bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of Aminocyclitols and Trihydroxylated Indolizidinone from a D‐Mannitol‐Derived Common Building Block
Authors: Gupta Preeti , Pal A. P. John , Reddy Y. Suman , Vankar Yashwant D.
Published: December 2010

The synthesis of 4‐amino‐4‐deoxy‐muco‐quercitol (22), 4‐amino‐4‐deoxy‐(–)‐vibo‐quercitol (27) and also a trihydroxylated indolizidinone 38 from D‐mannitol is described using ring‐closing metathesis and diastereoselective dihydroxylation as the key steps.
Enantioselective Friedel–Crafts Alkylation of Thiophenes with Ethyl Glyoxylate: Easy Access to Chiral Secondary Alcohols
Authors: Huang Zhong , Zhang Jingchang , Zhou Yuqiang , Wang Nai‐Xing
Published: December 2010

Friedel–Crafts alkylation reactions of ethyl glyoxylate with various thiophenes to give the corresponding chiral secondary alcohols were demonstrated. The majority of these reactions proceeded with good enantioselectivities (up to 91 %) and satisfactory isolated yields. Notably, we found that 2‐substituted thiophenes underwent the reaction more smoothly than unsubstituted and 3‐substituted thiophenes.
Direct Nucleophilic SN1‐Type Reactions of Alcohols
Authors: Emer Enrico , Sinisi Riccardo , Capdevila Montse Guiteras , Petruzziello Diego , De Vincentiis Francesco , Cozzi Pier Giorgio
Published: December 2010

In 2005, the ACS Green Chemistry Institute (GCI) and the global pharmaceutical corporations developed the ACS GCI Pharmaceutical Roundtable to encourage the development of green chemistry and green engineering in the pharmaceutical industry. The Roundtable has established a list of key research areas including the direct nucleophilic reactions of alcohols. The substitution of activated alcohols is a frequently used approach for the preparation of active pharmaceutical ingredients. Alcohols are transformed into the reactive halides or sulfonate esters, thereby allowing their reaction with nucleophiles. Although the direct nucleophilic substitution of an alcohol should be an attractive process, as one of the byproducts from the reaction yields water, hydroxide is a poor leaving group that hinders the reaction. Recently, the direct substitution of allylic, benzylic, and tertiary alcohols has been achieved through an SN1 reaction with catalytic amounts of Brønsted or Lewis acids. In this review, the approaches leading to a greener process are examined in detail, and the advances achieved to date in this important transformation are presented.
Hypertension is a potential risk factor for vascular dementia: systematic review
Authors: Sharp Sally I. , Aarsland Dag , Day Sarah , Sønnesyn Hogne ,   Alzheimer's Society Vascular Dementia Systematic Review Group, Ballard Clive
Published: December 2010

Objective

The aim of the study was to conduct a meta‐analysis of epidemiological and case control studies to determine whether arterial hypertension is specifically associated with an increased risk of vascular dementia (VaD).

Design

Longitudinal and cross‐sectional prospective studies using operationalised criteria to define VaD and hypertension, with a normal control comparison group were systematically reviewed. Cochrane Library, Embase, Medline, and PsycInfo data sources were searched along with reference lists of included articles and reviews. Original, prevalence or incidence studies were included if operationalised criteria for hypertension and VaD as well as number of cases with and without hypertension in VaD and non‐demented groups were provided. Intervention studies and post‐stroke and CADASIL studies were excluded.

Results

Eleven studies recruiting either volunteers or clinical patients, or which were population‐based, examined a total of 768 people with VaD and 9857 control cases. A meta‐analysis of the six longitudinal studies showed that hypertension was significantly associated with increased risk of incident VaD (odds ratio, OR: 1.59, CI: 1.29–1.95, p < 0.0001). A similar association between hypertension and the risk of prevalent VaD was found in the five cross‐sectional studies (OR: 4.84, CI: 3.52–6.67, p < 0.00001).

Conclusions

Hypertension significantly increases the risk of vascular dementia. The current meta‐analysis highlights the potential importance of rigorous treatment of hypertension as a key measure to help prevent the development of VaD. Copyright © 2010 John Wiley & Sons, Ltd.
MRI‐defined vascular depression: a review of the construct
Authors: Culang‐Reinlieb Michelle E. , Johnert Lauren C. , Brickman Adam M. , Steffens David C. , Garcon Ernst , Sneed Joel R.
Published: December 2010

Objective

To review the construct of MRI‐defined vascular depression and to examine the substantive and methodological issues that bear on its validity as a distinct subtype of depression in late life.

Design

Literature review.

Results

We identified three areas that are critical to establishing the validity of MRI‐defined vascular depression: (1) understanding and delineating the relationship between MRI hyperintensities, executive dysfunction, and antidepressant treatment outcome; (2) understanding the relationship between, and establishing the validity of, qualitative and quantitative approaches to the measurement of MRI hyperintensities (the primary feature of the proposed subtype); (3) establishing the clinical presentation and course of the subtype in the context of other late‐life disorders.

