bluuebunny/crossref_metadata_2025 huggingface dataset:
Tectonic evolution of the Sibumasu–Indochina terrane collision zone in Thailand and Malaysia: constraints from new U–Pb zircon chronology of SE Asian tin granitoids
Authors: Searle M. P. , Whitehouse M. J. , Robb L. J. , Ghani A. A. , Hutchison C. S. , Sone M. , Ng S. W.-P. , Roselee M. H. , Chung S.-L. , Oliver G. J. H.
Published: July 2012

Three principal granite provinces are defined across SE Asia, as follows. (1) The Western Thailand–Myanmar/Burma province consists of hornblende–biotite I-type granodiorite–granites and felsic biotite–K-feldspar (± garnet ± tourmaline) granites associated with abundant tin mineralization in greisen-type veins. New ion microprobe U–Pb dating results from Phuket Island show zircon core ages of 212 ± 2 and 214 ± 2 Ma and a thermal overprint with rims of 81.2 ± 1.2 and 85–75 Ma. (2) The North Thailand–West Malaya Main Range province has mainly S-type biotite granites and abundant tin mineralization resulting from crustal thickening following collision of the Sibumasu plate with Indochina during the Mid-Triassic. Biotite granites around Kuala Lumpur contain extremely U-rich zircons (up to 38000 ppm) that yield ages of 215 ± 7 and 210 ± 7 Ma. (3) The East Malaya province consists of dominantly Permian–Triassic I-type hornblende–biotite granites but with subordinate S-type plutons and A-type syenite–gabbros. Biotite–K-feldspar granites from Tioman Island off the east coast of Malaysia also yield a zircon age of 80 ± 1 Ma, showing Cretaceous magmatism in common with province 1. Geological and U–Pb geochronological data suggest that two east-dipping (in present-day coordinates) subduction zones are required during the Triassic, one along the Bentong–Raub Palaeo-Tethyan suture, and the other west of the Phuket–Burma province 1 belt.

Supplementary material:

A full description of U–Pb analytical methods used and data tables are available at
www.geolsoc.org.uk/SUP18523
.
Facies and ichnology of an Upper Cretaceous chalk contourite drift complex, eastern Denmark, and the validity of contourite facies models
Authors: Rasmussen Susanne Lil , Surlyk Finn
Published: July 2012

The Upper Cretaceous chalk of the Danish Basin has been interpreted as a major contourite complex on the basis of high-resolution seismic data. The sea floor had a pronounced topography with kilometre-wide ridges and valleys up to almost 200 m deep, interpreted to have been formed by contour-parallel bottom currents. Only few ancient contourite systems have been recognized, mainly based on sedimentary facies and only rarely on architecture and morphology. Two cored boreholes, 345 and 443.3 m deep through the Danish chalk contourite complex, offer a unique possibility to compare seismic and sedimentary facies. The contourite chalk is completely bioturbated except for thin intraclast conglomerates and a few thin levels, showing possible primary lamination. In terms of lithology and trace fossils the contourite chalk is similar to horizontally bedded pelagic chalk uninfluenced by bottom currents. Published contourite models cannot normally be used for the chalk because of the very fine grain size, generally complete bioturbation, and lack of any vertical trends in grain size on a millimetre to centimetre scale. It is thus only rarely possible to document the influence of bottom currents on the basis of facies analysis alone and this can be inferred only by architectural analysis of seismic-scale outcrops.
Thermal structure of supra-detachment basins: a case study of the Devonian basins of western Norway
Authors: Souche Alban , Beyssac Olivier , Andersen Torgeir B.
Published: July 2012

We investigate the peak temperatures of the Devonian Hornelen, Kvamshesten and Solund basins in SW Norway to constrain their thermal history. These basins are the three largest Devonian units exposed in Norway and were formed as supra-detachment basins in the hangingwall of the Nordfjord Sogn Detachment Zone. The peak temperatures of the basins were obtained using a geothermometer based on Raman spectroscopy of carbonaceous material on detrital carbonaceous plant fossils. The data confirm an anchizone to low greenschist-facies metamorphism with temperatures (±30 °C) of 284–301 °C in the Hornelen and Solund basins and a significantly higher temperature, 345 °C in the Kvamshesten basin. The temperature increases toward the detachment fault and cannot be explained by ordinary burial alone. In the Kvamshesten basin this temperature increase is close to 100 °C. The new data demonstrate that exhumation of high-grade rocks in the footwall in the Nordfjord Sogn Detachment Zone played an important role in controlling temperatures in the hangingwall. We conclude that the dynamic evolution along large-scale detachments may introduce heat at the base of the hangingwall and thereby control the thermal state of supra-detachment basins formed during extension.
Transcriptomine, a web resource for nuclear receptor signaling transcriptomes
Authors: Ochsner Scott A. , Watkins Christopher M. , McOwiti Apollo , Xu Xueping , Darlington Yolanda F. , Dehart Michael D. , Cooney Austin J. , Steffen David L. , Becnel Lauren B. , McKenna Neil J.
Published: July 2012

