BRAF^V600E mutation has been thought to be a valuable molecular marker that may predict a worse prognosis for papillary thyroid cancer (PTC).But whether BRAF^V600E mutation is associated with lymph node metastasis (LN...BRAF^V600E mutation has been thought to be a valuable molecular marker that may predict a worse prognosis for papillary thyroid cancer (PTC).But whether BRAF^V600E mutation is associated with lymph node metastasis (LNM)remains controversial. Different surgical strategies may bring a bias in demonsstrating the association between them.In order to delineate a risk stratification to guide a tailored initial approach to tumors that express BRAF^V600E mutation,we performed this meta-analysis by using the articles in which total or near-total thyroidectomy plus bilateral central lymph node dissection was routinely performed to avoid the bias from the surgical strategy.We searched the Medline,Embase and CNKI database for eligible studies from January 2003 to May 2018.Meta-analysis was performed using the STATA 12.0 software.Odds ratios (ORs)and 95% confidence intervals (CIs)were calculated under fixed-effects or random-effects models.Fifteen clinical studies were included with a total of 4909 PTC patients. Our meta-analysis results reported that BRAF^V600E mutation was associated with LNM (OR=1.34;95% CI:1.09-1.65;P=0.005),as well as central LNM (OR=1.59;95% CI: 1.35-1.88;P<0.00001).Moreover,in patients with papillary thyroid microcarcinoma, we also confirmed the predictive value of BRAF^V600E mutation for LNM (OR=3.49;95% CI:2.02-6.02;P<0.00001).This meta-analysis demonstrates that BRAF^V600E mutation is closely related to LNM in PTC patients.The results suggest that BRAF^V600E mutation can be considered as a risk factor for LNM in PTC.Moreover,combining BRAF^V600E mutation with other risk factors to determine the initial surgical treatment may bring benefits for PTC patients.展开更多
Background BRAFV600E mutation is correlated with local aggressive clinicopathological features in papillary thyroid carcinoma; yet the relationship between this genetic variation and distant papillary thyroid carcinom...Background BRAFV600E mutation is correlated with local aggressive clinicopathological features in papillary thyroid carcinoma; yet the relationship between this genetic variation and distant papillary thyroid carcinoma metastasis was unclear.This study aimed to investigate whether BRAFV600E is predictive for distant metastasis in the Chinese population.Methods One hundred and seven patients with papillary thyroid carcinoma were enrolled in this study,including 43 patients with distant metastasis and 64 patients without.Quantitative real-time polymerase chain reaction was used to detect BRAFV600E mutation,while immunohistochemistry was performed to detect vascular endothelial growth factor （VEGF） expression.The associations between distant metastasis and BRAFV600E mutation,and VEGF expression as well as local clinicopathological factors were determined.Results A total of 28.6％ of the patients in the distant metastasis group harbored BRAFV600E mutation,which was significantly lower than in the without distant metastasis group （68.8％,P ＜0.001）.BRAFV600E mutation was negatively correlated with positive VEGF expression （P=0.001）.Furthermore,52.2％ of the patients with distant metastasis exhibited VEGF expression,compared with 25.0％ of those without.Higher levels of VEGF expression were also observed in the distant metastasis group.Tumor size,extra-thyroid invasion,and BRAFV600E mutation were independent predictors for distant metastasis according to multivariate analysis （odds ratios were 2.8,12.4,and 0.3; 95％ CI 1.483-5.334,and 2.950-52.407,0.100-0.890; P=0.002,0.001,and 0.030,respectively）.BRAFV600E mutation was negatively correlated with distant metastasis in adult subgroup analysis （P=0.005） but was not an independent parameter.Conclusions BRAFV600E mutation is predictive for distant metastasis in papillary thyroid carcinoma but not positively.VEGF may be involved in the pathogenesis of distant metastasis.展开更多
