bluuebunny/crossref_metadata_2025 huggingface dataset:
Restoration of absent in melanoma 2 (AIM2) induces G2/M cell cycle arrest and promotes invasion of colorectal cancer cells
Authors: Patsos Georgios , Germann Anja , Gebert Johannes , Dihlmann Susanne
Published: September 2009

Absent in melanoma 2 (AIM2) is a member of the interferon‐inducible HIN‐200 protein family. Recent findings point to a role of AIM2 function in both inflammation and cancer. In response to foreign cytoplasmic DNA, AIM2 forms an inflammasome, resulting in caspase activation in inflammatory cells. Moreover, AIM2 reduces breast cancer cell proliferation and mammary tumor growth in a mouse model and shows a high frequency of frameshift mutations in microsatellite unstable (MSI‐H) gastric, endometrial and colorectal cancers. However, the consequences of AIM2 restoration in AIM2‐deficient colon cancer cells have not yet been examined. Using different constructs for expression of AIM2 fusion proteins, we found that AIM2 restoration clearly suppressed cell proliferation and viability in HCT116 cells as well as in cell lines derived from other entities. In contrast to previous reports from breast cancer cells, our cell cycle analyses of colon cancer cells revealed that AIM2‐mediated inhibition of cell proliferation is associated with accumulation of cells at late S‐phase, resulting in G2/M arrest. The latter correlated well with upregulation of cyclin D3 and p21Waf1/Cip1 as well as with inhibition of cdc2 activity through Tyr‐15 phosphorylation. Furthermore, AIM2 restoration affected the adhesion of colorectal cancer cells to fibronectin and stimulated the invasion through extracellular matrix‐coated membrane in transwell assays. Consistent with this phenotype, AIM2 induced the expression of invasion‐associated genes such as VIM and MCAM, whereas ANXA10 and CDH1 were downregulated. Our data suggest that AIM2 mediates reduction of cell proliferation by cell cycle arrest, thereby conferring an invasive phenotype in colon cancer cells.
Determinants of delays in treatment initiation in children and adolescents diagnosed with leukemia or lymphoma in Canada
Authors: Dang‐Tan Tam , Trottier Helen , Mery Leslie S. , Morrison Howard I. , Barr Ronald D. , Greenberg Mark L. , Franco Eduardo L.
Published: September 2009

Minimizing delays that may occur along the cancer care pathway requires an understanding of their determinants. Few studies on childhood cancers have been published on the factors that influence the time it takes for patients to get a first medical consultation (patient delay) and treatment (health care system [HCS] delay) once cancer symptoms have been recognized. Our objective was to assess factors related to disease, patient and HCS on patient and HCS delay for children and adolescents with leukemias and lymphomas in Canada. A prospective cohort study was conducted on subjects enrolled in the Treatment and Outcomes Surveillance program of the Canadian Childhood Cancer Surveillance and Control Program, a national surveillance program. We studied 963 leukemia and 397 lymphoma patients who were less than 19‐years old at diagnosis in 1995–2000. Logistic regression models were used to measure the associations between candidate predictive factors and delays. Age was positively associated with patient delay for both leukemia and lymphoma patients, but not with HCS delay. Patients first seen in a hospital emergency room had a lower risk of HCS delay than patients first seen by a general practitioner. Cancer subtype was associated with patient delay for leukemia patients, and HCS delay for lymphoma patients. Longer patient delay was associated with a lower risk of long HCS delay for both cancers. Factors related to the patients, their disease and the HCS may exert different influences on varying segments of the care pathway of leukemia and lymphoma patients.
A blood‐based biomarker panel for stratifying current risk for colorectal cancer
Authors: Marshall Kenneth Wayne , Mohr Steve , Khettabi Faysal El , Nossova Nadejda , Chao Samuel , Bao Weisheng , Ma Jun , Li Xiao‐Jun , Liew Choong‐Chin
Published: September 2009

Colorectal cancer (CRC) is often curable and preventable using current screening modalities. Unfortunately, screening compliance remains low, partly due to patient dissatisfaction with faecal/endoscopic testing. Recent guidelines advise CRC screening should begin with risk stratification. A blood‐based test providing clinically actionable CRC risk information would likely improve screening compliance and enhance clinical decision making. We analyzed 196 gene expression profiles to select candidate CRC biomarkers. qRT‐PCR was performed on 642 samples to develop a 7‐gene biomarker panel using 112 CRC/120 controls (training set) and 202 CRC/208 controls (independent, blind test set). Panel performance characteristics and disease prevalence (0.7%) were then used to develop a scale assessing an individual's current risk of having CRC based on his/her gene signature. A 7‐gene panel (ANXA3, CLEC4D, LMNB1, PRRG4, TNFAIP6, VNN1 and IL2RB) discriminated CRC in the training set (area under the receiver‐operating‐characteristic curve (ROC AUC), 0.80; accuracy, 73%; sensitivity, 82%; specificity 64%). The independent blind test set confirmed performance (ROC AUC, 0.80; accuracy, 71%; sensitivity, 72%; specificity, 70%). Individual gene profiles were compared against the population results and used to calculate the current relative risk for CRC. We have developed a 7‐gene, blood‐based biomarker panel that can stratify subjects according to their current relative risk across a broad range in an average‐risk population. Across the continuous spectrum of risk as defined by the current relative risk scale, it is possible to identify clinically meaningful reference points that can assist patients and physicians in CRC screening decision making.
Biological and clinical relevance of transcriptionally active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma
Authors: Jung Alain C. , Briolat Jenny , Millon Régine , de Reyniès Aurélien , Rickman David , Thomas Emilie , Abecassis Joseph , Clavel Christine , Wasylyk Bohdan
Published: September 2009