Conclusions

Despite considerable data supporting the validity of MRI‐defined vascular depression, there are a number of critical issues that remain, including establishing a causal relationship between cerebrovascular disease and late‐life depression, establishing consistent diagnostic criteria, determining the importance of lesion type and location, and understanding the course of the disorder. Copyright © 2010 John Wiley & Sons, Ltd.
Differential effects between the loss of MMP-2 and MMP-9 on structural and tissue-level properties of bone
Authors: Nyman Jeffry S , Lynch Conor C , Perrien Daniel S , Thiolloy Sophie , O'Quinn Elizabeth C , Patil Chetan A , Bi Xiaohong , Pharr George M , Mahadevan-Jansen Anita , Mundy Gregory R
Published: December 2010

Matrix metalloproteinases (MMPs) are capable of processing certain components of bone tissue, including type 1 collagen, a determinant of the biomechanical properties of bone tissue, and they are expressed by osteoclasts and osteoblasts. Therefore, we posit that MMP activity can affect the ability of bone to resist fracture. To explore this possibility, we determined the architectural, compositional, and biomechanical properties of bones from wild-type (WT), Mmp2−/−, and Mmp9−/− female mice at 16 weeks of age. MMP-2 and MMP-9 have similar substrates but are expressed primarily by osteoblasts and osteoclasts, respectively. Analysis of the trabecular compartment of the tibia metaphysis by micro–computed tomography (µCT) revealed that these MMPs influence trabecular architecture, not volume. Interestingly, the loss of MMP-9 improved the connectivity density of the trabeculae, whereas the loss of MMP-2 reduced this parameter. Similar differential effects in architecture were observed in the L5 vertebra, but bone volume fraction was lower for both Mmp2−/− and Mmp9−/− mice than for WT mice. The mineralization density and mineral-to-collagen ratio, as determined by µCT and Raman microspectroscopy, were lower in the Mmp2−/− bones than in WT control bones. Whole-bone strength, as determined by three-point bending or compression testing, and tissue-level modulus and hardness, as determined by nanoindentation, were less for Mmp2−/− than for WT bones. In contrast, the Mmp9−/− femurs were less tough with lower postyield deflection (more brittle) than the WT femurs. Taken together, this information reveals that MMPs play a complex role in maintaining bone integrity, with the cell type that expresses the MMP likely being a contributing factor to how the enzyme affects bone quality. © 2011 American Society for Bone and Mineral Research.
miR‐21 downregulates the tumor suppressor P12CDK2AP1 and Stimulates Cell Proliferation and Invasion
Authors: Zheng Jun , Xue Hui , Wang Tao , Jiang Yuegui , Liu Bei , Li Jianhu , Liu Yanpu , Wang Wei , Zhang Bin , Sun Moyi
Published: December 2010

The present study was undertaken to investigate the regulation of P12CDK2AP1 by miRNAs. A conserved target site for miR‐21 within the CDK2AP1‐3′‐UTR at nt 349–370 was predicted by bioinformatics software and an inverse correlation of miR‐21 and CDK2AP1 protein was observed. Highly specific amplification and quantification of miR‐21 was achieved using real‐time RT‐PCR. Transfection of HaCaT cells with pre‐miR‐21 significantly suppressed a luciferase reporter including the CDK2AP1‐3′‐UTR, whereas transfection of Tca8113 with anti‐miR‐21 increased activity of this reporter. This was abolished when a construct mutated at the miR‐21/nt 349–370 target site was used instead. Anti‐miR‐21‐transfected Tca8113 cells showed an increase of CDK2AP1 protein and reduced proliferation and invasion. Resected primary tumors and tumor‐free surgical margins of 18 patients with head and neck squamous cell carcinomas demonstrated an inverse correlation between miR‐21 and P12CDK2AP1. This study shows that P12CDK2AP1 is downregulated by miR‐21 and that miR‐21 promotes proliferation and invasion in cultured cells. J. Cell. Biochem. 112: 872–880, 2011. © 2010 Wiley‐Liss, Inc.
Vitamin C down‐regulates VEGF production in B16F10 murine melanoma cells via the suppression of p42/44 MAPK activation
Authors: Kim Ha Na , Kim Hyemin , Kong Joo Myung , Bae Seyeon , Kim Yong Sung , Lee Naeun , Cho Byung Joo , Lee Seung Koo , Kim Hang‐Rae , Hwang Young‐il , Kang Jae Seung , Lee Wang Jae
Published: December 2010

It is known that vitamin C induces apoptosis in several kinds of tumor cells, but its effect on the regulation of the angiogenic process of tumors is not completely studied. Vascular endothelial growth factor (VEGF) is the most well‐known angiogenic factor, and it has a potent function as a stimulator of endothelial survival, migration, as well as vascular permeability. Therefore, we have investigated whether vitamin C can regulate the angiogenic process through the modulation of VEGF production from B16F10 melanoma cells. VEGF mRNA expression and VEGF production at protein levels were suppressed by vitamin C. In addition, we found that vitamin C suppressed the expression of cyclooxygenase (COX)‐2 and that decreased VEGF production by vitamin C was also restored by the administration of prostaglandin E2 which is a product of COX‐2. These results suggest that vitamin C suppresses VEGF expression via the regulation of COX‐2 expression. Mitogen‐activated protein kinases are generally known as key mediators in the signaling pathway for VEGF production. In the presence of vitamin C, the activation of p42/44 MAPK was completely inhibited. Taken together, our data suggest that vitamin C can down‐regulate VEGF production via the modulation of COX‐2 expression and that p42/44 MAPK acts as an important signaling mediator in this process. J. Cell. Biochem. 112: 894–901, 2011. © 2010 Wiley‐Liss, Inc.
Activation of CFTR trafficking and gating by vasoactive intestinal peptide in human bronchial epithelial cells
Authors: Qu Fei , Liu Hui‐Jun , Xiang Yang , Tan Yu‐Rong , Liu Chi , Zhu Xiao‐Lin , Qin Xiao‐Qun
Published: December 2010

Cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane chloride channel critical to the regulation of fluid, chloride, and bicarbonate transport in epithelia and other cell types. The most common cause of cystic fibrosis (CF) is the abnormal trafficking of CFTR mutants. Therefore, understanding the cellular machineries that transit CFTR from the endoplasmic reticulum to the cell surface is important. Vasoactive intestinal polypeptide (VIP) plays an important role in CFTR‐dependent chloride transport. The present study was designed to observe the affection of VIP on the trafficking of CFTR, and channel gating in human bronchial epithelium cells (HBEC). Confocal microscopy revealed CFTR immunofluorescence extending from the apical membrane deeply into the cell cytoplasm. After VIP treatment, apical extension of CFTR immunofluorescence into the cell was reduced and the peak intensity of CFTR fluorescence shifted towards the apical membrane. Western blot showed VIP increased cell surface and total CFTR. Compared with the augmented level of total CFTR, the surface CFTR increased more markedly. Immunoprecipitation founded that the mature form of CFTR had a marked increase in HBEC treated with VIP. VIP led to a threefold increase in Cl− efflux in HBEC. Glibenclamide‐sensitive and DIDS‐insensitive CFTR Cl− currents were consistently observed after stimulation with VIP (10−8 mol/L). The augmentation of CFTR Cl− currents enhanced by VIP (10−8 mol/L) was reversed, at least in part, by the protein kinase A (PKA) inhibitor, H‐89 and the protein kinase C (PKC) inhibitor, H‐7, suggesting PKA and PKC participate in the VIP‐promoted CFTR Cl− currents. J. Cell. Biochem. 112: 902–908, 2011. © 2010 Wiley‐Liss, Inc.
Metformin sensitizes insulin signaling through AMPK‐mediated pten down‐regulation in preadipocyte 3T3‐L1 cells
Authors: Lee Soo Kyung , Lee Jung Ok , Kim Ji Hae , Kim Su Jin , You Ga Young , Moon Ji Wook , Jung Jin Hee , Park Sun Hwa , Uhm Kyung‐Ok , Park Ji Man , Suh Pann‐Ghill , Kim Hyeon Soo
Published: December 2010

Insulin resistance is the primary cause responsible for type 2 diabetes. Phosphatase and tensin homolog (PTEN) plays a negative role in insulin signaling and its inhibition improves insulin sensitivity. Metformin is a widely used insulin‐sensitizing drug; however, the mechanism by which metformin acts is poorly understood. To gain insight into the role of PTEN, we examined the effect of metformin on PTEN expression. Metformin suppressed the expression of PTEN in an AMP‐activated protein kinase (AMPK)‐dependent manner in preadipocyte 3T3‐L1 cells. Knock‐down of PTEN potentiated the increase in insulin‐mediated phosphorylation of Akt/ERK. Metformin also increased the phosphorylation of c‐Jun N‐terminal kinase (JNK)‐c‐Jun and mammalian target of rapamycin (mTOR)‐p70S6 kinase pathways. Both pharmacologic inhibition and knock‐down of AMPK blocked metformin‐induced phosphorylation of JNK and mTOR. Knock‐down of AMPK recovered the metformin‐induced PTEN down‐regulation, suggesting the involvement of AMPK in PTEN regulation. PTEN promoter activity was suppressed by metformin and inhibition of mTOR and JNK by pharmacologic inhibitors blocked metformin‐induced PTEN promoter activity suppression. These findings provide evidence for a novel role of AMPK on PTEN expression and thus suggest a possible mechanism by which metformin may contribute to its beneficial effects on insulin signaling. J. Cell. Biochem. 112: 1259–1267, 2011. © 2010 Wiley‐Liss, Inc.
Nuclear protein isoforms: Implications for cancer diagnosis and therapy
Authors: Shen Fei , Kirmani Kashif Z. , Xiao Zhimin , Thirlby Benjamin H. , Hickey Robert J. , Malkas Linda H.
Published: December 2010

Post‐translational modifications (PTMs) of nuclear proteins play essential roles in the regulation of gene transcription and signal transduction pathways. Numerous studies have demonstrated a correlation between specific nuclear protein isoforms and cellular malignant process. This communication reviews the impact of major PTM events such as phosphorylation, acetylation, methylation, ubiquitination, and sumoylation on several important nuclear proteins including p53, histones, proliferating cellular nuclear antigen (PCNA), and retinoblastoma protein (Rb) in the process. In addition, the implications of the PTMs as cancer biomarkers and therapeutic targets are considered. J. Cell. Biochem. 112: 756–760, 2011. © 2010 Wiley‐Liss, Inc.
Roscovitine, a selective CDK inhibitor, reduces the basal and estrogen‐induced phosphorylation of ER‐α in human ER‐positive breast cancer cells
Authors: Węsierska‐Gądek Józefa , Gritsch David , Zulehner Nora , Komina Oxana , Maurer Margarita
Published: December 2010

Roscovitine (ROSC), a selective cyclin‐dependent kinase (CDK) inhibitor, arrests human estrogen receptor‐α (ER‐α) positive MCF‐7 breast cancer cells in the G2 phase of the cell cycle and concomitantly induces apoptosis via a p53‐dependent pathway. The effect of ROSC is markedly diminished in MCF‐7 cells maintained in the presence of estrogen‐mimicking compounds. Therefore, we decided to examine whether ROSC has any effect on the functional status of the ER‐α transcription factor. Exposure of MCF‐7 cells to ROSC abolished the activating phosphorylation of CDK2 and CDK7 in a concentration and time‐dependent manner. This inhibition of site‐specific modification of CDK7 at Ser164/170 prevented phosphorylation of RNA polymerase II and reduced basal phosphorylation of ER‐α at Ser118 in non‐stimulated MCF‐7 cells (resulting in its down‐regulation). In MCF‐7 cells, estrogen induced strong phosphorylation of ER‐α at Ser118 but not at Ser104/Ser106. ROSC prevented this estrogen‐promoted activating modification of ER‐α. Furthermore, we sought to determine whether the activity of ROSC could be enhanced by combining it with an anti‐estrogen. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), affected breast cancer cell lines irrespective of their ER status. In combination with ROSC, however, it had a different impact, enhancing G1 or G2 arrest. Our results indicate that ROSC prevents the activating phosphorylation of ER‐α and that its mode of action is strongly dependent on the cellular context. Furthermore, our data show that ROSC can be combined with anti‐estrogen therapy. The inhibitory effect of TAM on ER‐negative cancer cells indicates that SERMs crosstalk with other steroid hormone receptors. J. Cell. Biochem. 112: 761–772, 2011. © 2010 Wiley‐Liss, Inc.
Delayed production of arachidonic acid contributes to the delay of proteinase‐activated receptor‐1 (PAR1)‐triggered prostaglandin E2 release in rat gastric epithelial RGM1 cells
Authors: Sekiguchi Fumiko , Ohi Ai , Maeda Yuma , Takaoka Kaori , Sekimoto Teruki , Nishikawa Hiroyuki , Kawabata Atsufumi
Published: December 2010