BACKGROUND Ameloblastomas are common benign epithelial odontogenic neoplasms that present an aggressive and unpredictable behavior that may modify treatment strategies.Different signaling pathways that participate in ...BACKGROUND Ameloblastomas are common benign epithelial odontogenic neoplasms that present an aggressive and unpredictable behavior that may modify treatment strategies.Different signaling pathways that participate in the progression of these tumors have been identified.B-raf proto-oncogene serine/threonine kinase(BRAF)is a protein involved in the behavior of ameloblastomas,and it is related to many cell mechanisms.BRAF gene mutations have been identified in ameloblastomas,of which the BRAF V600E(valine substituted by glutamic acid at amino acid 600)mutation has been the most common and can be present concomitantly with other mutations that may be involved in its behavior.Targeted therapies have been used as an alternative in the case of resistance or contraindications to conventional treatments.AIM To document the presence of BRAF V600E and additional mutations,their behavior,and targeted therapies in these tumors.METHODS An electronic literature search was conducted according to PRISMA guidelines in PubMed/MEDLINE,Cochrane,EMBASE,and SpringerLink using the terms“ameloblastomas”,“BRAF V600E”,“additional mutations”,and“targeted therapies”.Ameloblastomas were classified according to WHO guidelines.Inclusion criteria were articles in English,published not more than 10 years ago,and studies with laboratory works related to BRAF V600E.Articles were evaluated by two independent reviewers and retrieved for full-text evaluation.The EBLIP Critical Appraisal Checklist was used to evaluate the quality of the eligible studies.Descriptive statistical analysis was performed.RESULTS Two independent reviewers,with a substantial concordance indicated by a kappa coefficient of k=0.76,evaluated a total of 19 articles that were included in this study.The analysis registered 521 conventional ameloblastomas(AM),81 unicystic ameloblastomas(UA),13 ameloblastic carcinomas(AC),three metastatic ameloblastomas(MA),and six peripheral ameloblastomas(PA),of which the histopathological type,anatomic location,laboratory tests,exp展开更多
Background:Adamantinomatous craniopharyngioma(ACP)is the commonest pediatric sellar tumor.No effective drug is available and interpatient heterogeneity is prominent.This study aimed to identify distinct molecular subg...Background:Adamantinomatous craniopharyngioma(ACP)is the commonest pediatric sellar tumor.No effective drug is available and interpatient heterogeneity is prominent.This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles,imaging findings,and histological features,in order to predict the response to anti-inflammatory treatment and immunotherapies.Methods:Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled,including 119 ACPs and 23 papillary craniopharyngiomas.Whole-exome sequencing(151 tumors,including recurrent ones),RNA sequencing(84 tumors),and DNA methylome profiling(95 tumors)were performed.Consensus clustering and non-negative matrix factorization were used for subgrouping,and Cox regression were utilized for prognostic evaluation,respectively.Results:Three distinct molecular subgroups were identified:WNT,ImA,and ImB.The WNT subgroup showed higher Wnt/β-catenin pathway activity,with a greater number of epithelial cells and more predominantly solid tumors.The ImA and ImB subgroups had activated inflammatory and interferon response pathways,with enhanced immune cell infiltration and more predominantly cystic tumors.Mitogen-activated protein kinases(MEK/MAPK)signaling was activated only in ImA samples,while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group,mostly consisting of children.The degree of astrogliosis was significantly elevated in the ImA group,with severe finger-like protrusions at the invasive front of the tumor.The molecular subgrouping was an independent prognostic factor,with the WNT group having longer event-free survival than ImB(Cox,P=0.04).ImA/ImB cases were more likely to respond to immune checkpoint blockade(ICB)therapy than the WNT group(P<0.01).In the preliminary screening of subtyping markers,CD38 was significantly downregulated in WNT compared with ImA and ImB(P=0.01).Conclusions:ACP comprises three molecular subtypes with distinct imaging and histological features.The prognosis展开更多