Human papillomaviruses (HPV) are associated with a subset of head and neck squamous cell carcinoma (HNSCC), particularly HPV16. This study analyzed the presence and genotype of high risk HPVs, viral DNA load and transcription of the E6/E7 mRNAs, in 231 consecutive HNSCC. Twelve out of 30 HPV16 DNA‐positive tumors displayed high E6/E7 mRNAs levels and were localized in the oropharyngeal region. While HPV‐free and non‐transcriptionally active HPV‐related patients showed similar 5‐years survival rates, E6/E7 expression was associated with a better prognosis. This emphasizes the importance of considering the transcriptional status of HPV‐positive tumors for patient stratification. A gene expression profiling analysis of these different types of tumors was carried out. The most significant differentially expressed gene was CDKN2A, a known biomarker for HPV‐related cancer. Assessing both the expression level of the E6/E7 mRNAs and of CDKN2A in HNSCC is required to detect active HPV infection. Chromosomic alterations were investigated by Comparative Genomic Hybridation (CGH) analysis of tumors with transcriptionally active HPV and HPV‐negative tumors. The loss of the chromosomal region 16q was found to be a major genetic event in HPV‐positive lesions. A cluster of genes located in 16q21‐24 displayed decreased expression levels, notably APP‐BP1 that is involved in the modulation of the transcriptional activity of p53. In conclusion, this study highlights important criteria required to predict clinically active HPV infection, identifies new biological pathways implicated in HPV tumorigenesis and increases the understanding of HPV‐HNSCC physiopathology that is required to develop new targets for therapy.
Multiple serological biomarkers for colorectal cancer detection
Authors: Chan Chung‐Chuan , Fan Chung‐Wei , Kuo Yung‐Bin , Chen Yu‐Han , Chang Pi‐Yueh , Chen Kuei‐Tien , Hung Ray‐Ping , Chan Err‐Cheng
Published: September 2009

The aim of this study was to initiate a survey of human autoantibody responses to a panel of select colorectal tumor‐associated antigens identified by previous serological analysis of a cDNA expression library and to subsequently identify multiple serological biomarkers for the detection of colorectal cancer. For screening of autoantibodies against colorectal tumor‐associated antigens, sera from 94 colorectal cancer patients and 54 normal controls were analyzed by enzyme‐linked immunosorbent assay using recombinant rCCCAP, rHDAC5, rP53, rNMDAR and rNY‐CO‐16 proteins as coating antigens. Seropositivity among colorectal cancer patients to the 5 individual coating antigens varied from 18.1% to 35.1%. Seropositivity to any of the 5 coating antigens was 58.5% and combining this analysis with evaluation of serum carcinoembryonic antigen (≥5 ng/ml) significantly increased the seropositivity to 77.6%. Seropositivity of early‐stage (Dukes' Stages A and B) colorectal cancer patients to CEA was 21.9%, and seropositivity to any of the 5 colorectal cancer‐associated antigens was 53.7%, and the combination of these 2 measurements resulted in a higher diagnostic capacity (65.9%) than either marker alone. In conclusion, these results collectively indicated that combined detection of serum autoantibody profiles against our panel of colorectal tumor‐associated antigens and the analysis of carcinoembryonic antigen provides a promising diagnostic biomarker for colorectal cancer, particularly among early‐stage patients.
Prospective study of body mass index, physical activity and thyroid cancer
Authors: Leitzmann Michael F. , Brenner Alina , Moore Steven C. , Koebnick Corinna , Park Yikyung , Hollenbeck Albert , Schatzkin Arthur , Ron Elaine
Published: September 2009

Increased body size and physical inactivity are positively related to risk of several cancers, but only few epidemiologic studies have investigated body‐mass index (BMI) and physical activity in relation to thyroid cancer. We examined the relations of BMI and physical activity to thyroid cancer in a prospective cohort of 484,326 United States men and women, followed from 1995/1996 to 2003. During 3,490,300 person‐years of follow‐up, we documented 352 newly incident cases of thyroid cancer. The multivariate relative risks (RR) of thyroid cancer for BMI values of 18.5–24.9 (reference), 25.0–29.9 and ≥30 kg m−2were 1.0, 1.27 and 1.39 [95% confidence interval (CI) = 1.05–1.85]. Adiposity predicted papillary thyroid cancers (RR comparing extreme BMI categories = 1.47; 95% CI = 1.03–2.10) and, based on small numbers, suggestively predicted follicular thyroid cancers (RR = 1.49; 95% CI = 0.79–2.82) and anaplastic thyroid cancers (RR = 5.80; 95% CI = 0.99–34.19). No relation with BMI was noted for medullary thyroid cancers (RR = 0.97; 95% CI = 0.27–3.43). The positive relation of BMI to total thyroid cancer was evident for men but not for women. However, the test of interaction (p= 0.463) indicated no statistically significant gender difference. Physical activity was unassociated with thyroid cancer. The RRs of total thyroid cancer for low (reference), intermediate, and high level of physical activity were 1.0, 1.01 and 1.01 (95% CI = 0.76–1.34,pfor trend = 0.931), respectively. Our results support an adverse effect of adiposity on risk for developing total and papillary, and possibly follicular thyroid cancers. Based on only 15 cases, adiposity was unrelated to medullary thyroid cancers. Physical activity was unrelated to total thyroid cancer.
Tumor‐targeted intracellular delivery of anticancer drugs through the mannose‐6‐phosphate/insulin‐like growth factor II receptor
Authors: Prakash Jai , Beljaars Leonie , Harapanahalli Akshay K. , Zeinstra‐Smith Mieke , de Jager‐Krikken Alie , Hessing Martin , Steen Herman , Poelstra Klaas
Published: September 2009

