Ideal sequencing in Stage IV epidermal growth factor receptor mutant Non朣mall?Cell Lung Cancer

Evidence from several studies has shown improved progression?free survival (PFS) with first? or second?generation epidermal growth factor receptor (EGFR)杢yrosine kinase inhibitors (TKIs) compared with chemotherapy for advanced NSCLC patients. But resistance to first or second?generation TKI therapies after 9 to 12 months of treatment initiation is a concern. Osimertinib is a third?generation, irreversible, oral EGFR?TKI that potently and selectively inhibits both EGFRm (epidermal growth factor receptor mutated) and EGFR T790M and has demonstrated efficacy in NSCLC central nervous system (CNS) metastases. Trials have reported significantly longer PFS and higher median duration of response with osimertinib compared with first?generation EGFR?TKIs (erlotinib, gefitinib) and chemotherapy, respectively. And relatively lower rates of discontinuation due to adverse events (AEs). Significant improvement in overall survival was also observed when used as first?line treatment. Because EGFR?mutated tumors are highly dependent on EGFR signaling, optimal sequence of available TKIs � erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib � is necessary. The sequencing of EGFR?TKIs has changed over the past decade and depends on factors such as expected efficacy, CNS activity, tolerability, and options available after progression. Third?generation TKI may be the preferred first?line treatment because patients may not opt for or die before the start of second?line therapy, and it is difficult to predict which patients will eventually develop T790M mutation. The favorable tolerability profile alongside a longer time to disease progression makes osimertinib a preferred first?line treatment. Though clinical practice guidelines do not provide clear consensus on the most preferred EGFR?TKI, recent updates recommend osimertinib as a first?line treatment for advanced NSCLC patients. Also, improved patient selection incorporating clinical and molecular characteristics will help translate to better survival outcomes and improved quality of life. This review aims to determine the optimal sequence of administration of the EGFR?TKIs considering toxicity, quality of life, and survival outcomes among advanced NSCLC patients.

Cell HE staining smears and paired cell paraffin sections in detection of epithelial growth factor receptor gene of pleural fluid specimens / 中南大学学报(医学版)

OBJECTIVES@#The advanced non-small cell lung cancer (NSCLC) patients with pleural effusion have no opportunity for surgery treatment. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first-line drugs for these patients with EGFR-sensitive mutation. However, the disease progression and drug update during or after treatment of EGFR-TKIs bring more challenges and puzzles to clinical diagnosis and treatment, which inevitably requires archived pleural cell samples for EGFR re-examination or comparative study. Understanding the DNA quality of archived pleural fluid samples and effectively using archival data of pleural fluid cells are of great significance for tracing the origin of cases and basic medical research. This study aims to evaluate the consistency of EGFR mutant gene expression between the 2 methods, and to explore a reliable way for preserving cytological data and making full use of cytological archival data via cell HE staining smear and cell paraffin section.@*METHODS@#A total of 57 pleural fluid cytology cases in the Department of Pathology of China Aerospace Center Hospital from October 2014 to April 2021 were selected. Tumor cells were detected by cell HE staining smears and immunohistochemical staining for TTF-1 and Napsin A in the paired cell paraffin sections. There were more than 200 tumor cells in cell HE staining smear and the proportion of tumor cells were ≥70% in matched cell paraffin sections. Patients with 2 cell smears (one for cell data retention and the other for DNA extraction) were selected as the research subjects, and 57 pleural fluid samples were enrolled. EGFR gene mutation was detected by amplification refractory mutation system-polymerase chain reaction in 57 paired cell HE staining smears and cell paraffin sections. DNA concentration was 2 ng/μL. Cell HE smear was amplified side-by-side with DNA samples from paired cell paraffin sections. Result determination was according to the requirements of the reagent instructions. The external control cycle threshold (Ct) value of the No. 8 well of the samples to be tested was between 13 and 21, which was considered as successful and reliable samples. When the Ct value of EGFR gene mutation was <26, it was considered as positive; when the Ct value was between 26 and 29, it was critical positive; when the Ct value was equal or more than 29, it was negative. ΔCt value was the difference between mutant Ct value and externally controlled Ct value. The smaller the ΔCt value was, the better the quality of DNA of the detected sample was.@*RESULTS@#Among the 57 pleural effusion samples, 42 patients were hospitalized with pleural effusion as the first symptom, accounting for 73.7% (42/57). EGFR mutation was detected in 37 samples [64.9% (37/57)]. The mutation rate for 19del was 37.8% (14/37) while for L858R was 48.6% (18/37). Females were 56.7% (21/37) of mutation cases. The mutation consistency rate of cell HE staining smear and matched cell paraffin sections was 100%. The ΔCt values of cell HE staining smears were less than those of matched cell paraffin sections. The mutation Ct values of 37 cytological samples were statistically analyzed according to the preservation periods of the years of 2014-2015, 2016-2017, 2018-2019, and 2020-2021. There were significant differences in cell paraffin section in the years of 2014-2015 and 2016-2017 compared with the years of 2018-2019 and 2020-2021, while no significant differences were found in cell HE staining smear. Statistical analysis of externally controlled Ct values of 57 cytological samples showed that there were significant differences between cell HE staining smears and cell paraffin section in the years of 2014-2015 and 2016-2017, compared with the years of 2018-2019 and 2020-2021. The mutational Ct values of 37 paired cell blocks and smears were all <26, and the externally controlled Ct values of 57 paired cell paraffin sections and HE staining smears were all between 13 and 21.@*CONCLUSIONS@#The DNA quality of cell HE smears and matched cell paraffin section met the qualified requirements. Two methods possess show an excellent consistency in detecting EGFR mutation in NSCLC pleural fluid samples. The DNA quality of cell HE staining smear is better than that of cell paraffin sections, so cell HE staining smear can be used as important supplement of the gene test source. It should be noted that the limitation of cell HE staining smears is non-reproducibility, so multiple smears of pleural fluid are recommended to be prepared for multiple tests.

