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  • 1
    Publication Date: 2018-11-02
    Description: Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies. Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR 12 weeks ). Results: A total of 166 patients were included in the final analysis. Overall, the PFR 12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%–18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR 12 weeks , median PFS and OS were: 58%, 4.1 and 11 months for UPS ( n = 19); 63%, 5.6 and 13 months for LPS ( n = 13); 75%, 11 and 15 months for LMS ( n = 26); 75%, 7.7 and 12 months for SS ( n = 47); 81%, 5.6 and 12 months for FS ( n = 18); 77%, 21 and not reached for ASPS ( n = 13); 54%, 11 and 16 months for CCS ( n = 7); and 44%, 2.8 and 8.8 months for other sarcoma ( n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred. Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233–8. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2018-04-12
    Description: B 4 C ceramics with different contents of graphene platelets (GPL) were synthesized by a pressureless process in Ar atmosphere. The influences of GPL on mechanical properties, thermal conductivity and electrical resistivity of the B 4 C ceramics were investigated. Mechanical properties ran up to optimal condition with hardness of 29.1 GPa, bending strength of 383.9 GPa and fracture toughness of 5.72 MPa m 1/2 with 0.8 wt% GPL separately. Thermal conductivity and electrical resistivity reached extreme values of 26.35 W m –1 k –1 and 0.1 cm –1 . Performances of the ceramics were mainly affected by the generation of non-functional-GPL and the result indicated that a large amount of non-functional-GPL could contribute to poorer overall performance. Meanwhile, two particular pullout mechanisms concerning toughness enhancing was discussed in detail.
    Keywords: inorganic chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 3
    Publication Date: 2018-01-09
    Description: The surface receptor FcRIIIA (CD16a) is encoded by the FCGR3A gene and is acquired by human NK cells during maturation. NK cells bind the Fc portion of IgG via CD16a and execute Ab-dependent cell-mediated cytotoxicity, which is critical for the effectiveness of several antitumor mAb therapies. The role of epigenetic regulatory mechanisms controlling transcriptional and posttranscriptional CD16 expression in NK cells is unknown. In this study, we compared specific patterns of DNA methylation and expression of FCGR3A with FCGR3B , which differ in cell type–specific expression despite displaying nearly identical genomic sequences. We identified a sequence within the FCGR3A promoter that selectively exhibits reduced methylation in CD16a + NK cells versus CD16a – NK cells and neutrophils. This region contained the transcriptional start site of the most highly expressed CD16a isoform in NK cells. Luciferase assays revealed remarkable cell-type specificity and methylation-dependent activity of FCGR3A- versus FCGR3B -derived sequences. Genomic differences between FCGR3A and FCGR3B are enriched at CpG dinucleotides, and mutation of variant CpGs reversed cell-type specificity. We further identified miR-218 as a posttranscriptional negative regulator of CD16a in NK cells. Forced overexpression of miR-218 in NK cells knocked down CD16a mRNA and protein expression. Moreover, miR-218 was highly expressed in CD16a – NK cells compared with CD16a + NK cells. Taken together, we propose a system of FCGR3A regulation in human NK cells in which CpG dinucleotide sequences and concurrent DNA methylation confer developmental and cell type–specific transcriptional regulation, whereas miR-218 provides an additional layer of posttranscriptional regulation during the maturation process.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  124. Kongress der Deutschen Gesellschaft für Chirurgie; 20070501-20070504; München; DOC07dgch7244 /20071001/
    Publication Date: 2007-10-02
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 5
    Keywords: RENAL-FUNCTION ; ASSOCIATION ; MYOCARDIAL-INFARCTION ; PREVALENCE ; ARTERY-DISEASE ; US ADULTS ; GLOMERULAR-FILTRATION-RATE ; CHINA HEART SURVEY ; GLUCOSE REGULATION ; MICROALBUMINURIA
