bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using genome‐wide pathway analysis to unravel the etiology of complex diseases
Authors: Elbers Clara C. , van Eijk Kristel R. , Franke Lude , Mulder Flip , van der Schouw Yvonne T. , Wijmenga Cisca , Onland‐Moret N. Charlotte 
Published: February 2009

AbstractSeveral genome‐wide association studies (GWAS) have been published on various complex diseases. Although, new loci are found to be associated with these diseases, still only very little of the genetic risk for these diseases can be explained. As GWAS are still underpowered to find small main effects, and gene‐gene interactions are likely to play a role, the data might currently not be analyzed to its full potential. In this study, we evaluated alternative methods to study GWAS data. Instead of focusing on the single nucleotide polymorphisms (SNPs) with the highest statistical significance, we took advantage of prior biological information and tried to detect overrepresented pathways in the GWAS data. We evaluated whether pathway classification analysis can help prioritize the biological pathways most likely to be involved in the disease etiology. In this study, we present the various benefits and limitations of pathway‐classification tools in analyzing GWAS data. We show multiple differences in outcome between pathway tools analyzing the same dataset. Furthermore, analyzing randomly selected SNPs always results in significantly overrepresented pathways, large pathways have a higher chance of becoming statistically significant and the bioinformatics tools used in this study are biased toward detecting well‐defined pathways. As an example, we analyzed data from two GWAS on type 2 diabetes (T2D): the Diabetes Genetics Initiative (DGI) and the Wellcome Trust Case Control Consortium (WTCCC). Occasionally the results from the DGI and the WTCCC GWAS showed concordance in overrepresented pathways, but discordance in the corresponding genes. Thus, incorporating gene networks and pathway classification tools into the analysis can point toward significantly overrepresented molecular pathways, which cannot be picked up using traditional single‐locus analyses. However, the limitations discussed in this study, need to be addressed before these methods can be widely used. Genet. Epidemiol. 33:419–431, 2009. © 2009 Wiley‐Liss, Inc.
Adapting the logical basis of tests for Hardy‐Weinberg Equilibrium to the real needs of association studies in human and medical genetics
Authors: Goddard Katrina A. B. , Ziegler Andreas , Wellek Stefan 
Published: February 2009

AbstractThe standard procedure to assess genetic equilibrium is a χ2 test of goodness‐of‐fit. As is the case with any statistical procedure of that type, the null hypothesis is that the distribution underlying the data is in agreement with the model. Thus, a significant result indicates incompatibility of the observed data with the model, which is clearly at variance with the aim in the majority of applications: to exclude the existence of gross violations of the equilibrium condition. In current practice, we try to avoid this basic logical difficulty by increasing the significance bound to the P‐value (e.g. from 5 to 10%) and inferring compatibility of the data with Hardy Weinberg Equilibrium (HWE) from an insignificant result. Unfortunately, such direct inversion of a statistical testing procedure fails to produce a valid test of the hypothesis of interest, namely, that the data are in sufficiently good agreement with the model under which the P‐value is calculated. We present a logically unflawed solution to the problem of establishing (approximate) compatibility of an observed genotype distribution with HWE. The test is available in one‐ and two‐sided versions. For both versions, we provide tools for exact power calculation. We demonstrate the merits of the new approach through comparison with the traditional χ2 goodness‐of‐fit test in 2×60 genotype distributions from 43 published genetic studies of complex diseases where departure from HWE was noted in either the case or control sample. In addition, we show that the new test is useful for the analysis of genome‐wide association studies. Genet. Epidemiol. 33:569–580, 2009. © 2009 Wiley‐Liss, Inc.
Targeting heat shock protein 90 with non-quinone inhibitors: A novel chemotherapeutic approach in human hepatocellular carcinoma #
Authors: Breinig Marco , Caldas-Lopes Eloisi , Goeppert Benjamin , Malz Mona , Rieker Ralf , Bergmann Frank , Schirmacher Peter , Mayer Matthias , Chiosis Gabriela , Kern Michael André 
Published: February 2009