Proteinase‐activated receptor‐1 (PAR1), upon activation, exerts prostanoid‐dependent gastroprotection, and increases prostaglandin E2 (PGE2) release through cyclooxygenase‐2 (COX‐2) upregulation in rat gastric mucosal epithelial RGM1 cells. However, there is a big time lag between the PAR1‐triggered PGE2 release and COX‐2 upregulation in RGM1 cells; that is, the former event takes 18 h to occur, while the latter rapidly develops and reaches a plateau in 6 h. The present study thus aimed at clarifying mechanisms for the delay of PGE2 release after PAR1 activation in RGM1 cells. Although a PAR1‐activating peptide, TFLLR‐NH2, alone caused PGE2 release at 18 h, but not 6 h, TFLLR‐NH2 in combination with arachidonic acid dramatically enhanced PGE2 release even for 1–6 h. TFLLR‐NH2 plus linoleic acid caused a similar rapid response. CP‐24879, a Δ5/Δ6‐desaturase inhibitor, abolished the PGE2 release induced by TFLLR‐NH2 plus linoleic acid, but not by TFLLR‐NH2 alone. The TFLLR‐NH2‐induced PGE2 release was not affected by inhibitors of cytosolic phospholipase A2 (cPLA2), Ca2+‐independent PLA2 (cPLA2) or secretory PLA2 (sPLA2), but was abolished by their mixture or a pan‐PLA2 inhibitor. Among PLA2 isozymes, mRNA of group IIA sPLA2 (sPLA2‐IIA) was upregulated following PAR1 stimulation for 6–18 h, whereas protein levels of PGE synthases were unchanged. These data suggest that the delay of PGE2 release after COX‐2 upregulation triggered by PAR1 is due to the poor supply of free arachidonic acid at the early stage in RGM1 cells, and that plural isozymes of PLA2 including sPLA2‐IIA may complementarily contribute to the liberation of free arachidonic acid. J. Cell. Biochem. 112: 909–915, 2011. © 2010 Wiley‐Liss, Inc.
RANKL increases migration of human lung cancer cells through intercellular adhesion molecule‐1 up‐regulation
Authors: Chen Li‐Mien , Kuo Chia‐Hua , Lai Tung‐Yuan , Lin Yueh‐Min , Su Cheng‐Chuan , Hsu His‐Hsien , Tsai Fuu‐Jen , Tsai Chang‐Hai , Huang Chih‐Yang , Tang Chih‐Hsin
Published: December 2010

Invasion of distant tissues by tumor cells is the primary cause of therapeutic failure in the treatment of malignant lung cancer cells. Receptor activator of nuclear factor‐κB ligand (RANKL) and its receptor, RANK, play a key role in osteoclastogenesis and tumor metastasis. Intercellular adhesion molecule‐1 (ICAM‐1, also called CD54), a member of the immunoglobulin supergene family, is an inducible surface glycoprotein that mediates adhesion‐dependent cell‐to‐cell interactions. The effects of RANKL on cell migration and ICAM‐1 expression in human lung cancer cells are largely unknown. We found that RANKL directed the migration and increased ICAM‐1 expression in human lung cancer (A549) cells. Pretreatment of A549 cells with the MAPK kinase (MEK) inhibitor PD98059 or U0126 inhibited RANKL‐mediated migration and ICAM‐1 expression. Stimulation of cells with RANKL increased the phosphorylation of MEK and extracellular signal‐regulating kinase (ERK). In addition, an NF‐κB inhibitor (PDTC) and IκB protease inhibitor (TPCK) also inhibited RANKL‐mediated cell migration and ICAM‐1 up‐regulation. Taken together, these results suggest that the RANKL and RANK interaction acts through MEK/ERK, which in turn activates NF‐κB, resulting in the activation of ICAM‐1 and contributing to the migration of human lung cancer cells. J. Cell. Biochem. 112: 933–941, 2011. © 2010 Wiley‐Liss, Inc.
Down‐regulation of cyclin E1 expression by microrna‐195 accounts for interferon‐β‐induced inhibition of hepatic stellate cell proliferation
Authors: Sekiya Yumiko , Ogawa Tomohiro , Iizuka Masashi , Yoshizato Katsutoshi , Ikeda Kazuo , Kawada Norifumi
Published: December 2010