Tumor‐targeting of anticancer drugs is an interesting approach for the treatment of cancer since chemotherapies possess several adverse effects. In the present study, we propose a novel strategy to deliver anticancer drugs to the tumor cells through the mannose‐6‐phosphate/insulin‐like growth factor receptor (M6P/IGF‐IIR) which are abundantly expressed in several human tumors. We developed a drug carrier against M6P/IGF‐II receptor by modifying human serum albumin (HSA) with M6P moieties. M6P‐HSA specifically bound and internalized into M6P/IGF‐IIR‐expressing B16 melanoma cells as demonstrated with radioactive studies and anti‐HSA immunostaining. In vivo, M6P‐HSA rapidly accumulated in subcutaneous tumors in tumor and stromal components after an intravenous injection. To demonstrate the application of M6P‐HSA as a drug carrier, we coupled doxorubicin to it. Dox‐HSA‐M6P conjugate could release doxorubicin at lysosomal pH and showed M6P‐specific binding and uptake in tumor cells. In vitro, a short exposure with Dox‐HSA‐M6P induced killing of tumor cells, which could be blocked by excess M6P‐HSA. In vivo, Dox‐HSA‐M6P distributed to tumors and some other organs while free doxorubicin distributed to all organs but slightly to tumors. In B16 tumor‐bearing mice, Dox‐HSA‐M6P significantly inhibited the tumor growth whereas an equimolar dose of free doxorubicin did not show any anti‐tumor effect. In addition, targeted doxorubicin did not show any side‐effects on liver and kidney function tests, body weight and blood cell counts. In conclusion, M6P‐HSA is a suitable carrier for delivery of anticancer drugs to tumors through M6P/IGF‐IIR. Improved antitumor effects of the targeted doxorubicin by M6P‐HSA suggest that this novel approach may be applied to improve the therapeutic efficacy of anticancer drugs.
Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas
Authors: Beckner Marie E. , Fellows‐Mayle Wendy , Zhang Zhe , Agostino Naomi R. , Kant Jeffrey A. , Day Billy W. , Pollack Ian F.
Published: September 2009

Glioblastomas, the most malignant type of glioma, are more glycolytic than normal brain tissue. Robust migration of glioblastoma cells has been previously demonstrated under glycolytic conditions and their pseudopodia contain increased glycolytic and decreased mitochondrial enzymes. Glycolysis is suppressed by metabolic acids, including citric acid which is excluded from mitochondria during hypoxia. We postulated that glioma cells maintain glycolysis by regulating metabolic acids, especially in their pseudopodia. The enzyme that breaks down cytosolic citric acid is ATP citrate lyase (ACLY). Our identification of increased ACLY in pseudopodia of U87 glioblastoma cells on 1D gels and immunoblots prompted investigation of ACLY gene expression in gliomas for survival data and correlation with expression of ENO1, that encodes enolase 1. Queries of the NIH's REMBRANDT brain tumor database based on Affymetrix data indicated that decreased survival correlated with increased gene expression of ACLY in gliomas. Queries of gliomas and glioblastomas found an association of upregulated ACLY and ENO1 expression by chi square for all probe sets (reporters) combined and correlation for numbers of probe sets indicating shared upregulation of these genes. Real‐time quantitative PCR confirmed correlation between ACLY and ENO1 in 21 glioblastomas (p < 0.001). Inhibition of ACLY with hydroxycitrate suppressed (p < 0.05) in vitro glioblastoma cell migration, clonogenicity and brain invasion under glycolytic conditions and enhanced the suppressive effects of a Met inhibitor on cell migration. In summary, gene expression data, proteomics and functional assays support ACLY as a positive regulator of glycolysis in glioblastomas.
Targeting slow‐proliferating ovarian cancer cells
Authors: Kondoh Eiji , Mori Seiichi , Yamaguchi Ken , Baba Tsukasa , Matsumura Noriomi , Cory Barnett J. , Whitaker Regina S. , Konishi Ikuo , Fujii Shingo , Berchuck Andrew , Murphy Susan K.
Published: September 2009

Advanced ovarian cancer has a high rate of recurrence and mortality despite relative chemosensitivity at the time of initial treatment. Conventional chemotherapeutic agents typically target rapidly dividing cells. Disease relapse may therefore result from the survival and later emergence of latent slow‐proliferating and/or quiescent cancer cells. We sought to identify drugs that target this cell population and to investigate the influence of these cells on outcome of patients in remission from advanced ovarian cancer. Drugs with increased efficacy against slower proliferating cells were identified using correlation‐based screening of 44,657 compounds tested on the NCI‐60 panel of cancer cell lines. Validation of candidates was performed in comparison with Cisplatin or Paclitaxel and by manipulation of proliferation rates by serum deprivation. Cytostatic and cytocidal effects were evaluated using MTT assays and active caspase‐3 immunocytochemistry. Ki‐67 proliferation indices were determined for tumors from 104 patients in remission. UCN‐01 efficacy was correlated with longer doubling time among the NCI‐60 cell lines (R = 0.54, p < 0.0001) and in a panel of 24 ovarian cancer cell lines (R = 0.42, p = 0.04), whereas this was not the case for Cisplatin (R = −0.10, p = 0.65) and Paclitaxel efficacy correlated with shorter doubling time (R = −0.52, p = 0.009). Cytostatic and cytocidal effects of UCN‐01 were increased in serum‐deprived cells. A low proliferation index was associated with presence of persistent disease at second‐look surgery (p = 0.01) and poor survival (disease‐free survival, p = 0.002; overall survival, p = 0.04). These results suggest that targeting quiescent ovarian cancer cells may be a worthwhile therapeutic approach to improving survival of women with ovarian cancer.
A fluorescence lifetime imaging scanning confocal endomicroscope
Authors: Kennedy Gordon T. , Manning Hugh B. , Elson Daniel S. , Neil Mark A. A. , Stamp Gordon W. , Viellerobe Bertrand , Lacombe François , Dunsby Chris , French Paul M. W.
Published: September 2009

