BRAF has been recognized as a promising target for cancer therapy. A number of crystal structures have been published. Molecular docking is one of the most effective techniques in the field of computer-aided drug des...BRAF has been recognized as a promising target for cancer therapy. A number of crystal structures have been published. Molecular docking is one of the most effective techniques in the field of computer-aided drug design（CADD）. Appropriate protein conformation and docking method are essential for the successful virtual screening experiments. One approach considering protein flexibility and multiple docking methods was proposed in this study. Six DFG-in/αC-helix-out crystal structures of BRAF, three docking programs（Glide, GOLD and Ligand Fit） and 12 scoring functions were applied for the best combination by judging from the results of pose prediction and retrospective virtual screening（VS）. The most accurate results（mean RMSD of about 0.6 A） of pose prediction were obtained with two complex structures（PDB： 3 C4 C and 3 SKC） using Glide SP. From the retrospective VS, the most active compounds were identified by using the complex structure of 3 SKC, indicated by a ROC/AUC score of 0.998 and an EF of 20.6 at 5% of the database screen with Glide-SP. On the whole, PDB 3 SKC could achieve a higher rate of correct reproduction, a better enrichment and more diverse compounds. A comparison of 3 SKC and the other X-ray crystal structures led to a rationale for the docking results. PDB 3 SKC could achieve a broad range of sulfonamide substitutions through an expanded hydrophobic pocket formed by a further shift of the αC-helix. Our study emphasized the necessity and significance of protein flexibility and scoring functions in both ligand docking and virtual screening.展开更多
Thyroid cancer is the most common endocrine system tumor.Ultrasound guided fine needle puncture(FNA)can identify benign and malignant thyroid nodules.However,due to the limitation of cytological detection,some thyroid...Thyroid cancer is the most common endocrine system tumor.Ultrasound guided fine needle puncture(FNA)can identify benign and malignant thyroid nodules.However,due to the limitation of cytological detection,some thyroid nodules are difficult to distinguish benign and malignant.BRAF gene mutation is a common human oncogenic mutation and the highest mutation frequency in papillary thyroid carcinoma.The combination of FNA and BRAF gene detection can significantly improve the diagnostic rate of benign and malignant thyroid nodules and make up for the deficiency of single diagnosis of cytology.Moreover,while the incidence of thyroid cancer is growing rapidly worldwide,its mortality remains stable.The problem of overdiagnosis and overtreatment of thyroid cancer is becoming more and more obvious.However,due to the limitations of current studies on BRAF genes,its prognostic value for papillary thyroid carcinoma remains controversial.Therefore,in order to reduce the adverse effects of overdiagnosis and treatment,the relationship between gene and tumor biological behavior needs further study in the future.展开更多
BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF...BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.展开更多
AIM:To evaluate the current role of sorafenib,an oral multikinase inhibitor in the treatment of breast cancer.METHODS:An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrial...AIM:To evaluate the current role of sorafenib,an oral multikinase inhibitor in the treatment of breast cancer.METHODS:An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov,by using the search terms "sorafenib" and "breast cancer".Papers found were checked for further relevant publications.Overall,21 relevant studies were found,18 in advanced breast cancer(16 in stage Ⅳ and two in stages Ⅲ-Ⅳ) and three in early breast cancer.RESULTS:Among studies in advanced breast cancer,there were two trials with sorafenib as monotherapy,four trials of sorafenib in combination with taxanes,two in combination with capecitabine,one with gemcitabine and/or capecitabine,one with vinorelbine,one with bevacizumab,one with pemetrexed and one with ixabepilone,three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy.In addition,there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting,and two trials in the neoadjuvant setting.In general,sorafenib was well tolerated in breast cancer patients,though its dosage had to be adjusted in some trials,and discontinuation rates were high,particularly for the combination of sorafenib with anastrozole.Sorafenib monotherapy and combinations with taxanes,bevacizumab and ixabepilone showed inadequate efficacy,while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising.CONCLUSION:At present,sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.展开更多
Metastatic colorectal cancer (mCRC) continues to be counted as a major health problem. The introduction of newer cytotoxics, irinotecan and oxaliplatin, has achieved a significant improvement in survival rates. Novel ...Metastatic colorectal cancer (mCRC) continues to be counted as a major health problem. The introduction of newer cytotoxics, irinotecan and oxaliplatin, has achieved a significant improvement in survival rates. Novel targeted therapies (bevacizumab, and cetux-imab) in combination with most efficient chemotherapy regimens have pushed the median survival beyond the 2-year mark and increased the proportion of patients which could benefit from resection of metastatic lesions. In addition, several studies have proved that the CRC mutation profiles should influence patient selection or stratif ication in prospective trials. KRAS mutational status represents a paradigm for biomarker development in the era of molecular targeted therapies. The present article is an overview of the most important studies in the development of biomarkers for the optimization of anti-epidermal growth factor receptor (anti-EGFR) treatment in mCRC, beyond KRAS mutations, which is a work in progress. The aim will be to identify molecular markers that might be used to select patients with a higher probability of response to anti-EGFR monoclonal antibodies. Overall the accumulating evidence of the molecular biology of CRC has substantially changed the approach to mCRC treatment and has given clinicians more rational options for treating this illness.展开更多