Recent studies have suggested that interferons (IFNs) have an antifibrotic effect in the liver independent of their antiviral effect although its detailed mechanism remains largely unknown. Some microRNAs have been reported to regulate pathophysiological activities of hepatic stellate cells (HSCs). We performed analyses of the antiproliferative effects of IFNs in HSCs with special regard to microRNA‐195 (miR‐195). We found that miR‐195 was prominently down‐regulated in the proliferative phase of primary‐cultured mouse HSCs. Supporting this fact, IFN‐β induced miR‐195 expression and inhibited the cell proliferation by delaying their G1 to S phase cell cycle progression in human HSC line LX‐2. IFN‐β down‐regulated cyclin E1 and up‐regulated p21 mRNA levels in LX‐2 cells. Luciferase reporter assay revealed the direct interaction of miR‐195 with the cyclin E1 3′UTR. Overexpression of miR‐195 lowered cyclin E1 mRNA and protein expression levels, increased p21 mRNA and protein expression levels, and inhibited cell proliferation in LX‐2 cells. Moreover miR‐195 inhibition restored cyclin E1 levels that were down‐regulated by IFN‐β. In conclusion, IFN‐β inhibited the proliferation of LX‐2 cells by delaying cell cycle progression in G1 to S phase, partially through the down‐regulation of cyclin E1 and up‐regulation of p21. IFN‐induced miR‐195 was involved in these processes. These observations reveal a new mechanistic aspect of the antifibrotic effect of IFNs in the liver. J. Cell. Physiol. 226: 2535–2542, 2011. © 2010 Wiley‐Liss, Inc.
Towards gene therapy for deafness
Authors: Di Domenico Marina , Ricciardi Carmela , Martone Tiziana , Mazzarella Nicoletta , Cassandro Claudia , Chiarella Giuseppe , D'Angelo Luigi , Cassandro Ettore
Published: December 2010

Many hearing disorders are associated with the damage or loss of sensory hair cells (HC) which can produce a profound and irreversible deafness. Apoptosis pathway is reported to play an important role leading to rapid expansion of the HC lesion after exposure to intense noise. Furthermore, progress made over the last year in understanding molecular mechanisms involved in the proliferative and regenerative capacity of sensory cells in the mammalian inner ear has raised the possibility that targeted therapies might prevent the loss of these cells and preserve the patient's hearing. A first step towards the successful therapeutic exploitation is a better understanding of the different pathways that control survival and proliferation of sensory cells. In this review, we provide an overview of recent findings concerning the possibility to prevent apoptosis in auditory cells. We also show the current knowledge on the molecular mechanisms involved in the potential regenerative behavior of these cells and the progress of gene therapy to prevent deafness noise‐induced. J. Cell. Physiol. 226: 2494–2499, 2011. © 2010 Wiley‐Liss, Inc.
TGFβ receptor activation enhances cardiac apoptosis via SMAD activation and concomitant NO release
Authors: Heger Jacqueline , Warga Björn , Meyering Bettina , Abdallah Yaser , Schlüter Klaus‐Dieter , Piper Hans Michael , Euler Gerhild
Published: December 2010

Transforming growth factor β (TGFβ) expression is induced in the myocardium during transition from compensated hypertrophy to heart failure. In cardiomyocytes, stimulation with TGFβ results in restricted contractile function and enhanced apoptosis. Nitric oxide (NO) also induces apoptosis and influences cardiac function. Therefore, we wanted to know whether NO is causally involved in TGFβ‐induced apoptosis. In isolated ventricular cardiomyocytes of adult rat incubation with TGFβ1 increased NO release which was inhibited by NOS inhibitor ETU but not with iNOS inhibitor (1400 W) or nNOS inhibitor (TFA). In addition, TGFβ‐induced apoptosis was blocked with ETU and ODQ, but not with 1400 W or TFA. The consequent assumption that endothelial NOS is involved in TGFβ‐induced NO formation and apoptosis was supported by increased phosphorylation of eNOS at serine 1177 and by the fact that TGFβ did not increase NO release in eNOS KO mice. Furthermore, TGFβ‐induced apoptosis, NO formation, SMAD binding activity and SMAD2 phosphorylation were blocked by a TGFβ receptor antagonist, but only apoptosis and NO formation could be blocked with ETU. Expression of SMAD7 was increased after TGFβ stimulation and blocked with TGFβ receptor antagonist but not after blocking NO synthase with ETU. Conclusion: In cardiomyocytes TGFβ‐induced apoptosis is mediated via TGFβ receptor activation that concomitantly activates SMAD transcription factors and the eNOS/NO/sGC pathway. Both of these pathways are needed for apoptosis induction by TGFβ. This reveals a new pathway of cardiac NO release and identifies NO as a possible contributor to heart failure progression mediated by TGFβ. J. Cell. Physiol. 226: 2683–2690, 2011. © 2010 Wiley‐Liss, Inc.
The synthesis and use of [14C]carbon monoxide in Pd‐catalyzed carbonylation reactions
Authors: Elmore Charles S.
Published: December 2010

The [14C]carbonylation reaction is a very powerful method of incorporating C‐14 into a drug molecule late in a radiochemical synthesis. The first and perhaps most critical step in [14C]carbonylation reactions is the generation of 14CO and its subsequent delivery to the reaction flask. There are three published methods for generating 14CO: conversion of 14CO2 with Zn at 400°C, pyrolysis of Ca14CO3, and dehydration of NaOCH. Additionally, a newly published method for the in situ carbonylation of aryl and vinyl halides to give acids has been investigated using NaOCH as the labeled precursor. Finally, the application of 14CO in Pd‐catalyzed [14C]carbonylation reactions will be discussed. Copyright © 2010 John Wiley & Sons, Ltd.
Synthesis of a labeled inhibitor of HIV‐1 attachment: 1‐(4‐benzoylpiperazin‐1‐yl)‐2‐(4,7‐dimethoxy‐1H‐pyrrolo[2,3‐c]pyridinyl‐3‐yl‐[U‐14C]ethane‐1,2‐dione, BMS‐488043‐14C
Authors: Ekhato I. Victor , Rinehart J. Kent
Published: December 2010

BMS‐488043 is a potent inhibitor of the interaction between HIV‐1 gp120 and the host cell receptor CD4. We prepared the carbon‐14‐labeled version to support preclinical studies of the compound. It was prepared from ethyl [U‐14C]oxalyl chloride by a sequence using Friedel–Crafts acylation reaction. The overall radiochemical yield was 82% with a purity of >99.9%. Copyright © 2010 John Wiley & Sons, Ltd.
Hip transposition as a limb salvage procedure following the resection of periacetabular tumors
Authors: Gebert Carsten , Wessling Martin , Hoffmann Christiane , Roedl Robert , Winkelmann Winfried , Gosheger Georg , Hardes Jendrik
Published: December 2010

Background and Objectives

One of the most difficult problems in tumor surgery is the treatment of pelvic tumors, particularly those in the periacetabular region. This retrospective study serves to analyze clinical and functional outcome of the new surgical technique of hip transposition.