Abstract
The inhibition of heat shock protein 90 (Hsp90) has emerged as a promising antineoplastic strategy in diverse human malignancies. Hsp90 has been predicted to be involved in hepatocellular carcinoma (HCC) development; however, its role in hepatocarcinogenesis remains elusive. Using chemically distinctive Hsp90 inhibitors, we show that Hsp90 capacitates the aberrant expression and activity of crucial hepatocarcinogenesis-driving factors (e.g., insulin-like growth factor receptor 1, hepatocyte growth factor receptor, protein kinase B, v-raf-1 murine leukemia viral oncogene homolog 1, and cyclin-dependent kinase 4). In vitro, Hsp90 inhibition with both geldanamycin analogs (17-allylamino-17-desmethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-desmethoxygeldanamycin (17-DMAG)) and the non-quinone compound 8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine (PU-H71) reduced the viability of various HCC cell lines, induced the simultaneous degradation of numerous hepatocarcinogenic factors, and caused substantial cell cycle arrest and apoptosis. In contrast, nontumorigenic hepatocytes were less susceptible to Hsp90 inhibition. Because conventional geldanamycin-derivate Hsp90 inhibitors induce dose-limiting liver toxicity, we tested whether novel Hsp90 inhibitors lacking the benzoquinone moiety, which has been deemed responsible for hepatotoxicity, can elicit antineoplastic activity without causing significant liver damage. In HCC xenograft mouse models, PU-H71 was retained in tumors at pharmacologically relevant concentrations while being rapidly cleared from nontumorous liver. PU-H71 showed potent and prolonged in vivo Hsp90 inhibitory activity and reduced tumor growth without causing toxicity. Conclusion: Hsp90 constitutes a promising therapeutic target in HCC. Non-quinone Hsp90 inhibitors exhibit tumor-specific accumulation and exert potent antineoplastic activity without causing significant hepatotoxicity. (Hepatology 2009.)
Social isolation prevents exercise‐induced proliferation of hippocampal progenitor cells in female rats
Authors: Leasure J. Leigh , Decker Linda 
Published: February 2009

AbstractSocial isolation negatively affects the behavior and health of laboratory rats. Recently, it has been found that social isolation retards exercise‐induced neurogenesis in the hippocampal dentate gyrus (DG) of male rats (Stranahan et al. (2006) Nat Neurosci 9:526–533). Since male and female rats react differently to housing changes and exercise opportunities, we investigated whether social isolation would also suppress the exercise‐dependent increase in proliferation of dentate gyrus progenitor cells in females. Accordingly, female rats were housed either alone (isolated) or in groups (social) with (exercise) or without (sedentary) the opportunity to run in an exercise wheel. Proliferating progenitor cells were labeled with bromodeoxyuridine (BrdU). As expected, exercise increased the number of BrdU+ cells in socially housed animals. However, isolation prevented this running‐induced increase. Our results expand upon previous findings by showing that the female brain is also susceptible to the suppressive effect of social isolation on exercise‐induced neurogenesis. © 2009 Wiley‐Liss, Inc.
Secoiridoid Glycosides from the Pitcher Plant Sarracenia alata
Authors: Hu Jin‐Feng , Starks Courtney M. , Williams Russell B. , Rice Stephanie M. , Norman Vanessa L. , Olson Krista M. , Hough Grayson W. , Goering Matt G. , O'Neil‐Johnson Mark , Eldridge Gary R. 
Published: February 2009

Abstractmagnified imageThe new secoiridoid glycoside alatenoside (6) was isolated along with the known secoiridoid glycosides morroniside (1), (7α)‐7‐O‐methylmorroniside (2), (7β)‐7‐O‐methylmorroniside (3), alpigenoside (4), and kingiside (5). Complete NMR data for 2, 3, and 4 are presented here for the first time. The structure elucidation and de‐replication of the isolates were performed by utilizing a capillary‐scale NMR probe and HR‐ESI‐MS data. Alatenoside (6) represents the first naturally occurring morroniside dimer.
Synthesis and Evaluation of S‐ and C(1)‐Substituted Analogues of Lincomycin
Authors: Collin Marie‐Pierre , Hobbie Sven N. , Böttger Erik C. , Vasella Andrea 
Published: February 2009