The histogram features of quantitative parameters from synthetic MRI in predicting the expression of human epithelial growth factor receptor 2 in breast invasive ductual carcinoma / 中华放射学杂志

Objective:To evaluate the application value of the histogram features of quantitative parameters from synthetic MRI in predicting the expression of human epidermal growth factor receptor 2 (HER2) in breast invasive ductal carcinoma (IDC) and to compare the prediction efficiency with that of ADC histogram parameters.Methods:A total of 195 patients with breast lesions were prospectively enrolled in the Fudan University Cancer Hospital, from January 2020 to September 2020. All patients underwent preoperative synthetic MRI, DWI and dynamic contrast-enhanced MRI (DCE-MRI). All surgical specimens were confirmed by pathology. The histogram features of the quantitative parameters [T 1, T 2, and proton density (PD)] and ADC values were extracted by PyRadiomics software. Student t test or Mann-Whitney U test were used to compare the histogram characteristics of quantitative parameters (T 1, T 2, and PD) and ADC values between HER2-positive and HER2-negative breast cancers. The diagnostic efficacy of the variables in predicting HER2 expression state was evaluated using the area under curve (AUC) value of ROC. Results:A total of 122 patients with breast IDC were included into analysis, with 31 of HER2-positive and 91 of HER2-negative. There was no significant difference in the clinicopathological characteristics between HER2-positive and HER2-negative breast IDC patients. Univariate analysis showed that there was statistically significant difference in PD-median [79.80 (75.90, 83.90)ms vs. 76.56 (72.59, 79.09) ms, Z=-3.46, P<0.01], PD-mean [78.89 (74.80, 84.01) ms vs. 75.99 (71.70, 78.63) ms, Z=-2.61, P=0.01], PD-Kurtosis [6.45(3.45, 7.54) vs. 5.04 (3.55, 5.58), Z=-2.21, P=0.03], T 1-10 th percentile [731.52 (668.50, 975.39) ms vs. 726.51 (588.38, 852.19) ms, Z=-2.54, P=0.01], T 1-mean [1 161.97 (1 063.56, 1 253.78) ms vs. 1 072.75 (989.39, 1 154.04)ms, Z=-2.21, P=0.03] and ADC-Kurtosis [4.75 (2.72, 5.91) vs. 3.82 (2.69, 4.39), Z=-2.43, P=0.02] between HER2 positive and negative breast IDC patients. Multivariate analysis showed that PD-median ( P=0.004) and T 1-mean ( P=0.004) were independent risk factors for HER2 expression. The ROC curve of HER2 expression predicted by this model showed an AUC was 0.853(95%CI 0.779-0.926), with a sensitivity of 71% and a specificity of 81%. The ROC curve of ADC-Kurtosis for predicting the expression of HER2 showed that the AUC was 0.714 (95%CI 0.611-0.817), with the sensitivity of 45%, and the specificity of 85%. DeLong test showed that the diagnostic efficacy of quantitative parameters from synthetic MRI in predicting the status of HER2 was higher than that of ADC histogram parameters ( Z=2.18, P=0.04). Conclusion:Histogram features of synthetic MRI quantitative parameters contribute to the prediction of HER2 expression status in IDC and may therefore contribute to the determination of individualized anti-HER2 targeted therapy strategies.