Patients and Methods

Sixty‐two patients were analyzed (chondrosarcoma 15, Ewing's sarcoma or PNET 26, osteosarcoma 14, synovial cell sarcoma 2, others 5) and clinical, oncological, and functional outcome were evaluated.

Results

The surgical procedure focused on hip transpositions Type I (n = 9), Type IIa using the MUTARS® attachment tube (n = 36), and Type IIb using the MUTARS® attachment tube with a proximal femur endoprosthesis and bipolar cup (n = 17). In 53 patients (85.5%), wide margins were achieved.

The 1‐ and 5‐year overall survival rates were 96.4% and 80.5%, respectively. The 5‐year (10 years) overall survival was 82.1% (82.1%) for Ewing's sarcoma, 60.1% (40.6%) for osteosarcoma, and 92.3% (46.2%) for chondrosarcoma. Wound healing problems were observed in 14 cases, deep infection in 20 cases. The mean Musculoskeletal Tumor Society (MSTS) score was 62% (18.6 Pts ± 3.73).

Conclusion

Hip transposition can be considered as an easy and safe surgical procedure to employ in order to achieve good functional outcome in periacetabular tumors. J. Surg. Oncol. 2011; 103:269–275. © 2010 Wiley‐Liss, Inc.
Results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy after early failure of adjuvant systemic chemotherapy
Authors: Klaver Yvonne L.B. , de Hingh Ignace H.J.T. , Boot Henk , Verwaal Victor J.
Published: December 2010

Background and Objectives

Failure to respond to systemic chemotherapy is considered an exclusion criterion by some institutions for treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). However, it is unknown if these patients benefit from HIPEC treatment. This study aimed to report on outcomes of HIPEC in patients who failed to respond to adjuvant systemic chemotherapy.

Methods

Patients were selected from a prospective database containing data on all patients who underwent HIPEC, using the following criteria: (1) Metachronous peritoneal carcinomatosis (PC) from colorectal origin, (2) adjuvant chemotherapy after primary tumor resection, (3) development of PC or local recurrence within 18 months after start of chemotherapy. Treatment and survival data were retrospectively collected.

Results

Twenty‐one patients (29% male, mean age 57 years) were included. Median time to recurrence of disease was 9 months (range 2–15) after first chemotherapy administration. Median survival was 28 months (range 3–100). One‐ and 2‐year survival were 71% and 43%, respectively.

Conclusions

Patients who initially failed to respond to systemic adjuvant treatment showed a survival after HIPEC similar to results reported in literature in patients with unknown responsiveness. Failure to respond to previous adjuvant systemic treatment should therefore not be considered an exclusion criterion for HIPEC treatment. J. Surg. Oncol. 2011; 103:431–434. © 2010 Wiley‐Liss, Inc.
Prognostic implications of miR‐16 expression levels in resected non‐small‐cell lung cancer
Authors: Navarro Alfons , Diaz Tania , Gallardo Elena , Viñolas Nuria , Marrades Ramon M. , Gel Bernat , Campayo Marc , Quera Angels , Bandres Eva , Garcia‐Foncillas Jesus , Ramirez Jose , Monzo Mariano
Published: December 2010

Background

MicroRNAs are novel regulators of gene expression that are linked to the main oncogene networks, including the p53 pathway. p53 regulates the maturation process of miR‐16 and miR‐143. We analyzed the role as prognostic markers of miR‐16 and miR‐143 in 70 non‐small‐cell lung cancer (NSCLC) patients.

Methods

MicroRNAs were analyzed by TaqMan MicroRNA assays. Disease‐free survival (DFS) and overall survival (OS) were examined using Kaplan–Meier curves with log‐rank tests and the Cox proportional hazard model.

Results

When patients were classified in three groups according to their miR‐16 expression levels, those with normal levels had the best outcome while those with high levels had the worst. DFS was 22.4 months for patients with high levels, 71.8 months for those with normal levels, and 55.8 months for those with low levels (P = 0.05). OS was 23.9 months for patients with high levels, 97.6 months for those with normal levels, and 63.5 months for those with low levels (P < 0.001). In the multivariate analyses, high miR‐16 levels emerged as an independent prognostic factor for poor DFS (P = 0.001) and OS (<0.001).

Conclusions

Our results provide the first hints that miR‐16 levels in tumor samples may be a prognostic marker in NSCLC. J. Surg. Oncol. 2011; 103:411–415. © 2010 Wiley‐Liss, Inc.
Measurement of creatine kinase reaction rate in human brain using magnetization transfer image‐selected in vivo spectroscopy (MT‐ISIS) and a volume 31P/1H radiofrequency coil in a clinical 3‐T MRI system
Authors: Jeong Eun‐Kee , Sung Young‐Hoon , Kim Seong‐Eun , Zuo Chun , Shi Xianfeng , Mellon Eric A. , Renshaw Perry F.
Published: December 2010