Abstractmagnified imageNew thioglycosides and C(1)‐alkylated thioglycosides (S‐ulosides) of lincomycin were synthesized, and their antibiotic activities were determined. The S‐aryl and S‐arylalkyl analogues 11a–11i were obtained by S‐glycosylation of the sulfoxides 7 with arenethiols, or by S‐alkylation of the thiol 14 with alkyl bromides. Lincomycin derivatives 27, 32a, 32b, 38a, 38b, 44, and 47 were prepared via Henry reaction or Michael addition of the lincosamine‐derived 1‐deoxy‐1‐nitropyranoses 22. The S‐alkyl derivatives showed a similar activity and specificity as lincomycin. Lipophilic S‐uloside analogues were two‐ to fourfold less active than the parent antibiotic, whilst the hydrophilic analogues were inactive.
Pressure drop in liquid–solid circulating fluidized beds
Authors: Hashizume Kenichi , Morita Shinichi , Nakamura Yuki , Wada Akira 
Published: February 2009

AbstractAn experiment was conducted to obtain data for pressure drop in risers of liquid–solid circulating fluidized beds, where two different risers (24 mm and 36 mm in diameter) were used. Tested particles were of glass and ceramics, and their diameter ranged from 2.10 to 4.95 mm. Water under ambient conditions was used as the fluidizing liquid. Pressure drop in the risers was measured using a reversed U‐tube manometer. Based on the experimental data, a calculation method was derived for predicting the pressure drop in the riser, which could reproduce almost all the data with an accuracy of ±20%. Furthermore, the effect of independent parameters was investigated on the pressure drop component ratios consisting of the total pressure drop. © 2009 Wiley Periodicals, Inc. Heat Trans Asian Res; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/htj.20241
Analogy between pressure drop and heat transfer in liquid–solid circulating fluidized beds
Authors: Hashizume Kenichi , Kimura Yoichi , Morita Shinichi 
Published: February 2009

AbstractAn analogy was found between the frictional pressure drop and the heat transfer in liquid–solid circulating fluidized beds. This investigation is based on the predicting correlations for the particle holdup, the heat transfer coefficient, and the pressure drop, which were all developed by the authors. When the heat transfer coefficients were expressed in terms of the modified j‐factor, then a close mutual relationship was observed between the modified j‐factor and the friction factor of the pressure drop due to liquid and particle flow. A correlation to express this mutual relationship was derived, which consists of the density ratio of particle to liquid and the non‐dimensional riser diameter. The heat transfer coefficient predicted from the derived correlation agreed well with the experimental data by the authors, and with existing data. © 2009 Wiley Periodicals, Inc. Heat Trans Asian Res; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/htj.20246
Diminished central nervous 5‐HT neurotransmission and mood self‐ratings in children and adolescents with ADHD: no clear effect of rapid tryptophan depletion
Authors: Zepf Florian Daniel , Holtmann Martin , Stadler Christina , Magnus Sophie , Wöckel Lars , Poustka Fritz 
Published: February 2009

AbstractIntroductionResearch on 5‐HT‐functioning in adult patients and healthy subjects using rapid tryptophan depletion (RTD) has indicated weak but stable effects on mood ratings. Altered mood in children and adolescents with attention‐deficit/hyperactivity disorder (ADHD) can confound the differential diagnosis between severe ADHD and mood disorders such as pediatric bipolar disorder. The present study investigated the effects of RTD induced lowered central nervous 5‐HT‐levels on mood self‐ratings in children with ADHD.MethodsSeventeen boys with ADHD participated in the study in a double‐blind within‐subject crossover‐design. They were administered RTD within an amino acid drink lacking tryptophan, thus lowering central nervous 5‐HT‐synthesis. On another day they received a placebo. Self‐rated mood was assessed on both days at baseline conditions and at three different post‐drink time‐points.ResultsRTD had no clear effect on mood within the whole sample. Low scorers on venturesomeness were more strongly affected by RTD in terms of feelings of inactivity and negative feelings compared to high venture patients.ConclusionsOur data did not show a significant effect of RTD on mood self‐ratings. However, the findings must be considered as preliminary and require further replication, in particular as they could be due to sampling bias. Copyright © 2009 John Wiley & Sons, Ltd.
Increased frequency of nonconventional double positive CD4CD8 αβ T cells in human breast pleural effusions
Authors: Desfrançois Juliette , Derré Laurent , Corvaisier Murielle , Le Mével Bernard , Catros Véronique , Jotereau Francine , Gervois Nadine 
Published: February 2009