    Abstract: AIM: Chronic kidney disease is highly prevalent in the diabetic population and it is also associated with adverse outcomes in patients with acute coronary syndrome (ACS). However, the risk of reduced kidney function (RKF) in ACS patients with undiagnosed diabetes or pre-diabetes is yet to be clear. Herein, the present study attempts to investigate the risk for RKF in ACS patients with special reference to undiagnosed diabetes and pre-diabetes, generating possible recommendations for early intervention and management in ACS patients. METHODS: A cross-sectional design was performed to evaluate the risk for RKF in 2232 ACS patients according to glycaemic status from the China Heart Survey between June 2005 and August 2005 by using multivariate logistic regression. RESULTS: The prevalence of RKF in ACS patients with normal glucose metabolism, pre-diabetes, undiagnosed diabetes and diagnosed diabetes was 11.6%, 17.7%, 16.7% and 28.8%, respectively. In multivariate analysis, apart from ACS patients with diagnosed diabetes, those with pre-diabetes (odds ratio = 1.58, 95%:1.08-2.31) and undiagnosed diabetes (odds ratio = 1.51, 95%:1.01-2.26) also suffered from an increased risk for RKF, compared with those with normal glucose metabolism. Stratified by ACS subtypes, the associations of RKF with ACS subtypes remained statistically significant. CONCLUSIONS: The increased risk of RKF was significantly associated with undiagnosed diabetes and pre-diabetes, relative to normal glucose metabolism. Screenings for RKF among ACS patients with pre-diabetes or newly diagnosed diabetes would be highly recommended.
    Type of Publication: Journal article published
    PubMed ID: 23332008
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  • 6
    Abstract: Purpose: Elevated levels of neutrophils have been associated with poor survival in various cancers, but direct evidence supporting a role for neutrophils in the immunopathogenesis of human cancers is lacking.Experimental Design: A total of 573 patients with gastric cancer were enrolled in this study. Immunohistochemistry and real-time PCR were performed to analyze the distribution and clinical relevance of neutrophils in different microanatomic regions. The regulation and function of neutrophils were assessed both in vitro and in vivoResults: Increased neutrophil counts in the peripheral blood were associated with poor prognosis in gastric cancer patients. In gastric cancer tissues, neutrophils were enriched predominantly in the invasive margin, and neutrophil levels were a powerful predictor of poor survival in patients with gastric cancer. IL17+ neutrophils constitute a large portion of IL17-producing cells in human gastric cancer. Proinflammatory IL17 is a critical mediator of the recruitment of neutrophils into the invasive margin by CXC chemokines. Moreover, neutrophils at the invasive margin were a major source of matrix metalloproteinase-9, a secreted protein that stimulates proangiogenic activity in gastric cancer cells. Accordingly, high levels of infiltrated neutrophils at the invasive margin were positively correlated with angiogenesis progression in patients with gastric cancer.Conclusions: These data provide direct evidence supporting the pivotal role of neutrophils in gastric cancer progression and reveal a novel immune escape mechanism involving fine-tuned collaborative action between cancer cells and immune cells in the distinct tumor microenvironment. Clin Cancer Res; 23(6); 1575-85. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 27620275
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  • 7
    Keywords: RISK ; OVARIAN-CANCER ; BRCA2 MUTATIONS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; ALLELES ; LOCI ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; IDENTIFIES 2
    Abstract: Background: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval 1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
    Type of Publication: Journal article published
    PubMed ID: 24548884
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  • 8
    Keywords: APOPTOSIS ; GENES ; TUMORS ; ACTIVATION ; PROMOTER ; SUBTYPES ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CYCLIN D1 EXPRESSION ; FUNCTIONAL VARIANTS
    Abstract: Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER-: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, p(trend) = 5.7 3 10(-44)) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, p(trend) = 3.0 x 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [p(cond) = 1.61 x 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER-: OR = 0.90, 95% CI = 0.87-0.93, p(cond) = 1.4 x 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
    Type of Publication: Journal article published
    PubMed ID: 25529635
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  • 9