B-Raf has been identified as promising targets for novel anticancer agents. To further explore the interactions between small molecules and B-Raf, and to elucidate structural characteristics that influence the B-Raf k...B-Raf has been identified as promising targets for novel anticancer agents. To further explore the interactions between small molecules and B-Raf, and to elucidate structural characteristics that influence the B-Raf kinase activity, molecular docking and three-dimensional quantitative structure-activity relationship（3D-QSAR） studies were performed on a dataset of 75 Type Ⅱ inhibitors. Molecular docking was applied to explore the detailed binding process between the inhibitors and B-Raf kinase in its DFG-out inactive conformation. Based on the conformations obtained by molecular docking strategy, 3D-QSAR models, including comparative molecular field analysis（CoMFA） and comparative molecular similarity indexes analysis（CoMSIA）, were constructed. The established 3D-QSAR models show significant statistical quality and satisfactory predictive ability, with high q^2 and r^2 values： CoMFA model（q^2= 0.759, r^2 = 0.922）, and CoMSIA model（q^2 = 0.685, r^2 = 0.945）. The systemic external validation indicated that both CoMFA and CoMSIA models were quite robust and possess high predictive abilities with r^2 pred values of 0.633 and 0.708, respectively. Several key structural features accounting for the inhibitory activities of these compounds were discussed based on the 3D contour maps generated by the CoMFA and CoMSIA models, which were in good accordance with the docking results. These theoretical results rendered by 3D-QSAR models along with the docking may provide a useful reference for understanding the action mechanism and designing novel potential B-Raf inhibitors.展开更多
B—RAF是促分裂素原活化蛋白激酶（mitogen—activated protein kinase，MAPK）信号转导通路中一个重要的丝氨酸一苏氨酸蛋白激酶。它的激活突变能够促进细胞的转化与增殖，因此与肿瘤发生密切相关。B-RAF的主要突变形式B—RAF V600E发...B—RAF是促分裂素原活化蛋白激酶（mitogen—activated protein kinase，MAPK）信号转导通路中一个重要的丝氨酸一苏氨酸蛋白激酶。它的激活突变能够促进细胞的转化与增殖，因此与肿瘤发生密切相关。B-RAF的主要突变形式B—RAF V600E发生于约8％的实体肿瘤中，其中占黑色素瘤的50％～80％、乳突型甲状腺癌的30％～70％、结肠癌的5％～15％以及非小细胞肺癌的2％～4％。目前，基于B-RAF的特异性抑制剂在临床上治疗B—RAF V600E的黑色素瘤取得了良好成效，但这些一代B-RAF抑制剂依然存在许多问题，包括不良反应大、迅速耐药以及适应症有限等。本文综述了B-RAF突变作为肿瘤治疗靶点的依据、3种FDA批准的针对B-RAF V600E突变的靶向抑制剂的临床疗效及其肿瘤耐药机制以及第2代B—RAF抑制剂的研发前景。展开更多
基金This study was supported by National Natural Science Foundation of China (No.81702650),Natural Science Foundation of Hubei Province (No.2016CFB323)and Innovation Foundation of Huazhong University of Science and Technology (No.2016YXMS229).
文摘BRAF^V600E mutation has been thought to be a valuable molecular marker that may predict a worse prognosis for papillary thyroid cancer (PTC).But whether BRAF^V600E mutation is associated with lymph node metastasis (LNM)remains controversial. Different surgical strategies may bring a bias in demonsstrating the association between them.In order to delineate a risk stratification to guide a tailored initial approach to tumors that express BRAF^V600E mutation,we performed this meta-analysis by using the articles in which total or near-total thyroidectomy plus bilateral central lymph node dissection was routinely performed to avoid the bias from the surgical strategy.We searched the Medline,Embase and CNKI database for eligible studies from January 2003 to May 2018.Meta-analysis was performed using the STATA 12.0 software.Odds ratios (ORs)and 95% confidence intervals (CIs)were calculated under fixed-effects or random-effects models.Fifteen clinical studies were included with a total of 4909 PTC patients. Our meta-analysis results reported that BRAF^V600E mutation was associated with LNM (OR=1.34;95% CI:1.09-1.65;P=0.005),as well as central LNM (OR=1.59;95% CI: 1.35-1.88;P<0.00001).Moreover,in patients with papillary thyroid microcarcinoma, we also confirmed the predictive value of BRAF^V600E mutation for LNM (OR=3.49;95% CI:2.02-6.02;P<0.00001).This meta-analysis demonstrates that BRAF^V600E mutation is closely related to LNM in PTC patients.The results suggest that BRAF^V600E mutation can be considered as a risk factor for LNM in PTC.Moreover,combining BRAF^V600E mutation with other risk factors to determine the initial surgical treatment may bring benefits for PTC patients.