Correlation between histological subtypes of invasive lung adenocarcinoma and epithelial growth factor receptor (EGFR) gene mutation / 中国胸心血管外科临床杂志

@#Objective    To investigate the correlation between histological subtypes of invasive lung adenocarcinoma and epithelial growth factor receptor (EGFR) gene mutation, and to provide a reference for clinical prediction of EGFR gene mutation status. Methods    From October 2017 to May 2019, 102 patients with invasive lung adenocarcinoma were collected, including 58 males and 44 females aged 62 (31-84) years. Invasive lung adenocarcinoma was classified into different histological subtypes. Scorpion probe amplification block mutation system (ARMS) real-time PCR was used to detect the mutation of EGFR gene in adenocarcinoma specimens, and the relationship between invasive lung adenocarcinoma subtypes and EGFR mutation status was analyzed. Results    In 102 patients with invasive lung adenocarcinoma, EGFR gene mutations were detected in 68 patients, and the mutation rate was 66.7% (68/102). The mutation sites were mainly concentrated in the exons 19 and 21; the mutation rate was higher in female patients (34/44, 77.3%) and non-smokers (34/58, 58.6%). EGFR mutation was mostly caused by acinar-like invasive lung adenocarcinoma, and was rare in solid-type lung adenocarcinoma. The EGFR gene mutation rates in different subtypes of adenocarcinoma were statistically different (P<0.05). Conclusion    The EGFR mutation status is related to gender, smoking status and histological subtype of invasive lung adenocarcinoma. EGFR mutation rates are higher in female, non-smoking and acinar-like invasive lung adenocarcinoma patients, and are lower in patients with solid type lung adenocarcinoma.

Efficacy of first generation EGFR-TKIs and chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations / 中华肿瘤杂志

Objective@#To investigate the clinical effects of first generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) compared with platinum-based chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations.@*Methods@#Clinical data of 4 276 patients diagnosed as advanced lung adenocarcinoma (ⅢB/Ⅳ) underwent EGFR gene detection at the Affiliated Cancer Hospital of Zhengzhou University from January 2012 to February 2018 were collected and 99 cases with uncommon EGFR mutations were selected. The clinical pathological features, treatment outcomes, treatment options and prognosis after first-line treatment of the 99 cases were analysed and compared with other patients with common EGFR mutations.@*Results@#The objective response rates of patients with uncommon EGFR mutations receiving EGFR-TKIs or platinum-based chemotherapy were 33.0% and 27.1%, respectively. The disease control rates were 76.5% and 87.5%, respectively. The progression-free survival (PFS) of patients treated with EGFR-TKIs was 7.2 months, significantly superior than 4.9 months of patients receiving chemotherapy (P=0.009). The overall survival of patients treated with EGFR-TKIs was 14.3 months, significantly worse than 20.7 months of patients receiving chemotherapy (P=0.034). Multivariate analysis showed that distant metastases (P=0.001) and smoking history (P=0.013) were independent prognostic factors for OS of lung adenocarcinoma patients with EGFR uncommon mutations.@*Conclusions@#Compared with chemotherapy, the usage of first generation of EGFR-TKIs as first-line therapy can improve the short-term efficacy of advanced lung adenocarcinoma patients with EGFR uncommon mutations. However, platinum-based chemotherapy shows a longer overall survival.

First-generation epithelial growth factor receptor tyrosine kinase inhibitor in the first-line treatment of advanced non-small cell lung cancer: 166 cases analysis of progression-free survival / 中国实用内科杂志

OBJECTIVE: Explore the clinical benefit factors of progression-free survival(PFS) in sensitive epithelial growth factor receptor(EGFR) gene mutated advanced non-small cell lung cancer patients treated with first-generation of EGFR tyrosine kinase inhibitor(TKI).METHODS: The clinical data of 166 patients who received first-line treatment with first-generation EGFR-TKI were retrospectively collected in 2016-2017 from Xiangya Hospital, Central South University. The patients were divided into three groups: PFS≤3 m,3 m

Plasma relative abundance of epidermal growth factor receptor mutations predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma / 中华内科杂志

Objective To determine whether relative abundance of epidermal growth factor receptor (EGFR) mutations in plasma predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced lung adenocarcinoma. Methods In this prospective study, adult patients with advanced lung adenocarcinoma were enrolled in our hospital from 1 April 2016 to 1 January 2017. EGFR mutations in tumor tissues were detected by ADx-amplification refractory mutation system (ADx-ARMS). EGFR mutations of plasma free tumor DNA were detected by ADx-ARMS and ADx-super amplification refractory mutation system (ADx-SuperARMS) at the same time. Patients with EGFR-mutant in tumor tissues and receiving EGFR-TKIs were finally enrolled. Plasma mutation-positive patients with both methods were high abundance group.Patients with positive mutations by ADx-SuperARMS but negative by ADx-ARMS were medium abundance group. Mutation-negative patients with both methods were recognized as low abundance group. The correlation between EGFR mutation abundance and clinical response to EGFR-TKIs were analyzed. Results Among 71 patients enrolled, 42 harbored EGFR mutations in plasma were detected by ADx-ARMS, while 53 were found by ADx-SuperARMS.There were 42 patients in high abundance group, 11 in medium group while the other 18 in low group. The objective response rates (ORRs) were 69.0%,7/11 and 10/18 in high, medium and low groups, respectively. The difference was significant between high and low abundances groups (P=0.006). Median progression-free survival (PFS) in high,medium and low groups were 11.0, 8.5 and 9.0 monthes, respectively (P<0.001). In patients with tumor 19-Del, the ORRs were 70.4%,5/7 and 6/11 in high,medium and low abundance groups, respectively. The median PFS of high abundance group was significantly longer than the other two groups (12.0 monthes vs 9.0, 9.0 monthes). As to subjects with L858R mutation, the ORRs were 10/15,2/4 and 3/6,respectively, with median PFS 9.6, 5.5 and 9.5 monthes. Conclusions The relative abundance of EGFR mutations in plasma predicts clinical response to EGFR-TKIs in patients with advanced lung adenocarcinoma. The higher the mutation abundance is, the better the efficacy of EGFR-TKIs is.