AbstractBreast cancer remains a leading cause of cancer‐related death within the female population. Immunotherapy is expected to provide additional therapeutic benefits but has met so far limited success. This may be due in part to the poor understanding of immune responses to breast cancer. Although CD4+ and CD8+ T lymphocytes infiltrate these tumors, the phenotype and functions of these cells remain ill defined. This study was designed to investigate further about these questions, taking advantage of multiparameter flow cytometry on lymphocytes derived from peripheral blood, solid tumors, metastatic lymph nodes and pleural effusions samples of patients with breast cancer. Results showed that, in addition to conventional CD4+ and CD8+ αβ T cells, individual tumors and most pleural effusions contained significant fractions of unconventional double positive (DP) CD4+CD8+ αβ T cells. These DP T cells displayed the phenotype and cytotoxic potential of effector/memory activated CD8+ T cells but differed essentially from these cells by a high production of IL‐5 and IL‐13. The increased frequency of DP T cells in advanced breast cancer and their high lytic potential and original cytokine profile suggest that this T‐cell subset may play a specific role in the regulation of immune responses to human breast cancer. © 2009 UICC
Double stranded‐RNA‐mediated activation of P21 gene induced apoptosis and cell cycle arrest in renal cell carcinoma
Authors: Whitson Jared M. , Noonan Emily J. , Pookot Deepa , Place Robert F. , Dahiya Rajvir 
Published: February 2009

AbstractSmall double stranded RNAs (dsRNA) are a new class of molecules which regulate gene expression. Accumulating data suggest that some dsRNA can function as tumor suppressors. Here, we report further evidence on the potential of dsRNA mediated p21 induction. Using the human renal cell carcinoma cell line A498, we found that dsRNA targeting the p21 promoter significantly induced the expression of p21 mRNA and protein levels. As a result, dsP21 transfected cells had a significant decrease in cell viability with a concomitant G1 arrest. We also observed a significant increase in apoptosis. These findings were associated with a significant decrease in survivin mRNA and protein levels. This is the first report that demonstrates dsRNA mediated gene activation in renal cell carcinoma and suggests that forced over‐expression of p21 may lead to an increase in apoptosis through a survivin dependent mechanism. © 2009 UICC.
Gender‐specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood
Authors: Khamly Kenneth K. , Thursfield Vicky J. , Fay Michael , Desai Jayesh , Toner Guy C. , Choong Peter F.M. , Ngan Samuel Y.K. , Powell Gerard J. , Thomas David M. 
Published: February 2009

AbstractGood evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender‐related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms. © 2009 UICC
Enhanced insulin production from murine islet beta cells incubated on poly(3‐hydroxybutyrate‐co‐3‐hydroxyhexanoate)
Authors: Yang Xiao‐Di , Li Hong‐Ming , Chen Miao , Zou Xiang‐Hui , Zhu Lin‐Yun , Wei Chi‐ju , Chen Guo‐Qiang 
Published: February 2009