基金The study was supported by a grant from the National Natural Science Foundation of China （No. 30970850/C 100703）.Acknowledgements： The authors would like to thank ZHAO Xiao- juan and YANG Tao of the Medical Record Room of Peking Union Medical College Hospital for helping with the review of the medical records.
文摘Background BRAFV600E mutation is correlated with local aggressive clinicopathological features in papillary thyroid carcinoma; yet the relationship between this genetic variation and distant papillary thyroid carcinoma metastasis was unclear.This study aimed to investigate whether BRAFV600E is predictive for distant metastasis in the Chinese population.Methods One hundred and seven patients with papillary thyroid carcinoma were enrolled in this study,including 43 patients with distant metastasis and 64 patients without.Quantitative real-time polymerase chain reaction was used to detect BRAFV600E mutation,while immunohistochemistry was performed to detect vascular endothelial growth factor （VEGF） expression.The associations between distant metastasis and BRAFV600E mutation,and VEGF expression as well as local clinicopathological factors were determined.Results A total of 28.6％ of the patients in the distant metastasis group harbored BRAFV600E mutation,which was significantly lower than in the without distant metastasis group （68.8％,P ＜0.001）.BRAFV600E mutation was negatively correlated with positive VEGF expression （P=0.001）.Furthermore,52.2％ of the patients with distant metastasis exhibited VEGF expression,compared with 25.0％ of those without.Higher levels of VEGF expression were also observed in the distant metastasis group.Tumor size,extra-thyroid invasion,and BRAFV600E mutation were independent predictors for distant metastasis according to multivariate analysis （odds ratios were 2.8,12.4,and 0.3; 95％ CI 1.483-5.334,and 2.950-52.407,0.100-0.890; P=0.002,0.001,and 0.030,respectively）.BRAFV600E mutation was negatively correlated with distant metastasis in adult subgroup analysis （P=0.005） but was not an independent parameter.Conclusions BRAFV600E mutation is predictive for distant metastasis in papillary thyroid carcinoma but not positively.VEGF may be involved in the pathogenesis of distant metastasis.
文摘BACKGROUND Ameloblastomas are common benign epithelial odontogenic neoplasms that present an aggressive and unpredictable behavior that may modify treatment strategies.Different signaling pathways that participate in the progression of these tumors have been identified.B-raf proto-oncogene serine/threonine kinase(BRAF)is a protein involved in the behavior of ameloblastomas,and it is related to many cell mechanisms.BRAF gene mutations have been identified in ameloblastomas,of which the BRAF V600E(valine substituted by glutamic acid at amino acid 600)mutation has been the most common and can be present concomitantly with other mutations that may be involved in its behavior.Targeted therapies have been used as an alternative in the case of resistance or contraindications to conventional treatments.AIM To document the presence of BRAF V600E and additional mutations,their behavior,and targeted therapies in these tumors.METHODS An electronic literature search was conducted according to PRISMA guidelines in PubMed/MEDLINE,Cochrane,EMBASE,and SpringerLink using the terms“ameloblastomas”,“BRAF V600E”,“additional mutations”,and“targeted therapies”.Ameloblastomas were classified according to WHO guidelines.Inclusion criteria were articles in English,published not more than 10 years ago,and studies with laboratory works related to BRAF V600E.Articles were evaluated by two independent reviewers and retrieved for full-text evaluation.The EBLIP Critical Appraisal Checklist was used to evaluate the quality of the eligible studies.Descriptive statistical analysis was performed.RESULTS Two independent reviewers,with a substantial concordance indicated by a kappa coefficient of k=0.76,evaluated a total of 19 articles that were included in this study.The analysis registered 521 conventional ameloblastomas(AM),81 unicystic ameloblastomas(UA),13 ameloblastic carcinomas(AC),three metastatic ameloblastomas(MA),and six peripheral ameloblastomas(PA),of which the histopathological type,anatomic location,laboratory tests,exp
