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71.
72.
Isabelle Fitton Roel J H M Steenbakkers Lambert Zijp Joop C Duppen Emile F I Comans Saar H Muller Peter J C M Nowak Coen R N Rasch Marcel van Herk 《Radiotherapy and oncology》2007,83(1):42-48
PURPOSE: To evaluate the image quality of retrospectively attenuation corrected Positron Emission Tomography (PET) scans used for gross tumor volume (GTV) delineation in lung cancer patients. MATERIALS AND METHODS: Data of 13 lymph node positive lung cancer patients were acquired on separate CT and PET scanners under free breathing conditions (for radiotherapy planning). First we determined a protocol for CT/PET registration. Second, we compared the image quality of attenuation-corrected PET images using positron transmission images and CT images, in terms of signal-to-noise ratio (SNR) and lesion-to-background ratio (contrast). RESULTS: The largest differences between manual and automatic CT/PET registration were found in the anterior-posterior direction with a mean of 1.8 mm (SD 1.0 mm). Differences in rotations were always smaller than 1.0 degrees . The attenuation-corrected images using CT showed a larger SNR (mean 30%, SD 17%) and larger contrast (mean 14.0%, SD 8.5%) compared to attenuation-corrected images using positron transmission. For lymph nodes, the mean contrast was 16% (SD 6.4%) larger. CONCLUSIONS: This study demonstrated that attenuation correction based on CT provides a better image quality for GTV delineation than when using positron transmission for attenuation correction. Retrospective attenuation correction of PET scans based on registered CT is a good alternative for a dedicated PET/CT scanner if a free-breathing CT is available, e.g., for radiotherapy planning, and allows the use of CT with diagnostic quality for attenuation correction. 相似文献
73.
Kim Cryns Alon Shamir Joseph Shapiro Gie Daneels Ilse Goris Hansfried Van Craenendonck Roel Straetemans R H Belmaker Galila Agam Dieder Moechars Thomas Steckler 《Neuropsychopharmacology》2007,32(4):881-891
Lithium is a potent mood-stabilizing medication in bipolar disorder. Despite 50 years of clinical use, the mechanism of action is unknown. Multiple effects have been attributed to lithium including the uncompetitive inhibition of inositol monophosphatase (IMPase). IMPA2, one of the genes that encode IMPase, is located in a region with linkage to bipolar disorder. Owing to the role of IMPase in cell signaling and the possibility that this enzyme is a target for mood-stabilizing drugs, we generated IMPA2(-/-) mice. Possible involvement of IMPase in complex behaviors related to affective disorders was assessed by monitoring the behavior of the IMPA2(-/-) mice in the forced swim test, the tail suspension test (TST), the elevated zero-maze and open field test. It has been described that chronically lithium-treated mice exhibit reduced immobility time in the forced swim test and decreased exploratory behavior. We found increased rearing of IMPA2(-/-) mice in the open field, suggesting an increased exploratory behavior. Although immobility time of IMPA2(-/-) female but not male mice in the forced swim test was reduced, no difference was found between male and female IMPA2(-/-) and IMPA2(+/+) mice in the TST and overall there was no clear effect of the deletion of IMPA2 on depression-like behavior. Frontal cortex IMPase activity and inositol levels in the IMPA2(-/-) mice did not differ from IMPA2(+/+) mice, but kidney inositol levels were reduced. In conclusion, phenotypic characterization of the IMPA2(-/-) mouse indicates that deleting IMPA2 does not mimic the effects of lithium treatment. 相似文献
74.
EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation. 总被引:1,自引:0,他引:1
Torsten Trowe Sotiria Boukouvala Keith Calkins Richard E Cutler Ryan Fong Roel Funke Steven B Gendreau Yong D Kim Nicole Miller John R Woolfrey Valentina Vysotskaia Jing Ping Yang Mary E Gerritsen David J Matthews Peter Lamb Timothy S Heuer 《Clinical cancer research》2008,14(8):2465-2475
PURPOSE: Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib. EXPERIMENTAL DESIGN: We did in vitro screening using a randomly mutagenized ErbB2 expression library in Ba/F3 cells, which were dependent on ErbB2 activity for survival and growth. RESULTS: Lapatinib resistance screens identified mutations at 16 different ErbB2 amino acid residues, with 12 mutated amino acids mapping to the kinase domain. Mutations conferring the greatest lapatinib resistance cluster in the NH2-terminal kinase lobe and hinge region. Structural computer modeling studies suggest that lapatinib resistance is caused by multiple mechanisms; including direct steric interference and restriction of conformational flexibility (the inactive state required for lapatinib binding is energetically unfavorable). ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance. ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells, including L755S and T733I mutations known to occur in human breast and gastric carcinomas, supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers. The epidermal growth factor receptor/ErbB2/vascular endothelial growth factor receptor inhibitor EXEL-7647 was found to inhibit almost all lapatinib resistance-associated mutations. Furthermore, no ErbB2 mutations were found to be associated with EXEL-7647 resistance and lapatinib sensitivity. CONCLUSIONS: Taken together, these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects. 相似文献
75.
Johan W.P. Marsman Ronald Brand Roel Schats Rob E. Bernardus 《European journal of obstetrics, gynecology, and reproductive biology》1995,60(2):165-169
Objective: The purpose of the study was to establish whether it is useful to make a distinction between clinical and subclinical varicoceles with a view to deciding for treatment or not. Therefore, we compared our results of treatment of clinical vs. subclinical varicoceles. Study design: The changes of semen parameters and the occurrence of pregnancies in 40 infertile men treated for clinical varicocele were compared with those in 46 infertile men treated for subclinical varicocele. The significance of individual semen changes was analysed by paired t-test in both groups and the results of both groups were compared by analysis of covariance. The pregnancy rates were calculated and the life table curves of pregnancy of both groups were compared. Results: There were statistically significant increments in sperm density, motility and morphology both after treatment of clinical and subclinical varicoceles, and these increments did not differ significantly between both groups. The cumulative pregnancy rates after a mean follow-up period of 6.6 years amounted to 42.5% for clinical varicoceles and to 39.1% for subclinical varicoceles and the life table curves of pregnancy ran a rather similar course in both groups. Conclusion: We conclude that there is no reason to emphasize the palpatory findings in infertile men with varicocele. 相似文献
76.
77.
van Dongen CJ Vink R Hutten BA Büller HR Prins MH 《Archives of internal medicine》2003,163(11):1285-1293
BACKGROUND: After a first episode of venous thromboembolism, patients are treated with vitamin K (phytonadione) antagonists. There are indications that the risk of recurrence after treatment with vitamin K antagonists decreases relative to the time since the first event. The aim of the present meta-analysis is to describe the risk of recurrent venous thromboembolism after treatment with vitamin K antagonist in relation to the time since the index event. METHODS: Computerized searches in MEDLINE and EMBASE databases; reference checks of pertinent articles; personal communication with colleagues to find randomized clinical trials and cohort studies in which patients with venous thromboembolism were treated with vitamin K antagonists. Per treatment arm, 2 reviewers independently extracted data on the number of recurrent events and the duration of follow-up per time period of 3 months. RESULTS: A total of 135 potentially eligible studies were identified. Of these, 18 studies could be included, comprising 25 treatment arms that could be analyzed. Treatment arms were divided into 3 groups based on treatment duration (short, medium, and long). For all 3 groups, the monthly incidence immediately after discontinuation of treatment was high and declined rapidly thereafter. The monthly incidence after 9 months seemed independent of the treatment duration. CONCLUSIONS: There is a diminishing risk of recurrent venous thromboembolism over time and a stabilization after 9 months independent of the duration of the initial treatment with vitamin K antagonists. These findings have important implications for decision making about the optimal duration of treatment with vitamin K antagonists. 相似文献
78.