The nuclear receptor (NR) superfamily of ligand-regulated transcription factors directs ligand- and tissue-specific transcriptomes in myriad developmental, metabolic, immunological, and reproductive processes. The NR signaling field has generated a wealth of genome-wide expression data points, but due to deficits in their accessibility, annotation, and integration, the full potential of these studies has not yet been realized. We searched public gene expression databases and MEDLINE for global transcriptomic datasets relevant to NRs, their ligands, and coregulators. We carried out extensive, deep reannotation of the datasets using controlled vocabularies for RNA Source and regulating molecule and resolved disparate gene identifiers to official gene symbols to facilitate comparison of fold changes and their significance across multiple datasets. We assembled these data points into a database, Transcriptomine ( http://www.nursa.org/transcriptomine ), that allows for multiple, menu-driven querying strategies of this transcriptomic “superdataset,” including single and multiple genes, Gene Ontology terms, disease terms, and uploaded custom gene lists. Experimental variables such as regulating molecule, RNA Source, as well as fold-change and P value cutoff values can be modified, and full data records can be either browsed or downloaded for downstream analysis. We demonstrate the utility of Transcriptomine as a hypothesis generation and validation tool using in silico and experimental use cases. Our resource empowers users to instantly and routinely mine the collective biology of millions of previously disparate transcriptomic data points. By incorporating future transcriptome-wide datasets in the NR signaling field, we anticipate Transcriptomine developing into a powerful resource for the NR- and other signal transduction research communities.
Early Degenerative Effects of Diabetes Mellitus on Pancreas, Liver, and Kidney in Rats: An Immunohistochemical Study
Authors: Haligur Mehmet , Topsakal Senay , Ozmen Ozlem
Published: July 2012

Liver and kidney commonly affected by diabetes in chronic cases but pathogenetic mechanisms are not fully understood in early stages of the disease. The aim of this study was to investigate the immunohistochemical expression of caspase-3, cyclooxygenase (COX)-1 and-2, calcium sensing receptor (CSR), and hypoxia inducible factor-1α(HIF-1α) in pancreas, liver, and kidney in streptozotocin (STZ) induced DM. Study group (n= 6) were received streptozotocin (50 mg/kg) and control group (n= 6) physiologic saline. The blood glucose and ketonuria were measured, and necropsy was performed on them on third, fourth, and fifth days. Immunohistochemistry revealed that marked increase in caspase-3 reaction pancreas, liver, and kidney in the study group than control group. COX-1 slightly increased in these organs in study group compared to controls. Immunohistochemically COX-2 reaction was markedly positive in liver and kidney, but slightly increased in pancreas. The most increased reaction was observed in CRS and all organs were markedly positive. HIF-1αexpression was also increased but the reaction was more severe in pancreas than liver and kidney. This study indicated that degeneration starts in organs in early stages of the disease and the most effective route for degeneration related to increase of calcium influx and hypoxia upon cells in DM.
On Extreme Residual Lives after the Failure of the System
Authors: Eryilmaz Serkan , Bayramoglu Ismihan
Published: July 2012

The concept of residual lifetime has attracted considerable research interest in reliability theory. It is useful for evaluating the dynamic behavior of a system. In this paper, we study the extreme residual lives, that is, the minimum and maximum residual lives of the remaining components after the failure of the system. The system is assumed to have an arbitrary structure. We obtain signature‐based distributional and ordering results for the extreme residual lives.
Polystyrene Backbone Polymers Consisting of Alkyl-Substituted Triazine Side Groups for Phosphorescent OLEDs
Authors: Salert Beatrice Ch. D. , Wedel Armin , Grubert Lutz , Eberle Thomas , Anémian Rémi , Krueger Hartmut
Published: July 2012

This paper describes the synthesis of new electron-transporting styrene monomers and their corresponding polystyrenes all with a 2,4,6-triphenyl-1,3,5-triazine basic structure in the side group. The monomers differ in the alkyl substitution and in the meta-/paralinkage of the triazine to the polymer backbone. The thermal and spectroscopic properties of the new electron-transporting polymers are discussed in regard to their chemical structures. Phosphorescent OLEDs were prepared using the obtained electron-transporting polymers as the emissive layer material in blend systems together with a green iridium-based emitter13and a small molecule as an additional cohost with wideband gap characteristics (CoH-001). The performance of the OLEDs was characterized and discussed in regard to the chemical structure of the new electron-transporting polymers.
The Modified Block Iterative Algorithms for Asymptotically Relatively Nonexpansive Mappings and the System of Generalized Mixed Equilibrium Problems
Authors: Wattanawitoon Kriengsak , Kumam Poom
Published: July 2012

The propose of this paper is to present a modified block iterative algorithm for finding a common element between the set of solutions of the fixed points of two countable families of asymptotically relatively nonexpansive mappings and the set of solution of the system of generalized mixed equilibrium problems in a uniformly smooth and uniformly convex Banach space. Our results extend many known recent results in the literature.
Performance of a 1 kW Class Nafion-PTFE Composite Membrane Fuel Cell Stack
Authors: Krishnamurthy Pattabiraman , Krishnan Ramya , Kaveripatnam Samban Dhathathreyan
Published: July 2012