High‐energy phosphate metabolism, which allows the synthesis and regeneration of adenosine triphosphate (ATP), is a vital process for neuronal survival and activity. In particular, creatine kinase (CK) serves as an energy reservoir for the rapid buffering of ATP levels. Altered CK enzyme activity, reflecting compromised high‐energy phosphate metabolism or mitochondrial dysfunction in the brain, can be assessed using magnetization transfer (MT) MRS. MT 31P MRS has been used to measure the forward CK reaction rate in animal and human brain, employing a surface radiofrequency coil. However, long acquisition times and excessive radiofrequency irradiation prevent these methods from being used routinely for clinical evaluations. In this article, a new MT 31P MRS method is presented, which can be practically used to measure the CK forward reaction rate constant in a clinical MRI system employing a volume head 31P coil for spatial localization, without contamination from the scalp muscle, and an acquisition time of 30 min. Other advantages associated with the method include radiofrequency homogeneity within the regions of interest of the brain using a volume coil with image‐selected in vivo spectroscopy localization, and reduction of the specific absorption rate using nonadiabatic radiofrequency pulses for MT saturation. The mean value of kf was measured as 0.320 ± 0.075 s−1 from 10 healthy volunteers with an age range of 18–40 years. These values are consistent with those obtained using earlier methods, and the technique may be used routinely to evaluate energetic processes in the brain on a clinical MRI system. Copyright © 2010 John Wiley & Sons, Ltd.
A higher‐order extended finite element method for dislocation energetics in strained layers and epitaxial islands
Authors: Oswald Jay , Wintersberger Eugen , Bauer Günther , Belytschko Ted
Published: December 2010

This paper presents a higher‐order method for modeling dislocations with the extended finite element method (XFEM). This method is applicable to complex geometries, interfaces with lattice mismatch strains, and both anisotropic and spatially non‐uniform material properties. A numerical procedure for computing the J‐integral around a dislocation core to determine the energy release rate for a virtual advance of the dislocation line is described. Several examples in three dimensions illustrate the applicability of this method to material interfaces and semiconductor heterostructures, specifically the computation of the energetics of systems of dislocations in SiGe islands deposited on pure Si substrates. Copyright © 2010 John Wiley & Sons, Ltd.
Stable element‐free Galerkin solution procedures for the coupled soil–pore fluid problem
Authors: Hua Leina
Published: December 2010

It is always difficult to solve the coupled soil–pore fluid problem when the soil is saturated and impermeable, because this situation often results in intensive oscillations of the solutions. This topic has been discussed widely in the field of the finite element method but rarely by meshless methods. The Element‐Free Galerkin (EFG) method has outstanding advantages of solving this problem, based on the fact that its interpolation function can be constructed flexibly by the nodes in the compact domain. In this study, an EFG numerical model together with a stabilization technique is proposed to obtain stable solutions, especially for the saturated and impermeable soil. Close agreement between computational results and analytical solutions for one‐and two‐dimensional examples shows that the proposed numerical model not only provides highly accurate solutions for the saturated soil with relatively high permeability, but also eliminates the oscillations of the solutions very effectively for the saturated and impermeable soil. Furthermore, the influences of the hydraulic anisotropy, a typical property of two‐dimensional problems, on the proposed stabilization technique are discussed. It is suggested that the optimal distribution of the nodes of essential variables can be designed, according to the relative importance of the permeability in different directions. Copyright © 2010 John Wiley & Sons, Ltd.
A hierarchical NXFEM for fictitious domain simulations
Authors: Becker Roland , Burman Erik , Hansbo Peter
Published: December 2010

We suggest a fictitious domain method, based on the Nitsche XFEM method of (Comput. Meth. Appl. Mech. Engrg 2002; 191:5537–5552), that employs a band of elements adjacent to the boundary. In contrast, the classical fictitious domain method uses Lagrange multipliers on a line (surface) where the boundary condition is to be enforced. The idea can be seen as an extension of the Chimera method of (ESAIM: Math. Model Numer. Anal. 2003; 37:495–514), but with a hierarchical representation of the discontinuous solution field. The hierarchical formulation is better suited for moving fictitious boundaries since the stiffness matrix of the underlying structured mesh can be retained during the computations.

Our technique allows for optimal convergence properties irrespective of the order of the underlying finite element method. Copyright © 2010 John Wiley & Sons, Ltd.
Multiple pole residue approach for 3D BEM analysis of mathematical degenerate and non‐degenerate materials
Authors: Buroni Federico C. , Ortiz Jhonny E. , Sáez Andrés
Published: December 2010

In this paper we develop an alternative boundary element method (BEM) formulation for the analysis of anisotropic three‐dimensional (3D) elastic solids. Our implementation is based on the derivation of explicit expressions for the fundamental solution displacements and tractions, of general validity for any class of anisotropic materials, by means of Stroh formalism and Cauchy's residue theory. The resulting fundamental solution remains valid for mathematical degenerate cases when Stroh's eigenvalues are coincident, meanwhile it does not exhibit numerical instabilities for quasi‐degenerate cases when Stroh's eigenvalues are nearly equal. A multiple pole residue approach is followed, leading to general explicit expressions to evaluate the traction fundamental solution for poles of m‐multiplicity. Despite the existence of general displacement solutions in the literature, and for the sake of completeness, the same approach as for the traction solution is considered to derive the displacement fundamental solution as well. Based on these solutions, an explicit BEM approach for the numerical solution of 3D linear elastic problems for solids with general anisotropic behavior is presented. The analysis of cracked anisotropic solids is also considered. Details on the numerical implementation and its validation for degenerate cases are discussed. Copyright © 2010 John Wiley & Sons, Ltd.
Higher‐order extended finite elements with harmonic enrichment functions for complex crack problems
Authors: Mousavi S. E. , Grinspun E. , Sukumar N.
Published: December 2010

