiloside is present in groundwater below bracken vegetation
Authors: Clauson-Kaas Frederik , Jensen Pia H. , Jacobsen Ole S. , Juhler René K. , Hansen Hans Christian B.
Published: January 2014

The present study demonstrates unequivocally the presence of the natural carcinogen ptaquiloside and its transformation product pterosin B in groundwater and surface water. Groundwater concentrations up to 0.23 nmol/L (92 ng/L) ptaquiloside and up to 2.2 nmol/L (0.47 µg/L) pterosin B were found. Of 21 groundwater samples, 5 contained ptaquiloside, exceeding the estimated threshold for drinking water (1.3–40 pmol/L). The results are critical for water abstraction in bracken-infested areas. Environ Toxicol Chem 2014;33:1030–1034. © 2014 SETAC
Correlation between traffic granularity and defragmentation periodicity in elastic optical networks
Authors: Khodashenas Pouria Sayyad , Comellas Jaume , Perelló Jordi , Spadaro Salvatore
Published: January 2014

While elastic optical network technologies have emerged as promising solutions for future ultra‐high‐speed optical transmission, the unavoidable spectral fragmentation problem that appears in such networks significantly degrades their performance. In light of this, spectral defragmentation technologies have been introduced in elastic optical networks, aiming to increase the spectrum utilisation. During the defragmentation operation, the available fragmented spectrum bands are consolidated by reallocating existing connections, either re‐routing them along alternative routes and/or re‐tuning them onto different spectrum portions. Obviously, spectral defragmentation increases network complexity and cost. Therefore, it is highly desirable to limit its application as much as possible, while keeping network performance within acceptable margins. In this paper, we focus on analyzing the correlation between the optimal (i.e. minimum) spectrum defragmentation periodicity in the network with the granularity of the supported traffic. For this purpose, we initially introduce a novel algorithm for efficient spectrum defragmentation. The proposed algorithm aims to consolidate the available fibre spectrum as much as possible, while limiting the number of reallocated active connections. Then, supported on extensive simulation results, we show how spectral defragmentation periodicity can be effectively configured by having knowledge of the offered traffic granularity. Copyright © 2014 John Wiley & Sons, Ltd.
Hepatic interferon-stimulated genes are differentially regulated in the liver of chronic hepatitis C patients with different interleukin-28B genotypes
Authors: Honda Masao , Shirasaki Takayoshi , Shimakami Tetsuro , Sakai Akito , Horii Rika , Arai Kuniaki , Yamashita Tatsuya , Sakai Yoshio , Yamashita Taro , Okada Hikari , Murai Kazuhisa , Nakamura Mikiko , Mizukoshi Eishiro , Kaneko Shuichi
Published: January 2014

Pretreatment up-regulation of hepatic interferon (IFN)-stimulated genes (ISGs) has a stronger association with the treatment-resistant interleukin (IL)28B minor genotype (MI; TG/GG at rs8099917) than with the treatment-sensitive IL28B major genotype (MA; TT at rs8099917). We compared the expression of ISGs in the liver and blood of 146 patients with chronic hepatitis C who received pegylated IFN and ribavirin combination therapy. Gene expression profiles in the liver and blood of 85 patients were analyzed using an Affymetrix GeneChip (Affymetrix, Santa Clara, CA). ISG expression was correlated between the liver and blood of the MA patients, whereas no correlation was observed in the MI patients. This loss of correlation was the result of the impaired infiltration of immune cells into the liver lobules of MI patients, as demonstrated by regional gene expression analysis in liver lobules and portal areas using laser capture microdissection and immunohistochemical staining. Despite having lower levels of immune cells, hepatic ISGs were up-regulated in the liver of MI patients and they were found to be regulated by multiple factors, namely, IL28A/B, IFN-λ4, and wingless-related MMTV integration site 5A (WNT5A). Interestingly, WNT5A induced the expression of ISGs, but also increased hepatitis C virus replication by inducing the expression of the stress granule protein, GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1), in the Huh-7 cell line. In the liver, the expression of WNT5A and its receptor, frizzled family receptor 5, was significantly correlated with G3BP1. Conclusions: Immune cells were lost and induced the expression of other inflammatory mediators, such as WNT5A, in the liver of IL28B minor genotype patients. This might be related to the high level of hepatic ISG expression in these patients and the treatment-resistant phenotype of the IL28B minor genotype. (HEPATOLOGY 2014;59:828–838)
Effect of topical vasoconstrictor exposure upon tumoricidal radiotherapy
Authors: Fahl William E.
Published: January 2014