    Abstract: Importance: The current staging system of gastric cancer is not adequate for defining a prognosis and predicting the patients most likely to benefit from chemotherapy. Objective: To construct a survival prediction model based on specific tumor and patient characteristics that enables individualized predictions of the net survival benefit of adjuvant chemotherapy for patients with stage II or stage III gastric cancer. Design, Setting, and Participants: In this multicenter retrospective analysis, a survival prediction model was constructed using data from a training cohort of 746 patients with stage II or stage III gastric cancer who satisfied the study's inclusion criteria and underwent surgery between January 1, 2004, and December 31, 2012, at Nanfang Hospital in Guangzhou, China. Patient and tumor characteristics were included as covariates, and their association with overall survival and disease-free survival with and without adjuvant chemotherapy was assessed. The model was internally validated for discrimination and calibration using bootstrap resampling. To externally validate the model, data were included from a validation cohort of 973 patients with stage II or stage III gastric cancer who met the inclusion criteria and underwent surgery at First Affiliated Hospital in Guangzhou, China, and at West China Hospital of Sichuan Hospital in Chendu, China, between January 1, 2000, and June 30, 2009. Data were analyzed from July 10, 2016, to September 1, 2016. Main Outcomes and Measures: Concordance index and decision curve analysis for each measure associated with postoperative overall survival and disease-free survival. Results: Of the 1719 patients analyzed, 1183 (68.8%) were men and 536 (31.2%) were women and the median (interquartile range) age was 57 (49-66) years. Age, location, differentiation, carcinoembryonic antigen, cancer antigen 19-9, depth of invasion, lymph node metastasis, and adjuvant chemotherapy were significantly associated with overall survival and disease-free survival, with P 〈 .05. The survival prediction model demonstrated good calibration and discrimination, with relatively high bootstrap-corrected concordance indexes in the training and validation cohorts. In the validation cohort, the concordance index for overall survival was 0.693 (95% CI, 0.671-0.715) and for disease-free survival was 0.704 (95% CI, 0.681-0.728). Two nomograms and a calculating tool were built on the basis of specific input variables to estimate an individual's net survival gain attributable to adjuvant chemotherapy. Conclusions and Relevance: The survival prediction model can be used to make individualized predictions of the expected survival benefit from the addition of adjuvant chemotherapy for patients with stage II or stage III gastric cancer.
    Type of Publication: Journal article published
    PubMed ID: 28538950
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  • 10
    Abstract: To determine whether p21-activated Kinase (PAK) 6 is a prognostic and predictive marker in gastric cancer (GC) and to construct a classifier that can identify a subset of patients who are highly sensitive to 5-fluorouracil/oxaliplatin chemotherapy. We retrospectively analyzed the expression levels of PAK6, cyclooxygenase 2, p21WAF1, Ki-67, excision repair cross-complementing gene 1, and thymidylate synthase in 242 paraffin-embedded GC specimens of the training cohort by immunohistochemistry. Then, we used support vector machine (SVM)-based methods to develop a predictive classifier for chemotherapy (chemotherapy score - CS-SVM classifier). Further validation was performed in an independent cohort of 279 patients. High PAK6 expression was associated with poor prognosis and increased chemoresistance to 5-FU/oxaliplatin chemotherapy. The CS-SVM classifier distinguished patients with stage II and III GC into low- and high-CS-SVM groups, with significant differences in the 5-year disease-free survival (DFS) and overall survival (OS) in chemotherapy patients. Moreover, chemotherapy significantly prolonged the DFS and OS of the high CS-SVM patients in the training and validation cohorts. In conclusion, PAK6 was an independent prognostic factor and increased chemoresistance. The CS-SVM classifier distinguished a subgroup of stage II and III patients who would highly benefit from chemotherapy, thus facilitating patient counseling and individualizing the management.
    Type of Publication: Journal article published
    PubMed ID: 28687498
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