More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but s...More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.展开更多
BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemis...BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.展开更多
Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important ...Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.展开更多
BACKGROUND Human epidermal growth factor receptor-2(HER-2)plays a vital role in tumor cell proliferation and metastasis.However,the prognosis of HER2-positive gastric cancer is poor.Inetetamab,a novel anti-HER2 target...BACKGROUND Human epidermal growth factor receptor-2(HER-2)plays a vital role in tumor cell proliferation and metastasis.However,the prognosis of HER2-positive gastric cancer is poor.Inetetamab,a novel anti-HER2 targeting drug independently developed in China,exhibits more potent antibody-dependent cell-mediated cytotoxicity than trastuzumab,which is administered as the first-line treatment for HER2-positive gastric cancer in combination with chemotherapy.In this case,the efficacy and safety of inetetamab combined with tegafur was investigated as a second-line treatment for HER2-positive gastric cancer.CASE SUMMARY A 52-year-old male patient with HER2-positive gastric cancer presented with abdominal distension,poor appetite,and fatigue two years after receiving six cycles of oxaliplatin combined with tegafur as first-line treatment after surgery,followed by tegafur monotherapy for six months.The patient was diagnosed with postoperative recurrence of gastric adenocarcinoma.He received 17 cycles of a combination of inetetamab,an innovative domestically developed anti-HER2 monoclonal antibody,and tegafur chemotherapy as the second-line treatment(inetetamab 200 mg on day 1,every 3 wk combined with tegafur twice daily on days 1–14,every 3 wk).Evaluation of the efficacy of the second-line treatment revealed that the patient achieved a stable condition and progression-free survival of 17 months.He tolerated the treatment well without exhibiting any grade 3-4 adverse events.CONCLUSION Inetetamab combined with chemotherapy for the treatment of metastatic HER2-positive gastric cancer demonstrates significant survival benefits and acceptable safety.展开更多
BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for h...BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.展开更多
The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitor...The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.展开更多
Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects...Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.展开更多
Patients with early-stage non-small-cell lung cancer(NSCLC)are candidates for curative surgery;however,despite multiple advances in lung cancer management,recurrence rates remain high.Adjuvant chemotherapy has been de...Patients with early-stage non-small-cell lung cancer(NSCLC)are candidates for curative surgery;however,despite multiple advances in lung cancer management,recurrence rates remain high.Adjuvant chemotherapy has been demonstrated to significantly prolong overall survival(OS),but this benefit is modest and there is an urgent need for effective new therapies to provide a cure for more patients.The high efficacy of tyrosine kinase inhibitors(TKIs)against epidermal growth factor receptor-mutated(EGFR)in patients with advanced EGFR-mutated NSCLC has led to the evaluation of these agents in early stages of the disease.Multiple clinical trials have evaluated the safety and efficacy of EGFR TKIs as an adjuvant treatment,in patients with resected EGFR-mutated NSCLC,and shown that they significantly prolong disease-free survival(DFS),but this benefit does not translate to OS.Recently,an interim analysis of the ADAURA trial demonstrated that,surprisingly,osimertinib improved DFS.This led to the study being stopped early,leaving many unanswered questions about its potential effect on OS and its incorporation as a standard adjuvant treatment in this patient subgroup.These targeted agents are also being evaluated in locally-advanced disease,with promising results,although prospective studies with larger sample sizes are needed to confirm these results.In this article,we review the most relevant studies on the role of EGFR TKIs in the management of early-stage EGFR-mutated NSCLC.展开更多