Topical application of the alpha adrenergic vasoconstrictors norepinephrine, phenylephrine or epinephrine to skin or mucosa in alcohol:water‐based delivery vehicles minutes before irradiation has recently been shown to protect skin and mucosa cells against radiotherapy‐induced toxicities in both preclinical and clinical studies. The protective mechanism is thought to involve transient skin or mucosal vasoconstriction with secondary, transient hypoxia and associated radioprotection. Regarding possible protection of tumor cell nests within the radiotherapy field, the endothelial cell‐abnormal stroma constructed blood vessels generally found in human tumors commonly lack adrenergic receptor‐containing smooth muscle cells that are required to achieve vasoconstriction. Consistent with this, we show here that topical application of norepinephrine or phenylephrine to broken or intact skin over human Cal‐27 or A‐431 xeonograft, or mouse solid L1210 allograft tumors growing subcutaneously in nude mice, showed no effect upon radiation‐induced tumor growth inhibition. Although vasoconstrictor‐induced nude mouse skin blanch was seen minutes after topical application of 600 mM norepinephrine, no blanching was seen within the A‐431 xenograft tumors. Radiation dermatitis was severe 11 days post‐irradiation (2 × 13.8 Gy) in the irradiated field containing xenograft tumors in mice that received topical delivery vehicle, but was absent in mice that received topical norepinephrine. Topical vasoconstrictor‐conferred prevention of radiation dermatitis without discernible radioprotection of three histologically diverse xenograft or allograft tumors supports further development of the topical vasoconstrictor therapeutic strategy in humans.
The Power of Shame in Men Who Are Depressed: Implications for Counselors
Authors: Shepard David S. , Rabinowitz Fredric E.
Published: January 2014

Socialization processes leave many men prone to experience pervasive feelings of shame when confronted by challenging life events. These feelings may be associated with a depressed mood, requiring the help of a counselor. The authors review the literature on shame, its relationship to depression, and the socialization experiences that leave men vulnerable to shame. They then propose a framework and strategies for reducing shame in depressed men, illustrated with 3 case studies.
The dual effect of ultrasound‐targeted microbubble destruction in mediating recombinant adeno‐associated virus delivery in renal cell carcinoma: transfection enhancement and tumor inhibition
Authors: Li Fan , Jin Lifang , Wang Huiping , Wei Fang , Bai Min , Shi Qiusheng , Du Lianfang
Published: January 2014

Background

Recombinant adeno‐associated virus (rAAV) is recognized as a promising vector for cancer gene therapy, although its low transfer efficiency in less permissive cells limits extensive application. Our previous studies reported that ultrasound‐targeted microbubble (MB) destruction (UTMD) enhanced rAAV transfer in its permissive retinal cells. In the present study, we investigated whether UTMD increased rAAV transfer in less permissive human renal cell carcinoma (hRCC) cells and tumors.

Methods

hRCC cells were treated with rAAV2 under different conditions of UTMD, and the viral transfer efficiency and cell viability were analyzed. Fifty‐two male nude mice (BALB/c) implanted with hRCC cells were randomly assigned to four groups consisting of rAAV, rAAV + ultrasound and rAAV + UTMD (20 µl and 40 µl of MBs). UTMD was initiated immediately after intratumoral viral injection, and viral transfer efficiency and tumor volumes were analyzed at 12 weeks after infection.