Composite membranes have been prepared by impregnation of Nafion into the expanded polytetrafluoroethylene (EPTFE) matrix. Nafion loading in the composite membranes was kept constant at 2 mg/cm2. The lower amount of electrolyte per unit area in the composite membranes offers cost advantages compared to conventional membrane of 50 μm thickness with an electrolyte loading of~9 mg/cm2. Composite membranes (30 μm thickness) were found to have higher thermal stability and mechanical strength compared to the conventional membranes (50 μm thickness). The performance of the membrane electrode assembly made with these composite membranes was comparable to that of the conventional membranes. Single cells fabricated from these MEAs were tested for their performance and durability before scaling them up for large area. The performance of a 20-cell stack of active area 330 cm2fabricated using these membranes is reported.
Preeclampsia 2012
Authors: Eiland Elosha , Nzerue Chike , Faulkner Marquetta
Published: July 2012

Preeclampsia is a common complication of pregnancy associated with high maternal morbidity and mortality and intrauterine fetal growth restriction. There is extensive evidence that the reduction of uteroplacental blood flow in this syndrome results from the toxic combination of hypoxia, imbalance of angiogenic and antiangiogenic factors, inflammation, and deranged immunity. Women treated for preeclampsia also have an increased risk for cardiovascular and renal disease. At present it is unclear if the increased cardiovascular and renal disease risks are due to residual and or progressive effects of endothelial damage from the preeclampsia or from shared risk factors between preeclampsia and cardiac disease. Moreover, it appears that endothelin-1 signaling may play a central role in the hypertension associated with preeclampsia. In this paper, we discuss emerging data on the pathogenesis of preeclampsia and review therapeutic options.
Pediatric Multiple Sclerosis—A Challenging Demyelinating Disease: Case Report and Brief Review of the Literature
Authors: de Albuquerque Regina Célia Ajeje Pires , de Paula Raquel Siqueira Leonel , Brito Manuelina Mariana Capellari Macruz , Filho José Roberto Lopes Ferraz , Meguins Lucas Crociati
Published: July 2012

Multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) of unknown etiology. The peak onset is between age 20 and 40 years and usually affects more women than men. Although much knowledge has been achieved on the diagnosis and treatment of adult patients with MS, it remains a matter of debate and controversy in childhood. We present a case of MS in 9-year-old girl, review the current state of the knowledge on pediatric MS, and discuss the available tools for the diagnosis and treatment.
Repeated Evolution of Testis-Specific New Genes: The Case of Telomere-Capping Genes inDrosophila
Authors: Dubruille Raphaëlle , Marais Gabriel A. B. , Loppin Benjamin
Published: July 2012

Comparative genome analysis has allowed the identification of various mechanisms involved in gene birth. However, understanding the evolutionary forces driving new gene origination still represents a major challenge. In particular, an intriguing and not yet fully understood trend has emerged from the study of new genes: many of them show a testis-specific expression pattern, which has remained poorly understood. Here we review the case of such a new gene, which involves a telomere-capping gene family inDrosophila. hiphopand its testis-specific paralogK81are critical for the protection of chromosome ends in somatic cells and male gametes, respectively. Two independent functional studies recently proposed that these genes evolved under a reproductive-subfunctionalization regime. The 2011 release of newDrosophilagenome sequences from themelanogastergroup of species allowed us to deepen our phylogenetic analysis of thehiphop/K81family. This work reveals an unsuspected dynamic of gene birth and death within the group, with recurrent duplication events through retroposition mechanisms. Finally, we discuss the plausibility of different evolutionary scenarios that could explain the diversification of this gene family.
Mycobacterium aviumsubsp.paratuberculosisin an Italian Cohort of Type 1 Diabetes Pediatric Patients
Authors: Manca Bitti Maria Luisa , Masala Speranza , Capasso Francesca , Rapini Novella , Piccinini Simona , Angelini Federica , Pierantozzi Andrea , Lidano Roberta , Pietrosanti Silvia , Paccagnini Daniela , Sechi Leonardo A.
Published: July 2012

Mycobacterium avium subsp. paratuberculosis(MAP) is the etiological agent of Johne’s disease in ruminants. Recent studies have linked MAP to type 1 diabetes (T1D) in the Sardinian population. The aim of this study was to investigate the prevalence of MAP infection in a T1D cohort from continental Italy compared with healthy control subjects. 247 T1D subjects and 110 healthy controls were tested for the presence of MAP. MAP DNA was detected using IS900-specific polymerase chain reaction (PCR). The presence of antibodies towards a MAP antigen, heparin binding hemoagglutinin (HBHA), was detected by ELISA. We demonstrated a higher MAP DNA prevalence in plasma samples from T1D patients and a stronger immune response towards MAP HBHA, compared with healthy control subjects. Moreover, in the recent onset patients, we observed an association between anti-MAP antibodies and HLA DQ2 (DQA1 0201/DQB1 0202). These findings taken together support the hypothesis of MAP as an environmental risk factor for the development of T1D in genetically predisposed subjects, probably involving a mechanism of molecular mimicry between MAP antigens and pancreatic isletβ-cells.
Mobile Sensor Waypoint Navigation via RF-Based Angle of Arrival Localization
Authors: Amundson Isaac , Sallai Janos , Koutsoukos Xenofon , Ledeczi Akos
Published: July 2012