We describe a fluorescence lifetime imaging endomicroscope employing a fibre bundle probe and time correlated single photon counting. Preliminary images of stained pollen grains, eGFP‐labelled cells exhibiting Förster resonant energy transfer and tissue autofluorescence are presented. (© 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Interactive effects of mechanical stretching and extracellular matrix proteins on initiating osteogenic differentiation of human mesenchymal stem cells
Authors: Huang Chien‐Hsun , Chen Min‐Huey , Young Tai‐Horng , Jeng Jiiang‐Huei , Chen Yi‐Jane
Published: September 2009

Human mesenchymal stem cells (hMSCs) are characterized by their abilities to differentiate into different lineages, including osteoblasts. Besides soluble factors, mechanical strain and extracellular matrix (ECM) proteins play important roles in osteogenic differentiation of hMSCs. However, interactions between them are still not fully understood. The purpose of this study was to investigate the combined effects of insoluble chemical and mechanical factors (ECM proteins vs. cyclic stretching) in driving hMSCs into osteogenic differentiation. To avoid the influence from osteogenic supplements, hMSCs were cultured in regular medium and subjected to cyclic mechanical stretching using a Flexcell Tension system (3% elongation at 0.1 Hz) when they were grown on substrates coated with various ECM proteins (collagen I (Col I), vitronectin (VN), fibronectin (FN), and laminin (LN)). Using alkaline phosphatase (ALP) activity and mineralized matrix deposition as respective indicators of the early and late stages of osteogenesis, we report herein that all of the ECM proteins tested supported hMSC differentiation into osteogenic phenotypes in the absence of osteogenic supplements. Moreover, cyclic mechanical stretching activated the phosphorylation of focal adhesion kinase (FAK), upregulated the transcription and phosphorylation of core‐binding factor alpha‐1 (Cbfa1), and subsequently increased ALP activity and mineralized matrix deposition. Among the ECM proteins tested, FN and LN exhibited greater effects of supporting stretching‐induced osteogenic differentiation than did Col I and VN. The ability of ECM proteins and mechanical stretching to regulate osteogenesis in hMSCs can be exploited in bone tissue engineering via approximate matrix design or application of mechanical stimulation. J. Cell. Biochem. 108: 1263–1273, 2009. © 2009 Wiley‐Liss, Inc.
Local flip angle correction for improved volume T1‐quantification in three‐dimensional dGEMRIC using the look‐locker technique
Authors: Siversson Carl , Tiderius Carl‐Johan , Dahlberg Leif , Svensson Jonas
Published: September 2009

Purpose

To present an evaluation method for three‐dimensional Look‐Locker (3D‐LL) based T1 quantification, calculating correct T1 values independent of local flip angle (FA) variations. The method was evaluated both in phantoms and in vivo in a delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC) study with 33 subjects.

Materials and Methods

T1 was measured with 3D‐LL, using both local FA correction and a precalculated FA slice profile, and compared with standard constant FA correction, for all slices in phantoms and in both femur condyles in vivo. T1 measured using two‐dimensional Inversion Recovery (2D‐IR) was used as gold standard.

Results

Due to the FA being slice dependent, the standard constant FA correction results in erroneous T1 (systematic error = 109.1 ms in vivo), especially in the outer slices. With local FA correction, the calculated T1 is excellent for all slices in phantoms (<5% deviation from 2D‐IR). In vivo the performance is lower (systematic error = −57.5 ms), probably due to imperfect inversion. With precalculated FA correction the performance is very good also in vivo (systematic error = 13.3 ms).

Conclusion

With the precalculated FA correction method, the 3D‐LL sequence is robust enough for in vivo dGEMRIC, even outside the centermost slices. J. Magn. Reson. Imaging 2009;30:834–841. © 2009 Wiley‐Liss, Inc.
Differentiating multiple sclerosis from other causes of demyelination using diffusion weighted imaging of the corpus callosum
Authors: Straus Farber Rebecca , DeVilliers Laetitia , Miller Aaron , Lublin Fred , Law Meng , Fatterpekar Girish , Delman Bradley , Naidich Thomas
Published: September 2009

Purpose

To compare diffusion weighted imaging metrics in gray and white matter brain regions of patients diagnosed with multiple sclerosis (MS) to those diagnosed with secondary demyelinating diseases such as neurosarcoid and acute disseminated encephalomyelitis (ADEM).

Materials and Methods

Diffusion weighted scans were performed and apparent diffusion coefficients of 12 regions of interest were determined in 30 MS patients, 21 neurosarcoid patients, and 4 ADEM patients.

Results

Mean apparent diffusion coefficients were significantly higher in MS patients than in non‐MS patients in 6 of 6 of the corpus callosal regions assessed but not in any of the non‐callosal white or gray matter regions assessed.