Aim: To investigate mechanisms of tryptase-induced reduction of sperm motility and explore whether epidermal growth factor receptor (EGF-R) and protease activated receptor 2 (PAR-2)- associated pathways are invol...Aim: To investigate mechanisms of tryptase-induced reduction of sperm motility and explore whether epidermal growth factor receptor (EGF-R) and protease activated receptor 2 (PAR-2)- associated pathways are involved. Methods: Fresh semen was collected from healthy donors (n = 15). Semen parameters and quality were assessed in accordance with the World Health Organization (WHO) criteria. Swim-up sperm were fixed and subjected to immunocytochemistry and immunoelectronmicroscopy with specific antibodies directed against PAR-2 and EGF-R. Protein extractions from swim-up spermatozoa were analyzed by Western blotting with antibodies for both receptors. Motility of spermatozoa was evaluated by computer-assisted semen analysis. Results: Immunocytochemistry found PAR-2 and EGF-R in approximately 30% of examined human ejaculated spermatozoa. Both receptors were localized in the plasma membrane. Like tryptase, the PAR-2 synthetic agonist SLIGKV reduced sperm motility, and this effect was inhibited by application of two specific EGF-R pathway blockers (AG1478 and PD168393). Conclusion: The observed reduction of sperm motility by tryptase through the PAR-2 receptor involves EGF-R pathways.展开更多
Objective: To explore the role of growth factor autocrine stimulation in the pathogenesis of human pituitary tumors. Methods: The expression of EGF, TGF-( and EGFR were studied by immunohisto-chemical method on paraf...Objective: To explore the role of growth factor autocrine stimulation in the pathogenesis of human pituitary tumors. Methods: The expression of EGF, TGF-( and EGFR were studied by immunohisto-chemical method on paraffin-embedded sections of 30 cases pituitary tumor. Results: EGFR and its ligands EGF, TGF-( expressed in majority of pituitary tumors. The expression of EGFR and its ligands varied with cells' intensity, density and type. Conclusion: The EGF autocrine stimulating exerted in the pituitary tumor development process, that tyrosine kinases inhibitors may be useful for pituitary tumors treatment.展开更多
BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal g...BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal growth factor receptor(EGFR)pathway.AIM To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor(HB-EGF)/EGFR pathway.METHODS We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis(GEPIA)website(http://gepia.cancer-pku.cn/index.html).Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues,and we constructed a stable lowexpressing FOXQ1 cell line and verified it with the above method.The expression changes of membrane-bound HB-EGF(proHB-EGF)and soluble HB-EGF(sHB-EGF)in the lowexpressing FOXQ1 cell line were detected by flow cytometry and ELISA.Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells.Proliferation experiments,transwell migration experiments,and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF,and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.RESULTS GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate.PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways.Knockdown of FOXQ1 suppressed the expression of HB-EGF,and led to a decrease in EGFR and its downstream genes AKT,RAF,KRAS expression levels.After knockdown of FOXQ1 in CRC cell lines,cell proliferation,migration and invasion were attenuated.Adding HB-EGF restored the migration and invasion ability of CRC,but not the cell proliferation ability.Kaplan–Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.CONCLUSION Based on these collective data,we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.展开更多
AIM:To investigate the cross-talk between oxidative stress and the epidermal growth factor receptor(EGFR)/AKT signaling pathway in retinal pigment epithelial( RPE) cells.METHODS:Human RPE cell lines(ARPE-19 cel...AIM:To investigate the cross-talk between oxidative stress and the epidermal growth factor receptor(EGFR)/AKT signaling pathway in retinal pigment epithelial( RPE) cells.METHODS:Human RPE cell lines(ARPE-19 cell) were treated with different doses of epidermal growth factor(EGF) and hydrogen peroxide(H2O2).Cell viability was determined by a methyl thiazolyl tetrazolium assay.Cell proliferation was examined by a bromodeoxyuridine(Brd U) incorporation assay.EGFR/AKT signaling was detected by Western blot.EGFR localization was also detected by immunofluorescence.In addition,EGFR/AKT signaling was intervened upon by EGFR inhibitor(erlotinib),PI3 K inhibitor(A66) and AKT inhibitor(MK-2206),respectively.H2O2-induced oxidative stress was blocked by antioxidant N-acetylcysteine(NAC).RESULTS:EGF treatment increased ARPE-19 cell viabili ty and proliferation through inducing phosphorylation of EGFR and AKT.H2O2 inhibited ARPE-19 cell viability and proliferation and also suppressed EGF-stimulated increase of RPE cell viability and proliferation by affecting the EGFR/AKT signaling pathway.EGFR inhibitor erlotinib blocked EGF-induced phosphorylation of EGFR and AKT,while A66 and MK-2206 only blocked EGF-induced phosphorylation of AKT.EGF-induced phosphorylation andendocytosis of EGFR were also affected by H2O2 treatment.In addition,antioxidant NAC attenuated H2O2-induced inhibition of ARPE-19 cell viability through all eviating reduction of EGFR,and phosphorylated and total AKT proteins.CONCLUSION:Oxidative stress affects RPE cell viability and proliferation through interfering with the EGFR/AKT signaling pathway.The EGFR/AKT signaling pathway may be an important target in oxidative stress-induced RPE cell dysfunction.展开更多