Over the past decade, wireless sensor networks have advanced in terms of hardware design, communication protocols, and resource efficiency. Recently, there has been growing interest in mobility, and several small-profile sensing devices that control their own movement have been developed. Unfortunately, resource constraints inhibit the use of traditional navigation methods because these typically require bulky, expensive sensors, substantial memory, and a generous power supply. Therefore, alternative navigation techniques are required. In this paper, we present a navigation system implemented entirely on resource-constrained sensors. Localization is realized using triangulation in conjunction with radio interferometric angle-of-arrival estimation. A digital compass is employed to keep the mobile node on the desired trajectory. We also present a variation of the approach that uses a Kalman filter to estimate heading without using the compass. We demonstrate that a resource-constrained mobile sensor can accurately perform waypoint navigation with an average position error of 0.95 m.
An Overview of Molecular Mechanism of Nephrotic Syndrome
Authors: Machado Juliana Reis , Rocha Laura Penna , Neves Precil Diego Miranda de Menezes , Cobô Eliângela de Castro , Silva Marcos Vinícius , Castellano Lúcio Roberto , Corrêa Rosana Rosa Miranda , Reis Marlene Antônia
Published: July 2012

Podocytopathies (minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS)) together with membranous nephropathy are the main causes of nephrotic syndrome. Some changes on the expression of nephrin, podocin, TGF-β, and slit diaphragm components as well as transcription factors and transmembrane proteins have been demonstrated in podocytopathies. Considering the pathogenesis of proteinuria, some elucidations have been directed towards the involvement of epithelial-mesenchymal transition. Moreover, the usefulness of some markers such as TGF-β1, nephrin, synaptopodin, dystroglycans, and malondialdehyde have been determined in the differentiation between MCD and FSGS. Experimental models and human samples indicated an essential role of autoantibodies in membranous glomerulonephritis, kidney damage, and proteinuria events. Megalin and phospholipase-A2-receptor have been described as antigens responsible for the formation of the subepithelial immune complexes and renal disease occurrence. In addition, the complement system seems to play a key role in basal membrane damage and in the development of proteinuria in membranous nephropathy. This paper focuses on the common molecular changes involved in the development of nephrotic proteinuria.
A Fatal Case of Nafcillin-Induced Hepatotoxicity: A Case Report and the Literature Review
Authors: Alam Mian Bilal , Kadoura Amin , Sathaiah Magesh
Published: July 2012

Background. Drug-induced hepatotoxicity (DIH) is quite common, and there are several recommendations for its treatment based upon its etiology. DIH may range from mild and subclinical to fulminant liver failure and death. Even though there is extensive list of drugs causing DIH, antibiotics, as a class of drugs, are the most common cause of DIH. Here, we present a fatal case of nafcillin-induced hepatotoxicity confirmed by liver biopsy, with total bilirubin peaking to 21.8 mg/dl and subsequent further extensive evaluation for hepatic injury turning out to be negative.
ATP-Citrate Lyase: A Key Player in Cancer Metabolism
Authors: Zaidi Nousheen , Swinnen Johannes V. , Smans Karine
Published: July 2012

ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes the generation of acetyl CoA from citrate. Acetyl CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. Acetyl CoA is also required for acetylation reactions that modify proteins, such as histone acetylation. ACLY is upregulated or activated in several types of cancers, and its inhibition is known to induce proliferation arrest in cancer cells both in vitro and in vivo. The present review highlights current knowledge about the role of ACLY in cancer cells, with special reference to the different pathways that are linked by ACLY. Cancer Res; 72(15); 3709–14. ©2012 AACR.
AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity
Authors: Yap Timothy A. , Walton Mike I. , Grimshaw Kyla M. , te Poele Robert H. , Eve Paul D. , Valenti Melanie R. , de Haven Brandon Alexis K. , Martins Vanessa , Zetterlund Anna , Heaton Simon P. , Heinzmann Kathrin , Jones Paul S. , Feltell Ruth E. , Reule Matthias , Woodhead Steven J. , Davies Thomas G. , Lyons John F. , Raynaud Florence I. , Eccles Suzanne A. , Workman Paul , Thompson Neil T. , Garrett Michelle D.
Published: July 2012

Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component.

Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148.

Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed.

Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial. Clin Cancer Res; 18(14); 3912–23. ©2012 AACR.
An In Vivo Immunotherapy Screen of Costimulatory Molecules Identifies Fc-OX40L as a Potent Reagent for the Treatment of Established Murine Gliomas
Authors: Murphy Katherine A. , Lechner Melissa G. , Popescu Flavia E. , Bedi Jessica , Decker Stacy A. , Hu Peisheng , Erickson Jami R. , O'Sullivan M. Gerard , Swier Lauryn , Salazar Andres M. , Olin Michael R. , Epstein Alan L. , Ohlfest John R.
Published: July 2012

Purpose: We tested the combination of a tumor lysate vaccine with a panel of costimulatory molecules to identify an immunotherapeutic approach capable of curing established murine gliomas.

Experimental Design: Glioma-bearing mice were primed with a tumor lysate vaccine, followed by systemic administration of the following costimulatory ligands: OX40L, CD80, 4-1BBL, and GITRL, which were fused to the Fc portion of human immunoglobulin. Lymphocytes and mRNA were purified from the brain tumor site for immune monitoring studies. Numerous variations of the vaccine and Fc-OX40L regimen were tested alone or in combination with temozolomide.

Results: Lysate vaccinations combined with Fc-OX40L led to the best overall survival, yielding cure rates of 50% to 100% depending on the timing, regimen, and combination with temozolomide. Cured mice that were rechallenged with glioma cells rejected the challenge, showing immunologic memory. Lymphocytes isolated from the draining lymph nodes of vaccine/Fc-OX40L–treated mice had superior tumoricidal function relative to all other groups. Vaccine/Fc-OX40L–treated mice exhibited a significant increase in proliferation of brain-infiltrating CD4 and CD8 T cells, as indicated by Ki67 staining. Fc-OX40L had single-agent activity in transplanted and spontaneous glioma models, and the pattern of inflammatory gene expression in the tumor predicted the degree of therapeutic response.

Conclusions: These data show that Fc-OX40L has unique and potent activity against experimental gliomas and warrants further testing. Clin Cancer Res; 18(17); 4657–68. ©2012 AACR.
First Evidence of Sphingosine 1-Phosphate Lyase Protein Expression and Activity Downregulation in Human Neoplasm: Implication for Resistance to Therapeutics in Prostate Cancer
Authors: Brizuela Leyre , Ader Isabelle , Mazerolles Catherine , Bocquet Magalie , Malavaud Bernard , Cuvillier Olivier
Published: July 2012

This is the first report of sphingosine 1-phosphate lyase (SPL) protein expression and enzymatic activity in human neoplasm. This enzyme drives irreversible degradation of sphingosine 1-phosphate (S1P), a bioactive lipid associated with resistance to therapeutics in various cancers, including prostate adenocarcinoma. In fresh human prostatectomy specimens, a remarkable decrease in SPL enzymatic activity was found in tumor samples, as compared with normal adjacent tissues. A significant relationship between loss of SPL expression and higher Gleason score was confirmed in tissue microarray (TMA) analysis. Moreover, SPL protein expression and activity were inversely correlated with those of sphingosine kinase-1 (SphK1), the enzyme producing S1P. SPL and SphK1 expressions were independently predictive of aggressive cancer on TMA, supporting the relevance of S1P in prostate cancer. In human C4-2B and PC-3 cell lines, silencing SPL enhanced survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. In contrast, enforced expression of SPL sensitized cancer cells to irradiation or docetaxel by tilting the ceramide/S1P balance toward cell death. Interestingly, the S1P degradation products failed to sensitize to chemo- and radiotherapy, supporting the crucial role of ceramide/S1P balance in cancer. Of note, the combination of SPL enforced expression with a SphK1 silencing strategy by further decreasing S1P content made prostate cancer cells even more sensitive to anticancer therapies, suggesting that a dual strategy aimed at stimulating SPL, and inhibiting SphK1 could represent a future approach to sensitize cancer cells to cancer treatments. Mol Cancer Ther; 11(9); 1841–51. ©2012 AACR.
Cell Intrinsic Role of COX-2 in Pancreatic Cancer Development
Authors: Hill Reginald , Li Yunfeng , Tran Linh M. , Dry Sarah , Calvopina Joseph Hargan , Garcia Alejandro , Kim Christine , Wang Ying , Donahue Timothy R. , Herschman Harvey R. , Wu Hong
Published: July 2012

COX-2 is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of nonsteroidal anti-inflammatory drugs (NSAID) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic versus microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 overexpression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 overexpression increases p-AKT levels in the precursor lesions of Pdx1+; K-rasG12D/+; Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes p-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. Mol Cancer Ther; 11(10); 2127–37. ©2012 AACR.
SLC45A3-ELK4 Chimera in Prostate Cancer: Spotlight on cis-Splicing
Authors: Kumar-Sinha Chandan , Kalyana-Sundaram Shanker , Chinnaiyan Arul M.
Published: July 2012

Summary: Using a series of detailed experiments, Zhang and colleagues establish that the prostate cancer RNA chimera SLC45A3-ELK4 is generated by cis-splicing between the 2 adjacent genes and does not involve DNA rearrangements or trans-splicing. The chimera expression is induced by androgen treatment likely by overcoming the read-through block imposed by the intergenic CCCTC insulators bound by CCCTC-binding factor repressor protein. The chimeric transcript, but not wild-type ELK4, is shown to augment prostate cancer cell proliferation. Cancer Discov; 2(7); 582–5. ©2012 AACR.