Conclusion

Elevated apparent diffusion coefficients within the corpus callosum on diffusion weighted imaging may potentially help differentiate between patients with MS and patients with other diseases affecting the central nervous system white matter. J. Magn. Reson. Imaging 2009;30:732–736. © 2009 Wiley‐Liss, Inc.
Mutual effects of caveolin and nerve growth factor signaling in pig oligodendrocytes
Authors: Schmitz Matthias , Klöppner Sabine , Klopfleisch Steve , Möbius Wiebke , Schwartz Peter , Zerr Inga , Althaus Hans H.
Published: September 2009

Signaling of growth factors may depend on the recruitment of their receptors to specialized microdomains. Previous reports on PC12 cells indicated an interaction of raft‐organized caveolin and TrkA signaling. Because porcine oligodendrocytes (OLs) respond to nerve growth factor (NGF), we were interested to know whether caveolin also plays a role in oligodendroglial NGF/TrkA signaling. OLs expressed caveolin at the plasma membrane but also intracellularly. This was partially organized in the classically Ω‐shaped invaginations, which may represent caveolae. We could show that caveolin and TrkA colocalize by using a discontinuous sucrose gradient (Song et al. [1996] J. Biol. Chem. 271:9690–9697), MACS technology, and immunoprecipitation. However, differential extraction of caveolin and TrkA with Triton X‐100 at 4°C indicated that caveolin and TrkA are probably not exclusively present in detergent‐resistant, caveolin‐containing rafts (CCRs). NGF treatment of OLs up‐regulated the expression of caveolin‐1 (cav‐1) and stimulated tyrosine‐14 phosphorylation of cav‐1. Furthermore, OLs were transfected with cav‐1‐specific small interfering RNA (siRNA). A knockdown of cav‐1 resulted in a reduced activation of downstream components of the NGF signaling cascade, such as p21Ras and mitogen‐activated protein kinase (MAPK) after NGF exposure of OLs. Subsequently, increased oligodendroglial process formation via NGF was impaired. The present study indicates that CCRs/caveolin could play a modulating role during oligodendroglial differentiation and regeneration. © 2009 Wiley‐Liss, Inc.
Interaction of Rab31 and OCRL‐1 in oligodendrocytes: Its role in transport of mannose 6‐phosphate receptors
Authors: Rodriguez‐Gabin A.G. , Ortiz E. , Demoliner K. , Si Q. , Almazan G. , Larocca J.N.
Published: September 2009

Rab31, a protein that we cloned from an oligodendrocyte cDNA library, is required for transport of mannose 6‐phosphate receptors (MPRs) from the trans‐Golgi network (TGN) to endosomes and for Golgi/TGN organization. Here we extend the knowledge of the mechanism of action of Rab31 by demonstrating its interaction with OCRL‐1, a phosphatidylinositol 4,5‐diphosphate 5‐phosphatase (PI(4,5)P2 5‐phosphatase) that regulates the levels of PI(4,5)P2 and PI(4)P, molecules involved in transport and Golgi/TGN organization. We show that Rab31 interacts with OCRL‐1 in a yeast two‐hybrid system, GST‐Rab31 pull‐down experiments, and coimmunoprecipitation of OCRL‐1 using oligodendrocyte culture lysates. Rab31 and OCRL‐1 colocalize in the TGN, post‐TGN carriers, and endosomes. Cation‐dependent MPR (CD‐MPR) is sorted to OCRL‐1‐containing carriers, but CD63 and vesicular stomatitis virus G (VSVG) are not. siRNA‐mediated depletion of endogenous Rab31 causes collapse of the TGN apparatus and markedly decreases the levels of OCRL‐1 in the TGN and endosomes. Our observations indicate that the role of Rab31 in the Golgi/TGN structure and transport of MPRs depends on its capability to recruit OCRL‐1 to domains of the TGN where the formation of carriers occurs. The importance of our observations is highlighted by the fact that mutation of OCRL‐1 causes demyelination in humans. © 2009 Wiley‐Liss, Inc.
Trimethyltin intoxication up‐regulates nitric oxide synthase in neurons and purinergic ionotropic receptor 2 in astrocytes in the hippocampus
Authors: Latini Laura , Geloso Maria Concetta , Corvino Valentina , Giannetti Stefano , Florenzano Fulvio , Viscomi Maria Teresa , Michetti Fabrizio , Molinari Marco
Published: September 2009

Nitric oxide (NO) and purinergic ionotropic receptors (P2X) mediate cellular events in the central nervous system (CNS) under physiological conditions as well as during pathological events, and they have been recently proposed to interact in mediating CNS response to injury (Viscomi et al. [2004] Neuroscience 123:393–404; Florenzano et al. [2008] Pflugers Arch. 452:622–644). Trimethyltin (TMT) is an organotin compound that generates neurotoxic effects, and it has been used in a model of neurodegenerative disease and memory dysfunction. TMT causes neuronal death and reactive gliosis primarily in the hippocampus and other limbic regions. In the present study, we examined the degenerative events and the expression of nitric oxide synthase (NOS) and P2X receptor subtypes (P2X1,2,4,7Rs) that were induced by TMT administration at different time points (3, 7, 14, and 21 days) by conventional and confocal microscopy and Western blotting. Massive glial activation and neuronal death in the CA1 and CA3 regions were observed after TMT treatment. In these areas, astrocytic P2X2R and neuronal NOS were temporarily enhanced in association with the progression of neuronal death. In the hippocampus, the physiological expression of P2X1R, P2X4R, and P2X7R was not modified by TMT. The present data demonstrate that, as in other neurodegenerative models, TMT‐induced hippocampal degeneration is associated with nitrergic and purinergic activations. Nevertheless, at odds with previous data, in this model the two systems are active in segregated cell populations, namely, P2XR in astrocytes and NOS in neurons. Finally, the temporal relations between P2XR and NOS expression and neuronal degeneration suggest interactions between P2XR/NO signaling and cell survival. © 2009 Wiley‐Liss, Inc.
A developmental approach to complex PTSD: Childhood and adult cumulative trauma as predictors of symptom complexity
Authors: Cloitre Marylene , Stolbach Bradley C. , Herman Judith L. , Kolk Bessel van der , Pynoos Robert , Wang Jing , Petkova Eva
Published: September 2009