Effect of hypoxia on epithelial growth factor receptor expression and cell apoptosis of breast cancer and cervical cancer xenografts in nude mice / 中华放射肿瘤学杂志

Objective To observe the effect of hypoxia on the expression of epithelial growth factor receptor (EGFR) and cell apoptosis of breast and cervical cancer xenografts in nude mouse models.Methods The nude mouse models with MCF-7 and HeLa xenografts were established.The degree of hypoxia and EGFR expression were observed by confocal microscopy.The influence of EGFR expression on cell apoptosis under hypoxia was observed by TUNEL assay.Results EGFR expression was either up-regulated or down-regulated in the MCF-7 and HeLa cells with high degree of hypoxia.Furthermore,the degree of apoptosis was reduced in tumor tissues with high EGFR expression compared with that in those with low expression of EGFR.Conclusion The hypoxia in MCF-7 and HeLa cells exerts heterogeneous effect on EGFR expression.Under hypoxic conditions,EGFR exoression is negatively correlated with cell apoptosis.

Expressions of bcl-2-associated athanogene 1 and epithelial growth factor receptor gene in triple negative breast cancer / 肿瘤研究与临床

Objective To investigate mRNA expressions of bcl-2-associated athanogene1 (BAG-1), epithelial growth factor receptor(EGFR)in triple negative breast cancer(TNBC). Methods Polymerase chain reaction (PCR) method was used to detect mRNA expression levels of BAG-1 and EGFR in 51 TNBC cases combined with adjacent tissues in Taihe Hospital of Shiyan City from October 2013 to August 2014, and the relationship between gene expression and the clinicopathologic parameters of TNBC patients was analyzed. Results The relative expressions of BAG-1 mRNA and EGFR mRNA were 0.57±0.25,0.61±0.21 respectively in TNBC. The expression level of mRNA in breast cancer (0.19±0.12, t = 5.12) was higher than that in adjacent tissues (0.21±0.11, t = 7.17), and there was no significant difference (P< 0.001). The difference of expressions of BAG-1 mRNA and EGFR mRNA in TNBC patients with different clinical stage or lymph node metastasis were statistically significant (all P< 0.05), but there was no significant difference in mRNA expression level of the patients with different tumor diameter or age (all P > 0.05). Conclusion BAG-1 mRNA, EGFR mRNA are highly expressed in TNBC, which may be related with the poor prognosis and may be a molecular index for predicting the prognosis of TNBC patients.

Design,synthesis and anti-NSCLC activity of hybrids of anilinopyrimidines and diazeniumdiolates / 中国药科大学学报

To search for potent drugs against non-small-cell lung cancer(NSCLC),a series of hybrids(9a-9e, 10a-10e and 11a-11e﹚ from anilinopyrimidines and diazeniumdiolates were designed and synthesized.The MTT assay was employed to evaluate their antiproliferative activity against H1975 cells harboring epithelial growth factor receptor(EGFR)L858R/T790M mutation.The results showed that compounds 9a-9e displayed remarkable inhibitory activity on H1975 cells.Among these compounds, the most potent was compound 9b(IC50=0.65 μmol/L),which was superior to the positive control gefitinib.Additionally,molecular docking study indicated that 9b could bind with EGFR T790M by forming hydrogen bond, electrostatic interactions, et al, suggesting that compound 9b may be a potential anti-NSCLC agent for further investigation.