In this paper, we analyze complex crack problems in elastic media using harmonic enrichment functions in a higher‐order extended finite element implementation. The numerically computed enrichment function of a crack is the solution of the Laplace equation with discontinuous Dirichlet boundary condition along the crack, and its interaction with branches or other cracks is realized by imposing vanishing Neumann boundary conditions along those cracks. The classical finite element displacement approximation is enriched by adding the enrichment function of a crack through the framework of partition of unity. A nested subgrid mesh is used in the Laplace solve with a rasterized approximation of a crack, which simplifies the numerical integration—no partitioning of finite elements is required. Harmonic enrichment functions readily permit the extension to handle multiple interacting and branched cracks without any special treatment around the junction points. Several numerical examples are presented that affirm the accuracy and effectiveness of the method when applied to complex crack configurations under mixed‐mode loading conditions. Copyright © 2010 John Wiley & Sons, Ltd.
Dispersion error reduction for acoustic problems using the edge‐based smoothed finite element method (ES‐FEM)
Authors: He Z. C. , Cheng A. G. , Zhang G. Y. , Zhong Z. H. , Liu G. R.
Published: December 2010

The paper reports a detailed analysis on the numerical dispersion error in solving 2D acoustic problems governed by the Helmholtz equation using the edge‐based smoothed finite element method (ES‐FEM), in comparison with the standard FEM. It is found that the dispersion error of the standard FEM for solving acoustic problems is essentially caused by the ‘overly stiff’ feature of the discrete model. In such an ‘overly stiff’ FEM model, the wave propagates with an artificially higher ‘numerical’ speed, and hence the numerical wave‐number becomes significantly smaller than the actual exact one. Owing to the proper softening effects provided naturally by the edge‐based gradient smoothing operations, the ES‐FEM model, however, behaves much softer than the standard FEM model, leading to the so‐called very ‘close‐to‐exact’ stiffness. Therefore the ES‐FEM can naturally and effectively reduce the dispersion error in the numerical solution in solving acoustic problems. Results of both theoretical and numerical studies will support these important findings. It is shown clearly that the ES‐FEM suits ideally well for solving acoustic problems governed by the Helmholtz equations, because of the crucial effectiveness in reducing the dispersion error in the discrete numerical model. Copyright © 2010 John Wiley & Sons, Ltd.
Detection and characterization of transport barriers in complex flows via ridge extraction of the finite time Lyapunov exponent field
Authors: Senatore Carmine , Ross Shane D.
Published: December 2010

This paper proposes an algorithm to detect and characterize ridges in the finite time Lyapunov exponent (FTLE) field obtained from a continuous dynamical system or flow. These ridges represent time‐dependent separatrices of the flow and are also called Lagrangian coherent structures (LCS). LCS have been demonstrated to be an effective way to analyze realistic time‐chaotic flows, although they can be quite complex. Therefore, in order to exploit the information that LCS can provide it is important to locate and characterize these structures in a systematic way. This can be accomplished by interpreting the FTLE as a height field and detecting the LCS as ridges of this graph. Methodologies developed in the image processing framework are integrated with dynamical system inspired approaches in order to characterize ridge strength and location. The main novel contribution of the proposed algorithm is a scheme to connect sets of points into curves or surfaces (rather than distributions of points around a ridge axis) and classify these curves or surfaces using a dynamical systems measure of strength. This approach provides the capability to track ranked LCS in space and time. The results are presented for a simple analytical model and noisy LCS from realistic three‐dimensional geophysical fluid data. Copyright © 2010 John Wiley & Sons, Ltd.
Late Epipaleolithic hunters of the central Taurus: Faunal remains from Direkli Cave, Kahramanmaraş, Turkey
Authors: Arbuckle B. S. , Erek C. M.
Published: December 2010

Newly initiated research at Direkli cave is helping to define an initial understanding of Epipaleolithic hunter‐gatherer traditions in the central Taurus region of southern Turkey. Detailed analysis of the Direkli faunal assemblage suggests that in the late Epipaleolithic the cave functioned as a short‐term logistical camp used to intercept wild goats (Capra aegagrus) in the high peaks around the cave, primarily in the late summer and fall. In addition, hunters opportunistically exploited deer and a variety of other small taxa, including tortoise, in the forested vicinity of the site. Evidence for low intensity and seasonal occupation of the cave indicates that Epipaleolithic foragers in the region were highly mobile, utilised a wide range of resources, but primarily scheduled use of the cave in order to exploit high ranked wild goat resources. This represents the first window into the nature of foraging systems just prior to the emergence of agricultural economies in this important region of Turkey. Copyright © 2010 John Wiley & Sons, Ltd.
Implications of age variation and sexual dimorphism in modern equids for Middle Pleistocene equid taxonomy
Authors: van Asperen E. N.
Published: December 2010

Interspecific variation in the equid lineage is limited when compared with other large mammal lineages, while a considerable amount of intraspecific ecomorphological variation occurs. This has led to considerable debate regarding the taxonomic status of palaeontological and archaeological equid remains. The possible confounding impact of sex and age variation on analyses of archaeological equid remains has so far remained untested. This could be especially problematic when it is unknown whether an assemblage contains more than one equid species, breed or hybrid. Here, sex and age variation in modern equid species is examined and compared to variation in Pleistocene equid assemblages from northwest Europe. Sex variation in the longbones of modern equid species was found to be lower than variation over time. Similarly, age variation in dental elements of the same species is predominantly lower than diachronic variation, although caution needs to be taken when an archaeological assemblages consists mostly of elements at a similar wear stage.

To assess whether late Middle Pleistocene caballoid horse fossils should be assigned to multiple species or be considered to form a monospecific group, the coefficients of variation for measurements on fossil horse remains were compared with those for modern equid specimens. Results indicate that the fossil assemblages are similarly variable to samples of modern material. Taken as a whole, the late Middle Pleistocene caballoid horse lineage is equally variable to an assemblage of modern ponies of a variety of different breeds. This implies that the variation observed between samples dating from different parts of the Middle Pleistocene can be characterised as intraspecific variation within a single species reflecting ecomorphological adaptations to the changeable Pleistocene climate. Copyright © 2010 John Wiley & Sons, Ltd.