Results

The efficiency of non‐augmented transfer of rAAV2 into hRCC cells was low (17.28 ± 2.44%). The use of UTMD enhanced viral transfer efficiency by two‐ to three‐fold, and enhanced viral genomic DNA by more than nine‐fold, without decreasing cell viability. In vivo studies also showed that UTMD increased rAAV2 transfer in tumor. The enhancements were maintained for a period of 12 weeks. Tumor growth in mice was inhibited by UTMD treatment, and UTMD treatment augmented by MBs (40 µl) produced an even stronger effect.

Conclusions

UTMD enhanced rAAV2 transfer into less permissive RCC cells and tumors, resulting in inhibition of tumor growth, which suggests that UTMD may be a useful delivery tool for cancer gene therapy. Copyright © 2014 John Wiley & Sons, Ltd.
Surgical management of perihilar cholangiocarcinoma: a Khon Kaen experience
Authors: Khuntikeo Narong , Pugkhem Ake , Titapun Attapol , Bhudhisawasdi Vajarabhongsa
Published: January 2014

Cholangiocarcinoma is the most common cancer in the northeast of Thailand. Most of the patients present when the disease is in an advanced stage. Improvement of preoperative diagnoses and surgical techniques provide more satisfactory results. Herein we reviewed our 30‐year experience in management of perihilar cholangiocarcinoma in Khon Kaen northeast Thailand. Between 1982 and 2012 we reviewed four specific studies of perihilar cholangiocarcinoma in Srinagarind Hospital, Khon Kaen, Thailand. The first study focused on advanced surgical pathology and palliative surgery, which were used to treat obstructive jaundice cholangiocarcinoma patients. Long‐term survival in this study was rare with a one‐year survival of just 15%. The second study was conducted on 30 consecutive cases of perihilar cholangiocarcinoma who presented with obstructive jaundice without preoperative biliary drainage. All the patients underwent major liver resection with bilio‐enteric reconstruction. Perioperative mortality was 6.7% without a 5‐year survival. The third study aimed to analyze the survival rates and factors affecting survival in extrahepatic CCA patients following surgical treatment at Srinagarind Hospital and concluded that resection margins are an important prognostic factor. The last study objective was the analysis of curative surgical attempt in 99 consecutive perihilar cholangiocarcinoma and results showed that R0 resection could improve long‐term survival. We evaluated four studies of perihilar cholangiocarcinoma in Srinagarind Hospital, Khon Kaen, Thailand from 1982–2012. Viewed chronologically there has been a progressive improvement of diagnosis and surgical treatment during the past 30 years. Despite these advances the 5‐year survival rate remains unsatisfactorily low. Future improvement of patient selection and surgical techniques can lead to a greater survival rate for patients.
Tissue kallikrein protects rat hippocampal CA1 neurons against cerebral ischemia/reperfusion‐induced injury through the B2R‐Raf‐MEK1/2‐ERK1/2 pathway
Authors: Wang Zheng , Han Xiang , Cui Mei , Fang Kun , Lu Zhengyu , Dong Qiang
Published: January 2014

We have documented that tissue kallikrein (TK) prevents neurons from hypoxia/reoxygenation injury through the B2R‐ERK1/2 pathway and the antihypoxic function of TK through Homer1b/c‐ERK1/2 signaling pathways. The present study investigates the molecular mechanisms of exogenous TK activation of the B2R‐ERK1/2 pathway through the β‐arrestin‐2 assembled B2R‐Raf‐MEK1/2 signaling module in vivo. The cresyl violet staining results indicated that exogenous TK protected the rat hippocampal CA1 neurons against cerebral ischemia/reperfusion (I/R) injury. The immunoprecipitation (IP) and immunoblotting (IB) results revealed that exogenous TK upregulated the β‐arrestin‐2 assembled B2R‐Raf‐MEK1/2 signaling module and upregulated the phosphorylation of Raf (p‐Raf), MEK1/2 (p‐MEK1/2), and ERK1/2 (p‐ERK1/2). Meanwhile, exogenous TK upregulated the expression of nuclear factor‐κB (NF‐κB), depressed the release of cytochrome c (Cyt c) and bax from mitochondria to the cytosol, and depressed the activation of caspase‐3. Take together, our results suggest that exogenous TK attenuated the cerebral I/R induced rat hippocampal CA1 neurons injury through activating the β‐arrestin‐2 assembled B2R‐Raf‐MEK1/2 signaling module and that the activated B2R‐Raf‐MEK1/2 signaling module could upregulate the expression of NF‐κB, decrease the release of cytochrome c and bax from mitochondria to the cytosol, and depress the activation of caspase‐3. © 2014 Wiley Periodicals, Inc.
Presynaptic membrane receptors in acetylcholine release modulation in the neuromuscular synapse
Authors: Tomàs Josep , Santafé Manel M. , Garcia Neus , Lanuza Maria A. , Tomàs Marta , Besalduch Núria , Obis Teresa , Priego Mercedes , Hurtado Erica
Published: January 2014