基金Fujian Medical University(No.XRCZX2017001 to XW)Natural Science Foundation of Fujian Province(No.2019J01294 to XW)+1 种基金Sanbo Brain Hospital Management Group(No.SBJT-KY-2020-002 to ZL)Capital Health Research and Development Special Fund(No.2022-2-8013 to ZL)
文摘Background:Adamantinomatous craniopharyngioma(ACP)is the commonest pediatric sellar tumor.No effective drug is available and interpatient heterogeneity is prominent.This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles,imaging findings,and histological features,in order to predict the response to anti-inflammatory treatment and immunotherapies.Methods:Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled,including 119 ACPs and 23 papillary craniopharyngiomas.Whole-exome sequencing(151 tumors,including recurrent ones),RNA sequencing(84 tumors),and DNA methylome profiling(95 tumors)were performed.Consensus clustering and non-negative matrix factorization were used for subgrouping,and Cox regression were utilized for prognostic evaluation,respectively.Results:Three distinct molecular subgroups were identified:WNT,ImA,and ImB.The WNT subgroup showed higher Wnt/β-catenin pathway activity,with a greater number of epithelial cells and more predominantly solid tumors.The ImA and ImB subgroups had activated inflammatory and interferon response pathways,with enhanced immune cell infiltration and more predominantly cystic tumors.Mitogen-activated protein kinases(MEK/MAPK)signaling was activated only in ImA samples,while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group,mostly consisting of children.The degree of astrogliosis was significantly elevated in the ImA group,with severe finger-like protrusions at the invasive front of the tumor.The molecular subgrouping was an independent prognostic factor,with the WNT group having longer event-free survival than ImB(Cox,P=0.04).ImA/ImB cases were more likely to respond to immune checkpoint blockade(ICB)therapy than the WNT group(P<0.01).In the preliminary screening of subtyping markers,CD38 was significantly downregulated in WNT compared with ImA and ImB(P=0.01).Conclusions:ACP comprises three molecular subtypes with distinct imaging and histological features.The prognosis
基金supported by the National Natural Science Foundation of China(21572273)
文摘B-Raf has been identified as promising targets for novel anticancer agents. To further explore the interactions between small molecules and B-Raf, and to elucidate structural characteristics that influence the B-Raf kinase activity, molecular docking and three-dimensional quantitative structure-activity relationship（3D-QSAR） studies were performed on a dataset of 75 Type Ⅱ inhibitors. Molecular docking was applied to explore the detailed binding process between the inhibitors and B-Raf kinase in its DFG-out inactive conformation. Based on the conformations obtained by molecular docking strategy, 3D-QSAR models, including comparative molecular field analysis（CoMFA） and comparative molecular similarity indexes analysis（CoMSIA）, were constructed. The established 3D-QSAR models show significant statistical quality and satisfactory predictive ability, with high q^2 and r^2 values： CoMFA model（q^2= 0.759, r^2 = 0.922）, and CoMSIA model（q^2 = 0.685, r^2 = 0.945）. The systemic external validation indicated that both CoMFA and CoMSIA models were quite robust and possess high predictive abilities with r^2 pred values of 0.633 and 0.708, respectively. Several key structural features accounting for the inhibitory activities of these compounds were discussed based on the 3D contour maps generated by the CoMFA and CoMSIA models, which were in good accordance with the docking results. These theoretical results rendered by 3D-QSAR models along with the docking may provide a useful reference for understanding the action mechanism and designing novel potential B-Raf inhibitors.