Application value of circulating tumor DNA monitoring effect of epithelial growth factor receptor monoclonal antibody therapy for metastatic colorectal cancer / 中华消化外科杂志

Objective To investigate the application value of circulating tumor DNA (ctDNA) monitoring effect of epithelial growth factor receptor (EGFR) monoclonal antibody therapy for metastatic colorectal cancer (mCRC).Methods The retrospective cross-sectional study was conducted.The clinicopathological data of 9 mCRC patients who were admitted to the Peking University Cancer Hospital between March 2012 and December 2013 were collected.Patients received single EGFR monoclonal antibody treatment (cetuximab or parni monoclonal antibody).The ctDNA concentration and variations of 22 genes in EGFR pathway of ctDNA were analyzed using high-throughput sequencing and ctDNA.Observation indicators:(1) treatment situations;(2) ctDNA concentration in plasma before and after treatment;(3) related gene mutations of EGFR pathway of ctDNA;(4) follow-up and survival situations.Follow-up using outpatient examination and telephone interview was performed to detect survival up to August 2015.Results (1) Treatment situations:of 9 patients,6 and 3 underwent respectively single drug treatment using cetuximab monoclonal antibody or parni monoclonal antibody.After EGFR monoclonal antibody treatment,best response was partial remission in 1 patient,stable disease in 6 patients and disease progression in 2 patients.(2) CtDNA concentration in plasma before and after treatment:ctDNA concentration of 9 patients was 1.7-25.0 μg/L before treatment,showing a significantly individual difference.There were some changes in ctDNA concentration of 9 patients during treatment:ctDNA concentration was increased in 1 patient during partial remission;of 6 patients during stable disease,ctDNA concentration was decreased in 5 patients and increased in 1 patient;of 9 patients during disease progression,ctDNA concentration was decreased in 4 patients and increased in 5 patients.(3) Related gene mutations of EGFR pathway of etDNA:① Of 9 patients,2 possessed RAS/RAF genetic mutations after treatment during disease progression,NRAS Q61H and BRAF V600E mutations were found in 1 patient,and mutation abundances were respectively 17.8％ and 5.2％;1 possessed KRAS G13D genetic mutation,a mutation abundance was 5.1％ before treatment and then was increased to 16.7％ during disease progression.② Seven patients possessed TP53 genetic mutation before treatment,5 had partial response or stable disease after treatment,including 4 with a reduced mutation abundance and 1 with an increased mutation abundance.Of 5 patients with partial response or stable disease to disease progression,mutation abundance of TP53 gene was increased in 4 patients and reduced in 1 patient;2 patients had disease progression after treatment and mutation abundances of TP53 gene were reduced.③ Two patients possessed SMAD4 genetic mutation.④ The intron mutations were found in EGFR,PIK3CA,AKT1,ERBB2,PTEN,STK11,MAP2K1,ALK,DDR2,CTNNB1,MET,FBX7,FGFR3,NOTCH1,ERBB4、FGFR1 and FGFR2 genes,without changes of amino acids,these were not included in analysis.(4) Follow-up and survival situations:9 patients were followed up for 1-31 months after treatment,with a median time of 7 months,and died at end of follow-up.Conclusion RAS/RAF gene mutations are detected by monitoring ctDNA when mCRC patients underwent EGFR monoclonal antibody therapy.

Protective effect of epithelial growth factor on oxidative damage of skeletal muscle cells in model rats of oxygen-glucose deprivation / 吉林大学学报(医学版)

Objective:To set up the rat skeletal muscle L6 cell models of oxygen-glucose deprivation(OGD)in vitro,and to investigate the protective effect of EGF in deep tissue inj ury(DTI)of pressure sores.Methods:The rat skeletal muscle cells in the logarithmic phase were divided into normal control group,OGD group,5 μg·L-1 EGF+OGD group,10 μg·L-1EGF+ OGD group and 20 μg·L-1EGF+ OGD group.The survival rates of skeletal muscle cells in various groups were measured by MTT assay;the cell apoptotic rates in various groups were detected by flow cytometry;the reactive oxygen species(ROS)levels were detected by DCFH-DA;Rhodamine 123 was used to detect the mitochondrial membrane potential;the expressions of Bax and Bcl-2 proteins were determined by Western blotting method.Results:Compared with normal control group,the survival rates of skeletal muscle cells in OGD group after 24 h OGD was significantly decreased(P<0.05);the apoptotic rate was markedly increased(P<0.01);the ROS level was increased(P<0.01);the mitochondrial membrane potential was decreased(P<0.01);the ratio of Bcl-2/Bax was significantly decreased(P<0.01).Compared with OGD group, the survival rates of skeletal muscle cells in different concentrations of EGF groups were increased and the apoptotic rates were decreased,especially in 10 and 20 μg·L-1EGF groups(P<0.05 or P<0.01);the ROS levels in skeletal muscle cells in different concentrations of EGF groups were decreased and the mitochondrial membrane potential were increased,especially in 10 and 20 μg·L-1EGF groups(P<0.05 or P<0.01);the Bcl-2/Bax ratios were significantly decreased in a concentration-dependent manner,especially in 10 and 20 μg·L-1EGF groups (P<0.05 or P<0.01).Conclusion:EGF can improve the skeletal muscle cell injury induced by OGD in a concentration-dependent manner via decreasing the ROS levels and protecting the cell mitochondrial function.