Aim: To investigate the expression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) and the possible mechanism in the development in androgen independent prostate cancer (AIPC). Methods:...Aim: To investigate the expression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) and the possible mechanism in the development in androgen independent prostate cancer (AIPC). Methods: Immunohistochemistry was performed on paraffin-embedded sections with goat polyclonal against COX-2 and mouse monoclonal antibody against EGFR in 30 AIPC and 18 androgen dependent prostate cancer (ADPC) specimens. The effect of epidermal growth factor (EGF) treatments on the expression of COX-2 and signal pathway in PC-3 and DU-145 cells was studied using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. ELISA was used to measure prostaglandin E2 (PGE2) levels in the media of PC-3 and DU-145 incubated with EGF for 24 h. Results: COX-2 was positively expressed in AIPC and ADPC, which were predominantly in endochylema of prostate cancer (PCa) cells. Intense staining was seen in AIPC (80%) and in ADPC (55.5%), but there was no significant association between the two groups. EGFR expression was also positive in the two groups (61.8% in ADPC and 90% in AIPC, P 〈 0.01). A significant association was found between EGFR expression and a higher Gleason score (P 〈 0.05) or tumor stage (P 〈 0.05). The expression of PGE2 was increased in PC-3 and DU-145 cells after being incubated with EGF. Both p38MAPK and PI-3K pathway were involved in the PC-3 cell COX-2 upregulation course. In DU- 145, only p38MAPK pathway was associated with COX-2 upregulation. Conclusion: EGFR activation induces COX-2 expression through PI-3K and/or p38MAPK pathways. COX-2 and EGFR inhibitors might have a cooperative anti-tumor effect in PCa.展开更多
Background: Epidermal growth factor receptor(EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors(TKIs) efficacy in non-small cell lung cancer(NSCLC). We conducted this study to verify the fea...Background: Epidermal growth factor receptor(EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors(TKIs) efficacy in non-small cell lung cancer(NSCLC). We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.Methods: A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system(ARMS). We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate(ORR), disease control rate(DCR) and progression free survival(PFS).Results: Of all patients, EGFR mutation rate was 28.6%(60/210) by direct sequencing and 45.2%(95/210) by ARMS(P〈0.001) respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR(48.0% vs. 80.9%, P=0.004) and shorter median PFS(7.4 vs. 10.5 months, P=0.009) as compared with that of EGFR mutation positive patients by both detection methods. Conclusions: Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.展开更多
Aim: To investigate human epidermal growth factor receptor type 2 (HER2) protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Met...Aim: To investigate human epidermal growth factor receptor type 2 (HER2) protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Methods: Immunohistochemistry (IHC) was performed to investigate HER2 protein expression in prostate biopsy specimens from 104 Chinese metastatic prostate cancer patients. After 3-11 months of hormonal therapy, 12 patients underwent transurethral resection of the prostate (TURP). HER2 protein expression of TURP specimens was compared with that of the original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores ≥ 2+ were investigated for HER2 gene amplification status by fluorescent in situ hybridization (FISH). Results: Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1+, 2+ and 3+ in 49 (47.1%), 45 (43.3%), 8 (7.7%) and 2 (1.9%) cases, respectively. There was a significant association between HER2 expression and Gleason score (P = 0.026). HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal therapy. None of the 14 specimens with HER2 IHC scores 〉 2+ showed HER2 gene amplification. Patients with HER2 scores 〉 2+ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0 (P = 0.004) and 1+ (P = 0.034). Multivariate Cox regression analysis showed that HER2 protein expression intensity was an independent predictor of cancer-related death (P = 0.039). Conclusion: An HER2 IHC score 〉 2+ should be defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual patients after hormonal therapy.展开更多