Exposure to multiple traumas, particularly in childhood, has been proposed to result in a complex of symptoms that includes posttraumatic stress disorder (PTSD) as well as a constrained, but variable group of symptoms that highlight self‐regulatory disturbances. The relationship between accumulated exposure to different types of traumatic events and total number of different types of symptoms (symptom complexity) was assessed in an adult clinical sample (N = 582) and a child clinical sample (N = 152). Childhood cumulative trauma but not adulthood trauma predicted increasing symptom complexity in adults. Cumulative trauma predicted increasing symptom complexity in the child sample. Results suggest that Complex PTSD symptoms occur in both adult and child samples in a principled, rule‐governed way and that childhood experiences significantly influenced adult symptoms.
Brainstem pathology in spasmodic dysphonia
Authors: Simonyan Kristina , Ludlow Christy L. , Vortmeyer Alexander O.
Published: September 2009

Spasmodic dysphonia (SD) is a primary focal dystonia of unknown pathophysiology, characterized by involuntary spasms in the laryngeal muscles during speech production. We examined two rare cases of postmortem brainstem tissue from SD patients compared to four controls. In the SD patients, small clusters of inflammation were found in the reticular formation surrounding solitary tract, spinal trigeminal, and ambigual nuclei, inferior olive, and pyramids. Mild neuronal degeneration and depigmentation were observed in the substantia nigra and locus coeruleus. No abnormal protein accumulations and no demyelination or axonal degeneration were found. These neuropathological findings may provide insights into the pathophysiology of SD. Laryngoscope, 2010
Positive family history of essential tremor influences the motor phenotype of Parkinson's disease
Authors: Hedera Peter , Fang John Y. , Phibbs Fenna , Cooper Michael K. , Charles P. David , Davis Thomas L.
Published: September 2009

Previous reports have suggested that essential tremor (ET) represents a risk factor for the development of Parkinson's disease (PD). Patients with long‐standing ET who develop PD tend to have a tremor‐dominant subtype. To further clarify this association, we examined patients from kindreds with autosomal dominant ET who had signs of isolated PD but did not meet criteria for overlapping ET. We identified 22 patients with PD meeting these diagnostic criteria, and 90% (20 of 22) had tremor‐predominant subtype of PD. Unilateral rest tremor was the presenting symptom in 15 of 22 patients, bradykinesia or rigidity in 5 of 22, and gait problems in 2 of 22. Postural tremor was relatively mild, and the severity of kinetic tremor tightly correlated with rest tremor (r = 0.83, P < 0.001). Tremor‐dominant subtype of PD in patients with a positive family history of ET suggests that these patients have inherited a genetic susceptibility factor for tremor, which affects the motor phenotype of PD. © 2009 Movement Disorder Society
Controversies in the Management of Alcoholic Liver Disease
Authors: Tan Hui‐Hui , Virmani Sharad , Martin Paul
Published: September 2009

Alcohol is a risk factor for chronic disease burden in developed countries. Alcoholic liver disease affects 1% of the North American population and is the second most frequent indication for liver transplantation in the United States. It is a spectrum that ranges from simple hepatic steatosis to alcoholic hepatitis to steatohepatitis and eventually cirrhosis. The clinical spectrum of alcoholic hepatitis is wide and ranges from the asymptomatic patient to overt liver failure and death. Liver biopsy as a means of prognostication in alcoholic hepatitis has mostly been replaced with less invasive scoring systems. The management of alcoholic liver disease is challenging. Abstinence is the cornerstone of therapy and should include rehabilitation with a multidisciplinary approach. No specific treatment is required in mild to moderate alcoholic hepatitis. In patients with severe hepatitis, there appears to be a moderate survival benefit from the use of either corticosteroids or pentoxifylline in the absence of contraindications to their use. Nonresponders should have steroid therapy withdrawn by day 7, as persistence with therapy is not beneficial. Orthotopic liver transplantation remains the definitive therapy for decompensated alcoholic cirrhosis despite alcohol abstinence. More studies are needed to define the optimal timing of orthotopic liver transplantation and patients at risk of alcohol relapse post‐transplant. Mt Sinai J Med 76:484–498, 2009. © 2009 Mount Sinai School of Medicine
The Bushmeat Trade: Increased Opportunities for Transmission of Zoonotic Disease
Authors: Karesh William B. , Noble Eric
Published: September 2009

Bushmeat is a term that refers to the use of wild animals, ranging from cane rats to gorillas, for food. The term typically refers to the practice in forests of Africa. The bushmeat trade is an example of an anthropogenic factor that provides opportunities for the transmission of diseases from wildlife to humans. The expansion of the bushmeat trade over the past 2 decades has provided a venue for the emergence of zoonotic diseases by providing an increased opportunity for the transmission of organisms known to cause disease and organisms with an unknown impact on humans. Because the bushmeat trade is embedded in a complex cultural, political, and economic context, efforts to prevent the emergence of zoonoses require a multidisciplinary approach. Mt Sinai J Med 76:429–434, 2009. © 2009 Mount Sinai School of Medicine
Non‐invasive and quantitative evaluation of peripheral vascular resistances in rats by combined NMR measurements of perfusion and blood pressure using ASL and dynamic angiography
Authors: Ménard Jacques C. , Giacomini Eric , Baligand Céline , Fromes Yves , Carlier Pierre G.
Published: September 2009