Commentary on Zhang et al., p. 598.
Long-Term Outcome of Polymyositis Treated with High Single-Dose Alternate-Day Prednisolone Therapy
Authors: Uchino Makoto , Yamashita Satoshi , Uchino Katsuhisa , Hara Akio , Koide Tatsuya , Suga Tomohiro , Hirahara Tomoo , Kimura En , Yamashita Taro , Ueda Akihiko , Kurisaki Ryoichi , Suzuki Junko , Honda Shoji , Maeda Yasushi , Hirano Teruyuki
Published: July 2012

Background: We previously reported no difference in the efficacies of high-dose alternate-day (ADT) and daily-dose (DDT) prednisolone therapies in myositis patients, but that the incidence of side effects was lower in the former. The aim of the present study was to compare the long-term outcomes of both treatments in polymyositis patients. Methods: We compared clinical courses, efficacies, adverse reactions, and outcomes of 115 consecutive, biopsy-proven polymyositis patients treated between 1970 and 2008 with ADT (32 patients) or DDT (83 patients). Results: Mean onset ages, disease severity, incidences of malignancy, and response rates did not differ between the ADT and DDT groups. Adverse reactions (incidence of diabetes) were significantly higher in the DDT group. In this group, the incidences of hyperlipidemia, infection, hypertension, and psychiatric symptoms were also slightly higher, but not significantly so. The 20-year survival rate of the ADT group (68%) was significantly higher (p = 0.0112) than that of the DDT group (37%). Conclusion: ADT might be useful as an initial treatment option for polymyositis.
Clinical Implication of Targeting of Cancer Stem Cells
Authors: Zhao L. , Zhao Y. , Bao Q. , Niess H. , Jauch K.-W. , Bruns C.J.
Published: July 2012

The existence of cancer stem cells (CSCs) is receiving increasing interest particularly due to its potential ability to enter clinical routine. Rapid advances in the CSC field have provided evidence for the development of more reliable anticancer therapies in the future. CSCs typically only constitute a small fraction of the total tumor burden; however, they harbor self-renewal capacity and appear to be relatively resistant to conventional therapies. Recent therapeutic approaches aim to eliminate or differentiate CSCs or to disrupt the niches in which they reside. Better understanding of the biological characteristics of CSCs as well as improved preclinical and clinical trials targeting CSCs may revolutionize the treatment of many cancers.
First Evidence for Family-Specific QTL for Temperature-Dependent Sex Reversal in Nile Tilapia (Oreochromis niloticus)
Authors: Lühmann L.M. , Knorr C. , Hörstgen-Schwark G. , Wessels S.
Published: July 2012

This study for the first time screens microsatellite markers for associations with the temperature-dependent sex of Oreochromis niloticus. Previous studies revealed markers on linkage groups (LG) 1, 3, and 23 to be linked to the phenotypic sex of Oreochromis spp. at normal rearing temperatures. Moreover, candidate genes for sex determination and differentiation have been mapped to these linkage groups. Here, 6 families of a temperature-treated genetically all-female (XX) F1-population were genotyped for 21 microsatellites on the 3 LGs. No population-wide QTL (quantitative trait loci) or marker trait associations could be detected. However, family-specific QTL were found on LG 1 flanked by UNH995 and UNH104, on LG 3 at the position of GM213, and on LG 23 next to GM283. Moreover, family-specific single marker associations for UNH995 and UNH104 on LG 1, GM213 on LG 3, as well as for UNH898 and GM283 on LG 23 were detected. Yet, marker trait associations could not explain the temperature-dependent sex of all fish in the respective families. The molecular cue for the temperature-dependent sex in Nile tilapia might partially coincide with allelic variants at major and minor genetic sex determining factors. Moreover, additional QTL contributing to variable liabilities towards temperature might persist on other LGs.
Redd1 Is a Novel Marker of Testis Development but Is Not Required for Normal Male Reproduction
Authors: Notini A.J. , McClive P.J. , Meachem S.J. , van den Bergen J.A. , Western P.S. , Gustin S.E. , Harley V.R. , Koopman P. , Sinclair A.H.
Published: July 2012

In an effort to identify novel candidate genes involved in testis determination, we previously used suppression subtraction hybridisation PCR on male and female whole embryonic (12.0–12.5 days post coitum) mouse gonads. One gene to emerge from our screen was Redd1. In the current study, we demonstrate by whole-mount in situ hybridisation that Redd1 is differentially expressed in the developing mouse gonad at the time of sex determination, with higher expression in testis than ovary. Furthermore, Redd1 expression was first detected as Sry expression peaks, immediately prior to morphological sex determination, suggesting a potential role for Redd1 during testis development. To determine the functional importance of this gene during testis development, we generated Redd1-deficient mice. Morphologically, Redd1-deficient mice were indistinguishable from control littermates and showed normal fertility. Our results show that Redd1 alone is not required for testis development or fertility in mice. The lack of a male reproductive phenotype in Redd1 mice may be due to functional compensation by the related gene Redd2.
Tubularized Urethral Replacement Using Tissue-Engineered Peritoneum-Like Tissue in a Rabbit Model
Authors: Gu Gang-Li , Xia Shu-Jie , Zhang Jie , Liu Guo-Hua , Yan Lei , Xu Zhong-Hua , Zhu Ying-Jian
Published: July 2012