Over the past few years, we have studied, in the mammalian neuromuscular junction (NMJ), the local involvement in transmitter release of the presynaptic muscarinic ACh autoreceptors (mAChRs), purinergic adenosine autoreceptors (P1Rs), and trophic factor receptors (TFRs; for neurotrophins and trophic cytokines) during development and in the adult. At any given moment, the way in which a synapse works is largely the logical outcome of the confluence of these (and other) metabotropic signalling pathways on intracellular kinases, which phosphorylate protein targets and materialize adaptive changes. We propose an integrated interpretation of the complementary function of these receptors in the adult NMJ. The activity of a given receptor group can modulate a given combination of spontaneous, evoked, and activity‐dependent release characteristics. For instance, P1Rs can conserve resources by limiting spontaneous quantal leak of ACh (an A1R action) and protect synapse function, because stimulation with adenosine reduces the magnitude of depression during repetitive activity. The overall outcome of the mAChRs seems to contribute to upkeep of spontaneous quantal output of ACh, save synapse function by decreasing the extent of evoked release (mainly an M2 action), and reduce depression. We have also identified several links among P1Rs, mAChRs, and TFRs. We found a close dependence between mAChR and some TFRs and observed that the muscarinic group has to operate correctly if the tropomyosin‐related kinase B receptor (trkB) is also to operate correctly, and vice versa. Likewise, the functional integrity of mAChRs depends on P1Rs operating normally. © 2014 Wiley Periodicals, Inc.
Effect of the N‐methyl‐D‐aspartate NR2B subunit antagonist ifenprodil on precursor cell proliferation in the hippocampus
Authors: Bunk E.C. , König H.‐G. , Prehn J.H.M. , Kirby B.P.
Published: January 2014

The N‐methyl‐D‐aspartate (NMDA) receptor, one of the ionotropic glutamate receptor, plays important physiological and pathological roles in learning and memory, neuronal development, acute and chronic neurological diseases, and neurogenesis. This work examines the contribution of the NR2B NMDA receptor subunit to adult neurogenesis/cell proliferation under physiological conditions and following an excitotoxic insult. We have previously shown in vitro that a discrete NMDA‐induced, excitotoxic injury to the hippocampus results in an increase in neurogenesis within the dentate gyrus. Here we have characterized adult neurogenesis or proliferation, using BrdU, in an in vivo model of excitotoxic injury to the CA1 subfield of the hippocampus. We demonstrate a peak in neural stem cell proliferation/neurogenesis between 6 and 9 days after the excitotoxic insult. Treatment with ifenprodil, an NR2B subunit‐specific NMDA receptor antagonist, without prior injury induction, also increased the number of BrdU‐positive cells within the DG and posterior periventricle, indicating that ifenprodil itself could modulate the rate of proliferation. Interestingly, though, the increased level of cell proliferation did not change significantly when ifenprodil was administered following an excitotoxic insult. In conclusion, our results suggest and add to the growing evidence that NR2B subunit‐containing NMDA receptors play a role in neural stem cell proliferation. © 2014 Wiley Periodicals, Inc.
Block Copolymer Morphology Formation on Topographically Complex Surfaces: A Self‐Consistent Field Theoretical Study
Authors: Ye Xianggui , Edwards Brian J. , Khomami Bamin
Published: January 2014

A self‐consistent field theoretic study is performed to study morphological development of lamellae‐forming diblock copolymers on substrates with a well‐defined roughness, modeled as trenches of varying depth and width engraved into the substrates. There are three possible lamellar orientations observed: horizontal lamellae, vertical lamellae that are parallel to the trench direction, and vertical lamellae that are perpendicular to the trench direction. Which of these three morphologies formed depends upon the trench width and surface affinity; however, trench depth has a relatively insignificant effect on the morphological development. Therefore, tuning trench width, but not trench depth, should allow for a reduction of the morphological defect density in directed self‐assembly of lamellar morphology of diblock copolymers.