Protective effect of epithelial growth factor on oxidative damage of skeletal muscle cells in model rats of oxygen-glucose deprivation / 吉林大学学报(医学版)

To set up the rat skeletal muscle L6 cell models of oxygen-glucose deprivation (OGD) in vitro, and to investigate the protective effect of EGF in deep tissue injury (DTI) of pressure sores. Methods: The rat skeletal muscle cells in the logarithmic phase were divided into normal control group, OGD group, 5 μg · L1 EGF+OGD group, 10 μg · L1 EGF+ OGD group and 20 μg · L1 EGF+ OGD group. The survival rates of skeletal muscle cells in various groups were measured by MTT assay; the cell apoptotic rates in various groups were detected by flow cytometry; the reactive oxygen species (ROS) levels were detected by DCFH-DA; Rhodamine 123 was used to detect the mitochondrial membrane potential; the expressions of Bax and Bel-2 proteins were determined by Western blotting method. Results: Compared with normal control group, the survival rates of skeletal muscle cells in OGD group after 24 h OGD was significantly decreased (P<0.05); the apoptotic rate was markedly increased (P<0.01); the ROS level was increased (P<0.01); the mitochondrial membrane potential was decreased (P<0.01); the ratio of Bcl-2/Bax was significantly decreased (P<0.01). Compared with OGD group, the survival rates of skeletal muscle cells in different concentrations of EGF groups were increased and the apoptotic rates were decreased, especially in 10 and 20 μg · L1 EGF groups (P<0.05 or P<0.01); the ROS levels in skeletal muscle cells in different concentrations of EGF groups were decreased and the mitochondrial membrane potential were increased, especially in 10 and 20 μg · L1EGF groups (P<0.05 or P<0.01); the Bcl-2/Bax ratios were significantly decreased in a concentration-dependent manner, especially in 10 and 20 μg · L1 EGF groups (P<0.05 or P<0.01). Conclusion: EGF can improve the skeletal muscle cell injury induced by OGD in a concentration-dependent manner via decreasing the ROS levels and protecting the cell mitochondrial function.

Effects of Tangzhiping Prescription on Non-proliferative Diabetic Retinopathy Damage / 中国中医药信息杂志

Objective To observe the clinical efficacy of Tangzhiping Prescription on non-proliferative diabetic retinopathy (NPDR) and the effects on serum vascular epithelial growth factor (VEGF) and pigment epithelium derived factor (PEDF). Methods Totally 86 NPDR patients were randomly divided into treatment group (43 cases) and control group (43 cases). Both groups were given hypoglycemic, anti hypertensive and lipid-regulatory basic therapy. The control group was given calcium distillate capsules, 0.5 g per time, 3 times a day, orally; the treatment group was treated with Tangzhiping Prescription based on the control group, 1 dosage per day, twice a day, orally. Four weeks were set as one treatment course. Treatment for both groups lasted for three courses. Clinical efficacy and fundus efficacy of both groups were evaluated. TCM symptom scores, fundus scores, and visual condition were observed; FPG, 2 h PG, Hb A1 C, TC, TG, HDL-C and LDL-C and changes in the contents of VEGF and PEDF were detected. Results The control group and the treatment group lost 2 and 3 cases respectively. The total effective rate of clinical efficacy and total fundus efficiency of the control group were 65.00％ and 68.35％, respectively, and the treatment group were 87.50％ and 84.62％ respectively, with statistical significance (P＜0.05). Compared with before treatment, TCM symptom scores and fundus scores decreased significantly after treatment in both groups (P＜0.01); After treatment, the TCM symptom scores and fundus scores in the treatment group were lower than those in the control group (P＜0.05, P＜0.01). Compared with before treatment, visual acuity improved significantly after treatment in both groups (P＜0.05, P＜0.01). Compared with before treatment, levels of FPG, 2 h PG, Hb A1 c, TC, TG, and LDL-C decreased significantly in both groups after treatment (P＜0.01). After treatment, the levels of 2 h PG, Hb A1 c, TC, TG, and LDL-C in the treatment group were significantly lower than the control group (P＜0.05, P＜0.01). Compared with before treatment, the levels of VEGF decreased and PEDF levels increased in both groups, with statistical significance (P＜0.01). After treatment, the improvement of VEGF and PEDF in the treatment group was better than that in the control group (P＜0.05, P＜0.01); negative correlation was found between VEGF and PEDF (r=-0.320, P＜0.01). Conclusion Tangzhiping Prescription can effectively improve the clinical symptoms of patients with NPDR and slow down the progress of NPDR via reducing the blood glucose and blood lipids, and regulating the contents of VEGF and PEDF.