The in vivo determination of peripheral vascular resistances (VR) is crucial for the assessment of arteriolar function. It requires simultaneous determination of organ perfusion (F) and arterial blood pressure (BP). A fully non‐invasive method was developed to measure systolic and diastolic BP in the caudal artery of rats based on dynamic NMR angiography. A good agreement was found between the NMR approach and the gold standard techniques (linear regression slope = 0.98, R2 = 0.96). This method and the ASL‐MRI measurement of skeletal muscle perfusion were combined into one single NMR experiment to quantitatively evaluate the local vascular resistances in the calf muscle of anaesthetized rats, in vivo and non‐invasively 1) at rest: VR = 7.0 ± 1.0 mmHg·min 100 g·ml−1, F = 13 ±  3 ml min−1.100 g−1 and mean BP (MBP) = 88 ± 10 mmHg; 2) under vasodilator challenge (milrinone): VR = 3.7 ± 1.1 mmHg min.100 g ml−1, F = 21 ± 4 ml min−1.100 g−1 and MBP = 75 ± 14 mmHg; 3) under vasopressor challenge (norepinephrine): VR = 9.8 ± 1.2 mmHg min 100 g ml−1, F = 14 ± 3 ml min−1.100 g−1 and MBP = 137 ± 2 mmHg. Copyright © 2009 John Wiley & Sons, Ltd.
The social processes of interorganizational collaboration and conflict in nonprofit organizations
Authors: Tsasis Peter
Published: September 2009

This article takes a qualitative approach to research in advancing knowledge of the social process by which interorganizational relationships are established and nurtured in nonprofit organizations. The findings reveal that a balance of dependence and autonomy is needed for initiating interorganizational relationships. These relationships are stabilized at the interpersonal level through positive attributes (attitudes, perceptions, and trust) and interpersonal ties of individuals representing their organizations. Sources of conflict, such as value differences, divergent goals, and personality clashes, also influence the working relationships of these organizations.
The ritual dugong bone mounds of Koey Ngurtai, Torres Strait, Australia: Investigating their construction
Authors: Skelly Robert , David Bruno , McNiven Ian J. , Barker Bryce
Published: September 2009

The islands of Western Torres Strait, between Papua New Guinea and Australia, saw the emergence of ritual dugong bone mounds approximately 400 years ago. These mounds were used as a means to commune with, and as an aid for the hunting of, dugongs. This paper explores the bone contents of three dugong bone mounds on the small, uninhabited island of Koey Ngurtai as a means to determine their construction and in doing so to explore the historical emergence of ritual bone mounds associated with dugong hunting magic—and thereby to historicise ethnographically known cultural practices—in Torres Strait. Copyright © 2009 John Wiley & Sons, Ltd.
Made in China at a crossroads: a recourse‐based view
Authors: Zhang Shujun , Su Xiaohua
Published: September 2009

The brand ‘Made in China’ has long stood for low cost and good value. But recent revelations about the quality of some Chinese products exported overseas have begun to put this brand at risk. In the end, much of what constitutes this country brand depends on the strategies Chinese firms pursue, which in turn subject to the firm resources. Drawing from the resource‐base theory, this paper investigates the sources of the competitive advantage of the brand ‘Made in China’ and discusses the choices to be made by the Chinese firms and government in order to maintain a stable and better country brand.

Copyright © 2009 John Wiley & Sons, Ltd.
Alcohol marketing and young people's drinking: what the evidence base suggests for policy
Authors: Gordon Ross , Hastings Gerard , Moodie Crawford
Published: September 2009

As the influence of alcohol marketing on young people remains a highly contested topic we review the recent literature to examine if the debate has moved on. The extant literature shows that while many econometric studies suggest alcohol marketing to have a minimal effect on youth alcohol consumption, more focussed consumer studies, particularly recent research employing sophisticated longitudinal designs, demonstrate clear links between alcohol advertising and drinking behaviour. Encouragingly, some of the more recent research studies assess marketing activity beyond advertising; sponsorship, new media, viral marketing, price promotions, new forms of distribution, product development and increased point of sale activity. The literature presents increasingly compelling evidence that alcohol marketing is directly impacting upon young people's drinking behaviour. The implications of this on the current policy debate surrounding alcohol marketing activities and regulation in the UK and beyond are discussed. Furthermore a research agenda for alcohol marketing for the future is offered.

Copyright © 2009 John Wiley & Sons, Ltd.
Use of block copolymer as compatibilizer in polyimide/zeolite composite membranes
Authors: Patel Rajkumar , Park Jung Tae , Hong Hyun Pyo , Kim Jong Hak , Min Byoung Ryul
Published: September 2009

In this work, we introduced a diblock copolymer (dBC), i.e., polystyrene‐b‐poly(hydroxyl ethyl acrylate) (PS‐b‐PHEA) as a compatibilizer to enhance interfacial adhesion between PI and zeolite in PI/Zeolite/dBC (1/0.1/0.05 wt%) membrane for gas separation. FT‐IR spectroscopy showed the formation of hydrogen bonding interactions of the carbonyl and the hydroxyl in dBC with both PI and zeolite. The differential scanning calorimeter (DSC) study showed that the glass transition temperature (Tg) of PI increased upon the introduction of dBC, indicating specific interactions in the mixed matrix membranes. The gas permeabilities of H2, N2, O2, and CO2 through PI/zeolite 5A/dBC membranes were reduced but the permselectivity were increased compared to neat PI membrane. Copyright © 2009 John Wiley & Sons, Ltd.
Polypharmacy in primary care practices: an analysis using a large health insurance database
Authors: Grimmsmann Thomas , Himmel Wolfgang
Published: September 2009

Purpose

To ascertain the rate and range of continuous polypharmacy in German general practices and compare practice characteristics and prescribing profiles in practices with a high rate of polypharmacy patients (HPP) and a low rate of polypharmacy patients (LPP), respectively.

Methods

This observational study used a database composed of prescription data from a large German statutory health insurance. We defined polypharmacy as the continuous prescription of five or more drugs and calculated the percentage of polypharmacy patients for each practice to identify HPP and LPP.