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19F DOSY NMR analysis for spin systems with nJFF couplings
Authors: Dal Poggetto Guilherme , Favaro Denize C. , Nilsson Mathias , Morris Gareth A. , Tormena Cláudio F.
Published: January 2014

NMR is a powerful method for identification and quantification of drug components and contaminations. These problems present themselves as mixtures, and here, one of the most powerful tools is DOSY. DOSY works best when there is no spectral overlap between components, so drugs containing fluorine substituents are well‐suited for DOSY analysis as 19F spectra are typically very sparse. Here, we demonstrate the use of a modified 19F DOSY experiment (on the basis of the Oneshot sequences) for various fluorinated benzenes. For compounds with significant nJFF coupling constants, as is common, the undesirable J‐modulation can be efficiently suppressed using the Oneshot45 pulse sequence. This investigation highlights 19F DOSY as a valuable and robust method for analysis of molecular systems containing fluorine atoms even where there are large fluorine–fluorine couplings. Copyright © 2014 John Wiley & Sons, Ltd.
Diffusion magnetic resonance monitors intramyocellular lipid droplet size in vivo
Authors: Cao Peng , Fan Shu‐Juan , Wang Anna M. , Xie Victor B. , Qiao Zhongwei , Brittenham Gary M. , Wu Ed X.
Published: January 2014

Purpose

Intramyocellular lipid (IMCL) droplets are dynamic organelles whose morphology reflects their vital roles in lipid synthesis, usage, and storage in muscle energy metabolism. To develop noninvasive means to measure droplet microstructure in vivo, we investigated the molecular diffusion behavior of IMCL with diffusion magnetic resonance spectroscopy.

Methods

Using extremely large diffusion weighting, we measured the IMCL apparent diffusion coefficients (ADCs) in hindlimb muscle of rodents from normal feeding, 60‐h fasting, streptozotocin‐induced diabetic, and high‐fat‐diet‐induced obese groups.

Results

IMCL ADCs decreased markedly with diffusion time, confirming the restricted diffusion of lipid molecules within IMCL droplets. IMCL droplet size, determined by transmission electron microscopy, was closely correlated with ADC. IMCL ADC was sensitive to metabolic alterations, decreasing in the 60‐h fasting and diabetic groups while increasing in the obese group. These findings indicated that the IMCL droplet size decreased following 60‐h fasting and in STZ‐induced diabetes but increased in high‐fat‐diet‐induced obesity.

Conclusion

MR diffusion characterization of IMCL droplet size provides a unique means to examine the intracellular lipid dynamics and metabolic abnormalities in vivo. Magn Reson Med 73:59–69, 2015. © 2014 Wiley Periodicals, Inc.
Ophthalmic adverse drug reactions to systemic drugs: a systematic review
Authors: Miguel Ana , Henriques Filipe , Azevedo Luís Filipe , Pereira Altamiro Costa
Published: January 2014

Purpose

To perform a comprehensive and systematic review regarding ophthalmic adverse drug reactions (ADRs) to systemic drugs to: (i) systematically summarize existing evidence, (ii) identify areas, ophthalmic ADRs or drugs that lacked systematization or assessment (namely drugs with original studies characterizing specific ophthalmic ADRs but without causality assessment nor without meta‐analysis).