Expression of human epithelial growth factor receptor 2 in advanced lung adenocarcinoma with epithelial growth factor receptor mutation and its significance / 肿瘤研究与临床

Objective To detect the expression of human epithelial growth factor receptor 2 (HER-2) in advanced lung adenocarcinoma with epithelial growth factor receptor (EGFR) mutation, and to explore the potential of HER-2 as a therapeutic target for drug resistance in patients with EGFR mutations. Methods HER-2 is commonly expressed in the advanced lung adenocarcinoma with EGFR mutations, mainly in the cell membrane. Results The overexpression rate of HER-2 protein in tissues of advanced lung adenocarcinoma with EGFR mutations was 33.3%(28/84). The overexpression rate of HER-2 protein in patients>50 years of age was 40.3%(27/67), which was significantly higher than that of patients ≤50 years of age [5.9 % (1/17)], the difference was statistically significant (χ2=7.227, P=0.007). The overexpression rate of HER-2 protein in patients with high pathological differentiation [44.4 % (8/18)] was higher than that in patients with poor pathological differentiation [30.3%(20/66)], but the difference was not statistically significant (χ2=1.273, P=0.259). The overexpression of HER-2 protein in patients with EGFR 21 exon mutation [40.5 % (17/42)] was significantly higher than that of EGFR19 exon mutation [25.0%(10/40)], but the difference was not statistical significance (χ2=2.222, P=0.136). Conclusions The overexpression rate of HER-2 protein in advanced lung adenocarcinoma patients with EGFR mutation is high, which is related to the age and tumor differentiation. HER-2 is expected to be a potential therapeutic target for drug resistance patients with EGFR mutations.

Effects of Modified Zhisou Power on Epidermal Growth Factor Receptor and Neutrophil Elastase in Rats with Cold-Dryness Chronic Obstructive Pulmonary Disease / 中国中医药信息杂志

Objective To reveal the effects of cold-dryness and modified Zhisou Power on epidermal growth factor receptor (EGFR) and neutrophil elastase (NE) in rats with COPD. Methods COPD model was established with an elastase dose into the trachea combined with exposure to smoking for 90 d; cold-dryness COPD group was further developed by exposure to a cold, dry environment for 90 d. After 90 days, cold-dryness COPD rats was divided into cold-dryness group and Zhisou Power intervention group (treated with modified Zhisou Power for 7 days). On the 97th day, all rats were killed. Pathological changes in lungs were observed. mRNA and protein expression of EGFR were measured by RT-qPCR and Western blot, and the amount of NE in serum and BALF were examined by ELISA. Results EGFR mRNA and protein expression were significantly higher in COPD group, cold-dryness group and Zhisou Power intervention group than in control group. EGFR was significantly lower in Zhisou Power intervention group than in COPD group and cold-dryness group. NE was significantly higher in serum and BALF in COPD group, cold-dryness group and Zhisou Power intervention group than in control group. NE in BALF was significantly higher in cold-dryness group than in COPD group. NE in BALF was significantly lower in Zhisou Power intervention group than in cold-dryness group. Conclusion Modified Zhisou Power can down-regulate the expression of EGFR and the mount of NE in cold-dryness COPD rats to treat COPD.

Lorrelation of gene mutation of EGFR,the expressions of HER-2,VEGF in lung adenocarcinoma and clinical pathological factors / 国际检验医学杂志

Objective To investigate the gene mutation of epithelial growth factor receptor(EGFR) and the expressions of hu‐man epiderma1 growth factor receptor 2(HER‐2) and vascular endothelial growth factor(VEGF) in lung adenocarcinoma and their relationships with the clinical pathological factors .Methods ARMS‐PCR method was used to detect the gene mutation of EGFR in 49 lung adenocarcinoma specimens and 10 normal tissue specimens .Immunohistochemical method was also used to detect the ex‐pressions of the HER‐2 and VEGF in them .Results (1) The mutation rates of EGFR and the positive rates of HER‐2 and VEGF in lung adenocarcinoma were significantly higher than those in the normal tissues(P0 .05) .The HER‐2 and VEGF protein expressions in lung adenocarcinoma were correlated with differential ,the size of tumor ,TNM stages ,lymph nodes metastasis and pleural invasion(P0 .05) .(3) The expressions of HER‐2 and VEGF protein in the lung adenocarcinoma were positively correlated with each other(P<0 .01) .Conclusion EGFR mutation is closely related to the occurrence of lung ade‐nocarcinoma ,its high expressions in the women ,non smoking people have important clinical significance .HER‐2 and VEGF could promote the lung adenocarcinoma′s occurrence ,development and transfer .They could be used to evaluate the patients′prognosis ,and provide new molecular targeted therapy .

Research progress of targeting PD-1/PD-L1 in immunotherapy for non-small-cell lung cancer / 肿瘤研究与临床

Lung cancer is the leading cause of cancer-related death in the world.PD-1 is a member of the CD28 family expressed on the surface of a variety of immune cells.PD-L1, one of PD-1 ligands, plays a pivotal role in the ability of tumor cells to evade the host immune system.A recent study showed that signaling via mutant EGFR in lung tumor cells upregulates directly tumor PD-L1 expression.In this review, the clinical significance of the PD-1/PD-L1 pathway in immunotherapy for non-small-cell lung cancer (NSCLC) and the relevance to targeted therapy were summarized.