Introduction: This study aims to investigate whether mesothelial cells could function as seed cells to construct tissue-engineered peritoneum-like tissue for urethral reconstruction in a rabbit model. Materials and Methods: Bladder acellular matrices were prepared and trimmed to 1.5 × 1 cm. Nine male rabbits underwent omentum biopsy and autologous mesothelial cells were isolated. After in vitro expansion, the cells were seeded onto the matrices and incubated for 7 days. In 18 rabbits, a pendulous urethral segment 1.5 cm long was totally excised and urethroplasty was performed with tubularized matrices seeded with cells in 9 animals and without cells in 9 as controls. Urethrography was performed at 1, 2 and 6 months postoperatively. Meanwhile, the neourethras were harvested and analyzed grossly and histologically. Results: Histological analysis of the cell-seeded grafts revealed a loose collagen matrix covered with a single layer of mesothelim. Serial urethrography indicated a wide urethral caliber without stricture formation in animals implanted with cell-seeded matrices, while all animals of the control group developed stricture. Histological analysis of the implanted cell-seeded matrices demonstrated a normal urethral architecture by 1 month, composed of multilayers of urothelium surrounded by smooth muscle bundles, which became increasingly organized with time. By 6 months, the neourethra could be hardly distinguished from native urethra both grossly and histologically. Conclusions: Autologous mesothelial cells could be successfully used as seed cells for tubularized urethral reconstruction in male rabbits.
Fast-Track Surgery – Conditions and Challenges in Postsurgical Treatment: A Review of Elements of Translational Research in Enhanced Recovery after Surgery
Authors: Hoffmann Henry , Kettelhack Christoph
Published: July 2012

Background: Enhanced recovery after surgery (ERAS) or fast-track surgery is a perioperative and postoperative care concept initiated in the early 1990s aiming to reduce the length of hospital stays following elective abdominal surgery. Twenty treatment items defined in the Consensus Guidelines established in 2009 were included in this concept. The success of ERAS depends highly on multidisciplinary teamwork and patient compliance. Several ERAS items and their impact on perioperative and postoperative care have recently been discussed. In this connection, translational research topics triggered increasing interest in ERAS and new impulses aimed at improving the ERAS concept. We thus reviewed the surgical literature to highlight the role of translational research items in ERAS. Methods: A literature search of Medline®, PubMed® and the Cochrane Database was performed. Two investigators independently reviewed the abstracts and appropriate articles were included in this review. Results: Articles have been selected. The advantages of the ERAS concept over conventional postoperative care were established by four meta-analyses and several reviews. But, due to the lack of standardization of the protocols, the level of evidence is still low. The implementation of ERAS into clinical practice is furthermore hampered by the poor compliance with ERAS protocols and remains a challenge for the future. Moreover, recent trials challenge the role of some ERAS items, e.g. epidural anesthesia. Translational research trials investigating stress, immune and inflammatory response after surgery, new analgesic concepts, goal-directed fluid therapy and new drugs and substances to improve the outcome of ERAS provide first promising data but still need to be integrated in the ERAS concept. Conclusion: The Consensus Guidelines for ERAS are subject to the constant evolution of treatment strategies and implementation of translational research findings. Improvement of the compliance with ERAS protocols in surgical clinics and updating of ERAS items taking into account recent findings in translational research may improve the outcomes of ERAS but remain a long-term challenge in surgery for the next years.
Intranasal Insulin Modulates Intrinsic Reward and Prefrontal Circuitry of the Human Brain in Lean Women
Authors: Kullmann Stephanie , Frank Sabine , Heni Martin , Ketterer Caroline , Veit Ralf , Häring Hans-Ulrich , Fritsche Andreas , Preissl Hubert
Published: July 2012

Aim: There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. Methods: We performed ‘resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. Results: Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. Conclusion: This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy.
Association between cardiovascular disease risk factors and occurrence of venous thromboembolism
Authors: Lutsey Pamela L. , Bell Elizabeth J. , Gornik Heather , Cushman Mary , Heckbert Susan R. , Rosamond Wayne D. , Folsom Aaron R. , Wattanakit Keattiyoat
Published: July 2012