79.
CD154 is expressed during treatment with calcineurin inhibitors after organ transplantation 总被引:3,自引:0,他引:3
van Rijen MM Kuijf ML Metselaar HJ Tilanus HW Bouma GJ de Weger RA Jonker M Kwekkeboom J 《Transplantation》2002,73(10):1666-1672
BACKGROUND: CD154 (CD40 ligand) monoclonal antibody prevents allograft rejection in rodents and monkeys. Inasmuch as calcineurin inhibitors (CI) inhibit CD154 expression by pharmacologic agents in vitro, we investigated whether CD154 is also inhibited by CI in vivo and in vitro during allogeneic stimulation. METHODS: CD154 expression was determined by immunohistochemistry and flow cytometry in human lymph nodes and spleen sections from rhesus monkeys with or without CI treatment. The effect of CI on induction of CD154 expression was studied by stimulating lymphocytes with phorbol 12-myristate 13-acetate (PMA) and ionomycin or with allogeneic monocyte-derived mature dendritic cells. RESULTS: Lymph nodes from patients with or without CI cyclosporine (CsA) or FK506 (FK) treatment showed comparable CD154 expression, which was present on the cell surface of T cells. CD154-expressing cells were also present in spleens from monkeys treated with CsA in comparable numbers to those in the nontreated group. Moreover, in several liver transplant rejection biopsies taken during CI therapy CD154-expressing cells were observed. In vitro, CsA and FK strongly inhibited induction of CD154 expression on peripheral blood mononuclear cells by pharmacologic stimuli. Maximum inhibition was found at 50 ng/ml CsA and 20 ng/ml FK. CD154 expression induced by dendritic cells in peripheral blood mononuclear cells or spleen cells was also almost completely inhibited by CsA. CONCLUSION: Although CI strongly suppressed pharmacologic and allogeneic induction of CD154 expression on T cells in vitro at concentrations at approximately clinical trough levels, CD154 is prominently expressed during CI therapy in lymphoid tissue and (sporadically) in liver allografts. This suggests that the CD154-CD40 pathway remains functional during CI therapy, which may contribute to allograft rejections in the clinical setting. 相似文献
80.
BACKGROUND: The induction of excess matrix in renal fibrosis seems to be mediated, at least in part, by the transforming growth factor-beta (TGF-beta)-mediated induction of connective tissue growth factor (CTGF) in mesangial cells. METHODS: By examining CTGF protein and mRNA expression and promoter activity in the presence or absence of TGF-beta or inhibitors, the signaling pathways controlling basal and TGF-beta-induced CTGF expression in mesangial cells were investigated. RESULTS: TGF-beta enhances CTGF mRNA and protein expression in mesangial cells. Mutation of a consensus SMAD binding element in the CTGF promoter completely abolished TGF-beta-induced CTGF expression and reduced basal CTGF expression. The previously identified basal control element-1 (BCE-1) site, but not Sp1 contributes to basal CTGF promoter activity. Ras/MEK/ERK, protein kinase C (PKC) and tyrosine kinase activity also contribute to basal and TGF-beta-induced CTGF promoter activity in cultured mesangial cells. CONCLUSIONS: The TGF-beta-induction of CTGF in mesangial cells requires SMADs and PKC/ras/MEK/ERK pathways. SMADs are involved in basal CTGF expression, which presumably reflects the fact that mesangial cells express TGF-beta endogenously. TGF-beta also induces CTGF through ras/MEK/ERK. Inhibiting ras/MEK/ERK seems not to reduce phosphorylation (that is, activation) of SMADs, suggesting that SMADs, although necessary, are insufficient for the TGF-beta-stimulation of the CTGF promoter through ras/MEK/ERK. Thus, maximal TGF-beta induction of CTGF requires synergy between SMAD and ras/MEK/ERK signaling. 相似文献