The effects of recombinant human epithelial growth factor on ocular surface injury after phacomulsification / 中华实验眼科杂志

Background With the widely application of phacoemulsication for cataract,dry eye-associated symptoms,such as foreign body sensation and burning frequently occur after cataract surgery in some patients.Objective This study was to evaluate the repair effects of recombinant human epithelial growth factor (rhEGF) on ocular surface injuriy after phacomulsification. Methods This was a prospective study,and informed consent was obtained from each subject before the experiment.One hundreds and twenty eyes of 89 consecutive patients after phacomulsification for age-related cataract were collected and randomized into rhEGF group,hyaluronic acid group and control group and 40 eyes for each.RhEGF drops and hyaluronic acid drops were topically administered 4 times per day for consecutive 4 weeks after surgery in corresponding group,and no drops mentioned above was used in the control group.The 0.3％ ofloxacin eye ointment and tobramycin+dexamethasone drops were used as the element drops in all patients of each group.Corneal fluorescein staining score,tear film break-up time ( BUT),Schrimer Ⅰ test without topical anesthesia were performed 1 day before surgery and 1 day,1 week,2 weeks and 1 month after surgery.Results The demography and the relevant surface examinational outcomes were no significantly different among the rhEGF group,hyaluronic acid group and control group in preoperation (age:F =3.74; gender:x2 =0.615; corneal fluorescein staining:F =0.247 ; BUT:F =0.579 ; Schrimer Ⅰ test:F =0.475 ; all P＞ 0.05 ).With the prolong of the time,the corneal fluorescein staining scores and Schrimer Ⅰ test values appeared a early ascent and latterly decline,and the BUT value showed a early shorten and latterly restore,with a statistically significant differences among various time points( F时间 =6.754,6.079,6.233,P＜0.01 ).Meanwhile,statistically significant differences were found in the corneal fluorescein staining scores,Schrimer Ⅰ test values and BUT among these 3 groups (F分组 =4.953,4.511,4.071,P＜0.05 ).The corneal fluorescein staining scores in the rhEGF group were significantly lower than those in the hyaluronic acid group at 2 weeks and 1 month after operation(P=0.039,0.014),and the BUT values in the rhEGF group were significantly longer than ones in the hyaluronic acid group at 1 week and 2 weeks after operation (P =0.019,0.007).The Schrimer I test values were significantly reduced in the rhEGF group compared with hyaluronic acid group at 1 week,2 weeks and 1 month after operation (P=0.022,0.003,0.019). Conclusions RhEGF promotes the repair of the ocular surface injury in the patients with age-related cataract after phacomulsification.

Effect of ethyl-3,4 dihydroxybenzoate pretreatment on the tubular epithelial cells apoptosis induced by albumin and hypoxia / 中华肾脏病杂志

Objective To explore the effects of ethyl-3,4 dihydroxybenzoate(EDHB), a prolyl hydroxylase inhibitor, pretreatment on the tubular epithelial cells apoptosis induced by albumin and hypoxia. Methods To investigate the effects of albumin and hypoxia on cells, rat tubular epithelial cells(NRK-52E)were incubated for 24 h in:(1)normoxia(5%CO2);(2)hypoxia(1% O2);(3)albumin(30 g/L)under normoxia;(4)albumin(30 g/L)under hypoxia. To investigate the effects of EDHB pretreatment on cells apoptosis, NRK-52E were incubated in hypoxia for 24 h in:(1)normoxia;(2)hypoxia;(3)hypoxia+albumin(30 g/L);(4)hypoxia+EDHB(500 μmol/L);(5)EDHB pretreatment(albumin 30 min after EDHB). Apoptosis was measured by flow cytometry(AnnexinV-FITC-PI). bcl-2, bax and vascular epithelial growth factor(VEGF)mRNA expression were detected by RT-PCR. VEGF protein expression was detected by Western blotting. Results NRK-52E apoptosis was not significantly different between hypoxia and norraoxia groups(P>0.05), but increased significantly in albumin(30 g/L)under hypoxia group compared with albumin(30 g/L)under normoxia group(37.36%?.95% vs 25.59%?.32%, P< 0.05). There was an increase in bax mRNA expression and a decrease in bcl-2 mRNA expression in albumin(30 g/L)under hypoxia group compared with albumin(30 g/L)under normoxia group(P< 0.05). EDHB pretreatment improved these impairments of albumin(30 g/L)under hypoxia on NRK-52E(P< 0.05). VEGF expression elevated in hypoxia compared with normoxia(P<0.05), decreased in albumin(30 g/L)under hypoxia groups compared with that without albumin groups(P<0.05).EDHB pretreatment significantly improved VEGF expression compared with albumin(30 g/L)under hypoxia group(P <0.05). Conclusion NRK-52E cells apoptosis induced by albumin is accelerated by hypoxia, however partially improved by EDHB pretreatment, probably through the up-regulation of VEGF expression.