Methods

Systematic review of several electronic databases (last search 1/7/2012): Medline, SCOPUS, ISI web of knowledge, ISI Conference Proceedings, International Pharmaceutical Abstracts and Google scholar. Search query included: eye, ocular, ophthalmic, ophthalmology, adverse and reaction. Inclusion criteria were: (i) Primary purpose was to assess an ophthalmic ADR to a systemic medication; (ii) Patient evaluation performed by an ophthalmologist; (iii) Studies that specified diagnostic criteria for an ocular ADR. Different types of studies were included and analyzed separately. Two independent reviewers assessed eligibility criteria, extracted data and evaluated risk of bias.

Results

From 562 studies found, 32 were included (1 systematic review to sildenafil, 11 narrative reviews, 1 trial, 1 prospective study, 6 transversal studies, 6 spontaneous reports and 6 case series). Drugs frequently involved included amiodarone, sildenafil, hydroxychloroquine and biphosphonates. Frequent ophthalmic ADRs included: keratopathy, dry eye and retinopathy.

Conclusions

To increase evidence about ophthalmic ADRs, there is a need for performing specific systematic reviews, applying strictly the World Health Organization's (WHO) definition of ADR and WHO causality assessment of ADRs.

Some ophthalmic ADRs may be frequent, but require ophthalmological examination; therefore, ophthalmologists' education and protocols of collaboration between other specialties whenever they prescribe high‐risk drugs are suggestions for the future. Copyright © 2014 John Wiley & Sons, Ltd.
Origin of the blackhole information paradox
Authors: Brustein R.
Published: January 2014

It is argued that the blackhole information paradox originates from treating the blackhole geometry as strictly classical. It is further argued that the theory of quantum fields in a classical curved space with a horizon is an ill posed problem. If the geometry is allowed to fluctuate quantum mechanically, then the horizon effectively disappears. The sharp horizon emerges only in the classical limit when the ratio of the Compton wavelength of the black hole to its Schwarzschild radius vanishes. The region of strong gravity that develops when matter collapses to form the blackhole remains visible to the whole of spacetime and has to be described by a microscopic theory of strong gravity. The arguments imply that the information paradox is demoted from a paradox involving fundamental principles of physics to the problem of describing how matter at the highest densities gravitates.
Crystal structures of the archaeal UDP‐GlcNAc 2‐epimerase from Methanocaldococcus jannaschii reveal a conformational change induced by UDP‐GlcNAc
Authors: Chen Sheng‐Chia , Huang Chi‐Hung , Shin Yang Chia , Liu Jai‐Shin , Kuan Shu‐Min , Chen Yeh
Published: January 2014

Uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) 2‐epimerase catalyzes the interconversion of UDP‐GlcNAc to UDP‐N‐acetylmannosamine (UDP‐ManNAc), which is used in the biosynthesis of cell surface polysaccharides in bacteria. Biochemical experiments have demonstrated that mutation of this enzyme causes changes in cell morphology and the thermoresistance of the cell wall. Here, we present the crystal structures of Methanocaldococcus jannaschii UDP‐GlcNAc 2‐epimerase in open and closed conformations. A comparison of these crystal structures shows that upon UDP and UDP‐GlcNAc binding, the enzyme undergoes conformational changes involving a rigid‐body movement of the C‐terminal domain. We also present the crystal structure of Bacillus subtilis UDP‐GlcNAc 2‐epimerase in the closed conformation in the presence of UDP and UDP‐GlcNAc. Although a structural overlay of these two closed‐form structures reveals that the substrate‐binding site is evolutionarily conserved, some areas of the allosteric site are distinct between the archaeal and bacterial UDP‐GlcNAc 2‐epimerases. This is the first report on the crystal structure of archaeal UDP‐GlcNAc 2‐epimerase, and our results clearly demonstrate the changes between the open and closed conformations of this enzyme. Proteins 2014; 82:1519–1526. © 2014 Wiley Periodicals, Inc.
Photoresponse of pentacene‐based transistors
Authors: Loffredo Fausta , Bruno Annalisa , Del Mauro Anna De Girolamo , Grimaldi Immacolata Angelica , Miscioscia Riccardo , Nenna Giuseppe , Pandolfi Giuseppe , Petrosino Mario , Villani Fulvia , Minarini Carla , Facchetti Antonio
Published: January 2014