Apart from obesity, it remains controversial whether atherosclerosis and its cardiovascular risk disease (CVD) factors are associated with risk of venous thromboembolism (VTE). Using data from the Atherosclerosis Risk in Communities study (ARIC), we evaluated associations between CVD risk factors and incident VTE in a cohort of 15,340 participants who were free a history of VTE and/or anticoagulant use on enrolment. The CVD risk factors were updated during the follow-up period. Over a mean follow-up time of 15.5 years (237,375 person-years), 468 participants had VTE events. Adjusting for demographic variables and body mass index (BMI), current smokers were at greater risk [HR of 1.44 (95% CI: 1.12–1.86)] compared to non-smokers. There was a positive monotonic association between BMI and VTE risk. Individuals with a BMI ≥35 kg/m2 had a HR for VTE of 3.09 (95%CI: 2.26–4.23) compared to those with normal BMI (<25 kg/m2). Greater physical activity was associated with lower VTE risk in a demographic adjusted model; however, this association became non-significant following adjustment for BMI. Alcohol intake, diabetes, hypertension, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were not associated with VTE risk. In conclusion, among the well-established CVD risk factors, only current smoking and obesity were independently associated with VTE risk in this large cohort where risk factors were updated serially during follow-up. This finding corroborates that the pathogenesis of venous disease differs from that of atherosclerotic disease.
The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration
Authors: Poettler Marina , Unseld Matthias , Mihaly-Bison Judit , Uhrin Pavel , Koban Florian , Binder Bernd R. , Zielinski Christoph C. , Prager Gerald W.
Published: July 2012

Angiogenesis, the sprouting of blood vessels form pre-existing vasculature after injury or in neoplastic diseases, is initiated by growth factor-induced endothelial cell migration. Recently, the major angiogenic growth factor VEGF165 has become the target of therapeutic interventions. However, this approach has been clinically proven to be of limited efficacy, which might be due to the fact that tumour angiogenesis is not only induced by VEGF, but also by a variety of other growth factors. Thus, the identification of a common downstream mediator of growth-factor-induced endothelial cell migration is mandatory to effectively interfere with (tumour-) angiogenesis. We found that the urokinase-type plas-minogen activator (uPA)-system, which affects proteolytic as well as adhesive capacities, represents an essential regulatory mechanism in growth factor-induced endothelial cell migration and invasion. This mechanism was not limited to VEGF165, but mediated pro-angiogenic endothelial cell behaviour induced by various growth factors. Thus, VEGF165, VEGF-E, FGF-2, EGF as well as HGF induced a PI3k-dependent activation of pro-uPA when bound to uPAR, which led to an increase in cell surface fibrinolytic activity. As a consequence, uPAR became internalised and redistributed via LDLR-proteins. Interference with these events led to a reduced migratory response of endothelial cells towards VEGF in vitro as well as endothelial cell invasion in vivo. These data give first evidence that the uPA-system, which represents the only level-of-evidence-1 cancer biomarker system for prognosis and/or prediction in node negative breast cancer, might directly affect (tumour-) angiogenesis.
Management and adherence to VTE treatment guidelines in a national prospective cohort study in the Canadian outpatient setting
Authors: Springmann Vicky , Schulman Sam , Martineau Josée , Stewart John A. , Komari Nelly , McLeod Anne , Strulovitch Carla , Blostein Mark , Faucher Jacques-Philippe , Gamble Greg , Gordon Wendy , Kagoma Peter K. , Miron Marie-José , Laverdière David , Game Melaku , Mills Allan , Kahn Susan R.
Published: July 2012

Documenting patterns and outcomes of venous thromboembolism (VTE) management and degree of adherence by clinicians to treatment guidelines could help identify remediable gaps in patient care. Prospective, clinical practice-based data from Canadian outpatient settings on management of VTE, degree of adherence with treatment guidelines and frequency of recurrent VTE and bleeding during follow-up was obtained in a multicentre, prospective observational study. From 12 Canadian centres, we assessed 868 outpatients with acute symptomatic VTE who received the low-molecular-weight heparin (LMWH) enoxaparin alone or with vitamin K antagonists (VKA), at baseline and at six months (or at the end of treatment, whichever came first). Index VTE was limb deep venous thrombosis (DVT) in 583 (67.2%) patients, pulmonary embolism (PE) with or without DVT in 262 (30.2%) patients, and unusual site DVT in 23 (2.6%) patients. VTE was unprovoked in 399 (46.0%) patients, associated with cancer in 74 (8.5%) patients, transient risk factors in 327 (37.7%) patients and hormonal factors in 68 (7.8%) patients. With regard to guideline adherence, 58 (7.3%) patients received <5 days LMWH and 114 (14.5%) had overlap <1 day. Among patients with cancer-related VTE, 59.5% were prescribed LMWH monotherapy and 43.2% received such treatment for >3 months. Only 38.1% of patients with transient VTE risk factors had received thromboprophylaxis. Our study provides useful information on clinical presentation, management and related outcomes in Canadian outpatients with VTE. Our results suggest there may be important gaps in use of thromboprophylaxis to prevent VTE and use of LMWH mono-therapy to treat cancer-related VTE.

Note: Part of this study was presented as an Oral Abstract Presentation at the American Society of Hematology meeting, Dec. 4–7, 2010, Orlando, FL, USA.