基金supported by the National Natural Science Foundation of China(21102181,81302634 and 21572273)
文摘BRAF has been recognized as a promising target for cancer therapy. A number of crystal structures have been published. Molecular docking is one of the most effective techniques in the field of computer-aided drug design（CADD）. Appropriate protein conformation and docking method are essential for the successful virtual screening experiments. One approach considering protein flexibility and multiple docking methods was proposed in this study. Six DFG-in/αC-helix-out crystal structures of BRAF, three docking programs（Glide, GOLD and Ligand Fit） and 12 scoring functions were applied for the best combination by judging from the results of pose prediction and retrospective virtual screening（VS）. The most accurate results（mean RMSD of about 0.6 A） of pose prediction were obtained with two complex structures（PDB： 3 C4 C and 3 SKC） using Glide SP. From the retrospective VS, the most active compounds were identified by using the complex structure of 3 SKC, indicated by a ROC/AUC score of 0.998 and an EF of 20.6 at 5% of the database screen with Glide-SP. On the whole, PDB 3 SKC could achieve a higher rate of correct reproduction, a better enrichment and more diverse compounds. A comparison of 3 SKC and the other X-ray crystal structures led to a rationale for the docking results. PDB 3 SKC could achieve a broad range of sulfonamide substitutions through an expanded hydrophobic pocket formed by a further shift of the αC-helix. Our study emphasized the necessity and significance of protein flexibility and scoring functions in both ligand docking and virtual screening.
基金It was supported by Lanzhou Science and Technology Plan Project(2018-3-58)。
文摘Thyroid cancer is the most common endocrine system tumor.Ultrasound guided fine needle puncture(FNA)can identify benign and malignant thyroid nodules.However,due to the limitation of cytological detection,some thyroid nodules are difficult to distinguish benign and malignant.BRAF gene mutation is a common human oncogenic mutation and the highest mutation frequency in papillary thyroid carcinoma.The combination of FNA and BRAF gene detection can significantly improve the diagnostic rate of benign and malignant thyroid nodules and make up for the deficiency of single diagnosis of cytology.Moreover,while the incidence of thyroid cancer is growing rapidly worldwide,its mortality remains stable.The problem of overdiagnosis and overtreatment of thyroid cancer is becoming more and more obvious.However,due to the limitations of current studies on BRAF genes,its prognostic value for papillary thyroid carcinoma remains controversial.Therefore,in order to reduce the adverse effects of overdiagnosis and treatment,the relationship between gene and tumor biological behavior needs further study in the future.
基金Supported by the Henan Department of Science and Technology,China,No.162102310317
文摘BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
文摘AIM:To evaluate the current role of sorafenib,an oral multikinase inhibitor in the treatment of breast cancer.METHODS:An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov,by using the search terms "sorafenib" and "breast cancer".Papers found were checked for further relevant publications.Overall,21 relevant studies were found,18 in advanced breast cancer(16 in stage Ⅳ and two in stages Ⅲ-Ⅳ) and three in early breast cancer.RESULTS:Among studies in advanced breast cancer,there were two trials with sorafenib as monotherapy,four trials of sorafenib in combination with taxanes,two in combination with capecitabine,one with gemcitabine and/or capecitabine,one with vinorelbine,one with bevacizumab,one with pemetrexed and one with ixabepilone,three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy.In addition,there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting,and two trials in the neoadjuvant setting.In general,sorafenib was well tolerated in breast cancer patients,though its dosage had to be adjusted in some trials,and discontinuation rates were high,particularly for the combination of sorafenib with anastrozole.Sorafenib monotherapy and combinations with taxanes,bevacizumab and ixabepilone showed inadequate efficacy,while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising.CONCLUSION:At present,sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.
文摘Metastatic colorectal cancer (mCRC) continues to be counted as a major health problem. The introduction of newer cytotoxics, irinotecan and oxaliplatin, has achieved a significant improvement in survival rates. Novel targeted therapies (bevacizumab, and cetux-imab) in combination with most efficient chemotherapy regimens have pushed the median survival beyond the 2-year mark and increased the proportion of patients which could benefit from resection of metastatic lesions. In addition, several studies have proved that the CRC mutation profiles should influence patient selection or stratif ication in prospective trials. KRAS mutational status represents a paradigm for biomarker development in the era of molecular targeted therapies. The present article is an overview of the most important studies in the development of biomarkers for the optimization of anti-epidermal growth factor receptor (anti-EGFR) treatment in mCRC, beyond KRAS mutations, which is a work in progress. The aim will be to identify molecular markers that might be used to select patients with a higher probability of response to anti-EGFR monoclonal antibodies. Overall the accumulating evidence of the molecular biology of CRC has substantially changed the approach to mCRC treatment and has given clinicians more rational options for treating this illness.