Organic thin film phototransistor (OPTs) devices in bottom‐gate/top‐contact configuration were fabricated and used as analytic system to study the electrical and optical properties of pentacene. The channel of the OTFT devices was illuminated by laser radiation of wavelength 670 nm and the effect of irradiation on the electrical responses of the devices was investigated at different temperatures and incident optical powers. The photoresponse and the electrical parameters of the devices (mobility, threshold voltages and on/off ratios – ION/IOFF) were evaluated in order to investigate the relationship between the light sensing behavior of the phototransistors and their electrical performances. Moreover, the OPT's time‐resolved electrical response to light irradiation was modelled to decouple the fast‐varying photoexcitation effects from slow bias stress decays in order to investigate the reversibility properties, the time stability of electrical responses and the photocurrent.
Adaptive output feedback tracking control of stochastic nonlinear systems with dynamic uncertainties
Authors: Zhang Tianping , Xia Xiaonan
Published: January 2014

In this paper, adaptive output feedback tracking control is developed for a class of stochastic nonlinear systems with dynamic uncertainties and unmeasured states. Neural networks are used to approximate the unknown nonlinear functions. K‐filters are designed to estimate the unmeasured states. An available dynamic signal is introduced to dominate the unmodeled dynamics. By combining dynamic surface control technique with backstepping, the condition in which the approximation error is assumed to be bounded is avoided. Using It ô formula and Chebyshev's inequality, it is shown that all signals in the closed‐loop system are bounded in probability, and the error signals are semi‐globally uniformly ultimately bounded in mean square or the sense of four‐moment. Simulation results are provided to illustrate the effectiveness of the proposed approach. Copyright © 2014 John Wiley & Sons, Ltd.
Competing designs for drug combination in phase I dose‐finding clinical trials
Authors: Riviere M.‐K. , Dubois F. , Zohar S.
Published: January 2014

The aim of phase I combination dose‐finding studies in oncology is to estimate one or several maximum tolerated doses (MTDs) from a set of available dose levels of two or more agents. Combining several agents can indeed increase the overall anti‐tumor action but at the same time also increase the toxicity. It is, however, unreasonable to assume the same dose–toxicity relationship for the combination as for the simple addition of each single agent because of a potential antagonist or synergistic effect. Therefore, using single‐agent dose‐finding methods for combination therapies is not appropriate.

In recent years, several authors have proposed novel dose‐finding designs for combination studies, which use either algorithm‐based or model‐based methods. The aim of our work was to compare, via a simulation study, six dose‐finding methods for combinations proposed in recent years. We chose eight scenarios that differ in terms of the number and location of the true MTD(s) in the combination space. We then compared the performance of each design in terms of correct combination selection, patient allocation, and mean number of observed toxicities during the trials. Our results showed that the model‐based methods performed better than the algorithm‐based ones. However, none of the compared model‐based designs gave consistently better results than the others. Copyright © 2014 John Wiley & Sons, Ltd.
Optimal planning of soft starter for large drain motor based on simulated annealing method
Authors: Chou Chih‐Ju , Lee Chun‐Yao , Chen Chun‐Chi , Chen Chao‐Rong , Chen Mu‐Cheng
Published: January 2014

This paper proposes the optimal planning of soft starter characteristics for a large drain motor based on simulated annealing (SA). First, the planning of the soft starter characteristics is formulated as an optimization problem with minimal motor starting time; then, the constraints of the motor starting energy, power quality requirements, and minimal cost of transmission line are constructed. The system framework of an actual case in Taiwan is used as the basis of this study with simulation. Before and after the installation of three sets of soft starters, measuring instruments are used in the ﬁeld to investigate the changes of current and voltage during the motor starting, thus establishing the database of current swell and voltage sag. The searching algorithm based on the SA method is developed by the program MATLAB, such that the soft starter can regulate the minimal motor starting time and meet the above‐mentioned constraints. According to the model of the system circuit and the characteristic parameters constructed by an actual case, the simulation results verify the superiority of the proposed SA method. © 2014 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.