AbstractIslet transplantation represents an important alternative for the treatment of diabetes. However, the selection of suitable materials is critical for the success of such an implantation application. In this study, cellular migration, aggregation, and insulin production of a murine islet beta‐cell line, NIT‐1 cells on microbially produced polyesters poly(3‐hydroxybutyrate‐co‐3‐hydroxyhexanoate) (PHBHHx), poly(3‐hydroxybutyrate‐co‐4‐hydroxybutyrate) (P3HB4HB) or polylactic acid (PLA) films were investigated. Spherical islet‐like structures were only detected on PHBHHx films after 48 h cultivation. To understand the mechanism underlying the formation of cell aggregates, NIT‐1‐GFP, a stable transfectant of the green fluorescent protein was used in a time‐lapse imaging study. Cell aggregation began on PHBHHx at 2 h, and became obvious at 4 h. Furthermore, cells on PHBHHx displayed higher metabolic activities measured by MTT assay than that on tissue culture plate. More importantly, insulin gene expression as well as extracellular secretion was upregulated after growth on PHBHHx for 72 h. Thus, PHBHHx can be a strong candidate for islet transplantation. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
ERCC1 expression in aseptic loosening after total hip replacement
Authors: Landgraeber Stefan , von Knoch Marius , Löer Franz , Wegner Alexander , Tsokos Michael , Schmid Kurt Werner , Totsch Martin 
Published: February 2009

AbstractParticle‐induced osteolysis is a major cause of aseptic loosening after total joint replacement. The purpose of the current study was to evaluate the DNA damage repair capacity of macrophages in patients with aseptic hip loosening by determination of ERCC1. Moreover, we wanted to elucidate if the potency of the DNA‐repair mechanisms correlates with the survival of joint implants. For this purpose we compared the immunohistochemical ERCC1 expression in capsules and interface membranes of patients with loosening of a hip replacement in the first 10 years after implantation with those in patients with late loosening. In analogy with ERCC1 studies on cancer in humans we calculated the semi‐quantitative H‐score by multiplying the staining intensity with the proportion score of positive stained macrophages. The level of ERCC1 reaction in the specimens taken from patients with early aseptic loosening (mean H‐score 0.57) was clearly lower in comparison with those from patients undergoing exchange hip arthroplasty later than 10 years after surgery (mean H‐score 2.24). We determined an H‐score for ERCC1 expression of 1 as a cutoff point giving a sensitivity and specificity of 100% for identification of early aseptic loosening after less than 10 years. In summary, lower levels of ERCC1 were found in patients with early aseptic loosening compared to patients with aseptic loosening later than 10 years. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010
rhVEGF165 delivered in a porous β‐tricalcium phosphate scaffold accelerates bridging of critical‐sized defects in rabbit radii
Authors: Yang Pei , Wang Chunsheng , Shi Zhibin , Huang Xin , Dang Xiaoqian , Li Xudong , Lin Shien‐Fong , Wang Kunzheng 
Published: February 2009

AbstractSegmental bone defects are a common obstacle in major orthopedic procedures, and the treatment of these defects remains a challenging clinical problem. Bone tissue engineering has been attracting much attention in recent years. We evaluated the ability of the specific combination of 3 μg rhVEGF165 with a novel porous β‐tricalcium phosphate (β‐TCP) scaffold coated with fibrin sealant (FS) to facilitate bone regeneration. Unilateral 15‐mm long critical‐sized defects were prepared in the radial diaphysis of rabbits and treated with rhVEGF165/FS/scaffold or FS/scaffold. Healing of the defects was assessed at 4, 8, and 12 weeks, radiologically, histologically, and biomechanically. The results of the study demonstrated that the critical‐sized defects in the midshaft of the rabbit radius, treated with rhVEGF165 incorporated in porous β‐TCP scaffold by FS, can be completely bridged by cortical bone in 12 weeks. The bone marrow space was also reformed histologically and radiologically at 12 weeks postsurgery in the rhVEGF165‐treated group. Furthermore, biomechanical examination demonstrated that the segmental bone defects were not only radiologically and histologically repaired but were also mechanically repaired. Interestingly, none of the defects was completely repaired at 12 weeks following treatment with FS/scaffold without rhVEGF165. A solution‐driven process is likely the predominant mechanism of accelerating biodegradation of the β‐TCP scaffold in the presence of rhVEGF165; furthermore, cell‐mediated phagocytosis also contributes to biodegradation of the biomaterials. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010