Results

A total of 136 521 patients in 730 general practices received continuous medication. About 10% of these patients (14 293/136 521) received five or more different drugs. HPP had, on average, 15.1% polypharmacy patients compared to 4.2% in LPP. The total number of patients attending either a HPP or LPP was comparable (437 vs. 416; p = 0.102), but HPP had a higher number of patients with prescriptions (76.9% vs. 70.8%; p < 0.0001). The patients' age distribution was similar (68.0 in LPP vs. 68.8 in HPP) and there were slightly more female patients in LPP. Doctors in HPP prescribed proton pump inhibitors and NSAIDs more frequently than doctors in LPP, but there was no difference in the prescription of me‐too drugs.

Conclusion

The absolute differences in age and gender distribution between HPP and LPP were modest. Prescribing quality, as measured by the rate of me‐too drug prescriptions, was similar across all practices. Therefore, differences in the rate of polypharmacy in general practice cannot sufficiently be explained by these factors. Copyright © 2009 John Wiley & Sons, Ltd.
Effect of organoclay on the morphology, mechanical, thermal, and rheological properties of organophilic montmorillonite nanoclay based thermoplastic polyurethane nanocomposites prepared by melt blending
Authors: Barick Aruna K. , Tripathy Deba K.
Published: September 2009

Polymer nanocomposites based on the thermoplastic polyurethane (TPU) and organically modified montmorillonite (OMMT) was prepared by melt intercalation technique using a laboratory internal batch mixer followed by compression molding. Varying amount of organically modified nanoclays (1, 3, 5, 7, and 9 wt%) was added to the TPU matrix to examine the influence of organoclay on nanophase morphology and structure–property relationships. The interaction between TPU matrix and nanofiller was studied by infrared spectroscopy. The morphology of nanocomposites was studied by X‐ray diffraction, transmission electron microscopy, and atomic force microscopy that shows melt mixing by a batch mixer is an effective method for dispersing OMMT throughout the TPU matrix. Thermogravimetric analysis revealed that incorporation of organoclay enhances the thermal stability of the nanocomposites significantly. Differential scanning calorimetry was employed to measure the melting point and glass transition temperature (Tg) of soft segments. The reinforcing effect of the organoclay was determined by dynamic mechanical analysis and physico–mechanical testing. The effects of nanoclay concentration and processing parameters on the dynamic viscoelastic properties of the nanocomposites were studied by a rubber process analyzer using frequency sweep. A significant increase in the viscosity and storage modulus of the nanocomposites was found with the increasing clay content. POLYM. ENG. SCI., 2010. © 2009 Society of Plastics Engineers
High‐accuracy identification and bioinformatic analysis of in vivo protein phosphorylation sites in yeast
Authors: Gnad Florian , de Godoy Lyris M. F. , Cox Jürgen , Neuhauser Nadin , Ren Shubin , Olsen Jesper V. , Mann Matthias
Published: September 2009

Protein phosphorylation is a fundamental regulatory mechanism that affects many cell signaling processes. Using high‐accuracy MS and stable isotope labeling in cell culture‐labeling, we provide a global view of the Saccharomyces cerevisiae phosphoproteome, containing 3620 phosphorylation sites mapped to 1118 proteins, representatively covering the yeast kinome and a multitude of transcription factors. We show that a single false discovery rate for all peptide identifications significantly overestimates occurrence of rare modifications, such as tyrosine phosphorylation in yeast. The identified phosphorylation sites are predominantly located on irregularly structured and accessible protein regions. We found high evolutionary conservation of phosphorylated proteins and a large overlap of significantly over‐represented motifs with the human phosphoproteome. Nevertheless, phosphorylation events at the site level were not highly conserved between yeast and higher eukaryotes, which points to metazoan‐specific kinase and substrate families. We constructed a yeast‐specific phosphorylation sites predictor on the basis of a support vector machine, which – together with the yeast phosphorylation data – is integrated into the PHOSIDA database (www.phosida.com).
Strong activation of MgCl2‐supported Ziegler‐Natta catalysts by treatments with BCl3: Evidence and application of the “cluster” model of active sites
Authors: Ribour David , Monteil Vincent , Spitz Roger
Published: September 2009

Heterogeneous Ziegler‐Natta precatalysts (with phthalate as internal donor) were modified by treatments with BCl3 (2 h in heptane; T = 20–90 °C; B/Ti = 0.1–5) before their use in the polymerization of propylene to modify the active sites distribution. If performed on previously “detitanated” precatalysts, the treatment leads to a strong increase of productivity (up to one order of magnitude) without drastic modifications of polypropylenes properties (tacticity, molecular weight distribution). In addition, these findings are in good agreement with the hypothesis of a “cluster” organization of active sites allowing to rationalize activation by BCl3 by formation of heteronuclear B‐Ti clusters. The activation method was also applied to unmodified precatalysts and gave a significant gain of productivity. The simple and versatile activation process can also be performed under mild conditions (low T and low [BCl3]). © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5784–5791, 2009
Methacrylated dendrimers in thiol‐methacrylate networks and the effect of conversion on the thermoset properties
Authors: Nilsson Camilla , Malmström Eva , Johansson Mats , Trey Stacy M.
Published: September 2009

A series of well‐defined methacrylate‐functionalized polyester dendrimers based on 2,2‐bis(methylol)propionic acid (bis‐MPA) has been synthesized divergently. The thermal properties and conversion of the methacrylate functional dendrimers are investigated along with the structure‐property relationship of networks composed of the methacrylate dendrimers and two commercially available trifunctional thiols, trimethylolpropane tri(3‐mercaptopropanoate) (TRIS) and ethoxylated trimethylolpropane tri(3‐mercaptopropanoate) (ETTMP). The thiol‐methacrylate reactions were conducted at room temperature, under ambient conditions, and triggered by UV light in the presence of a photoinitiator. Crosslinked films were obtained and characterized with respect to conversion (FT‐Raman) and thermal (DSC and TGA) properties. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5815–5826, 2009