OBJECTIVE To investigate the role of connexin proteins(Cx),which form gap junctions(GJ),in progression and chemotherapeutic sensitivity of cervical cancer(CaC x).METHODS We analyze the expression of Cx26,Cx30,Cx32 and...OBJECTIVE To investigate the role of connexin proteins(Cx),which form gap junctions(GJ),in progression and chemotherapeutic sensitivity of cervical cancer(CaC x).METHODS We analyze the expression of Cx26,Cx30,Cx32 and Cx43 in human specimens consisting of:Normal cervix(n=78),CaCx FIGO stageⅠ(n=148),CaCx FIGO stageⅡ(n=165).In CaCx cell lines,Hela-Cx32(induced expression by doxycycline),C-33A(endogenously express Cx32)and si Ha(transiently transfected plasmid with Cx32),we detected the role of Cx32 against tostreptonigrin/cisplatin-induced apopotosisin presence or absence of functional GJ through using GJ inhibitors or low density cultural.Furtherly,we observed the relativity of Cx32 and EGFR expression in human specimens.Also,we detected the role of EGFR signaling pathway in the process of Cx32 anti-apoptosis through suppressed EGFR expression by inhibitors or si RNA sequences in cell lines.RESULTS We firstly demonstrated the expression of Cx32 was highly upregulated and accumulated in cytoplasm in the CaCx specimens,and the degree of upregulation correlated with advanced FIGO stages.Thus,in three human cervical cell lines,Cx32 was shown to suppress apoptosis when GJ formation is inhibited.No matter in cases of CaCx or cell lines,Cx32 expression was highly correlated with expression of EGFR and the EGFR pathway is an essential component of the Cx32-induced anti-apoptotic effect.CONCLUSION Cx32,traditionally tumor suppressive protein,was shown to be tumor protective against chemotherapy through EGFR pathway in a GJ-independent way.展开更多
Objective:To evaluate the human epidermal growth factor receptor 2(HER2)status in patients with breast cancer using multidetector computed tomography(MDCT)-based handcrafted and deep radiomics features.Methods:This re...Objective:To evaluate the human epidermal growth factor receptor 2(HER2)status in patients with breast cancer using multidetector computed tomography(MDCT)-based handcrafted and deep radiomics features.Methods:This retrospective study enrolled 339 female patients(primary cohort,n=177;validation cohort,n=162)with pathologically confirmed invasive breast cancer.Handcrafted and deep radiomics features were extracted from the MDCT images during the arterial phase.After the feature selection procedures,handcrafted and deep radiomics signatures and the combined model were built using multivariate logistic regression analysis.Performance was assessed by measures of discrimination,calibration,and clinical usefulness in the primary cohort and validated in the validation cohort.Results:The handcrafted radiomics signature had a discriminative ability with a C-index of 0.739[95%confidence interval(95%CI):0.661-0.818]in the primary cohort and 0.695(95%CI:0.609-0.781)in the validation cohort.The deep radiomics signature also had a discriminative ability with a C-index of 0.760(95%CI:0.690-0.831)in the primary cohort and 0.777(95%CI:0.696-0.857)in the validation cohort.The combined model,which incorporated both the handcrafted and deep radiomics signatures,showed good discriminative ability with a C-index of 0.829(95%CI:0.767-0.890)in the primary cohort and 0.809(95%CI:0.740-0.879)in the validation cohort.Conclusions:Handcrafted and deep radiomics features from MDCT images were associated with HER2 status in patients with breast cancer.Thus,these features could provide complementary aid for the radiological evaluation of HER2 status in breast cancer.展开更多
BACKGROUND: Dicer, a large multidomain ribonuclease, is responsible for processing double-stranded RNAs (dsRNAs) to 20-bp-long small interfering RNAs (siRNAs), which act as effectors during RNA interference (RNA...BACKGROUND: Dicer, a large multidomain ribonuclease, is responsible for processing double-stranded RNAs (dsRNAs) to 20-bp-long small interfering RNAs (siRNAs), which act as effectors during RNA interference (RNAi). OBJECTIVE: To observe the efficacy of siRNA cocktails generated by recombinant human Dicer on the down-regulation of epidermal growth factor receptor (EGFR) expression in human glioma cells. DESIGN, TIME AND SETTING: The following in vitro experiment was performed at the Department of Neurosurgery, Tianjin Medical University General Hospital and Laboratory of Neuro-Oncology, Tianjin Neurological Institute. MATERIALS: Mini-RNA isolation kit, human placenta complimentary DNA (cDNA) was produced by Tiangen Biotech (Beijing, China), human glioblastoma U251-MG cells were produced by the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences. METHODS: A PCR product from the human EGFR, which corresponded to the tyrosine kinase domain of the 3'-end fragment, was used as the T7-promotor for in vitro transcription. siRNA cocktails were generated by in vitro dicing of double stranded RNA. A total of 500, 250 and 125 μg siRNA cocktails were transiently transfected into U251 glioma cells through the use of the GeneSilencer. MAIN OUTCOME MEASURE: Expression of EGFR was detected by real-time PCR. RESULTS: The total PCR product of the human EGFR, corresponding to the tyrosine kinase domain, is approximately 680 bp in length. The PCR transcriptants included GCC leader sequences and a T7 promoter sequence, with a fragment of EGFR cDNA at the center. The T7 promoter was prepared for in vitro transcription of dsRNA. After dicing for 24 hours, the 21-nt siRNA cocktails were verified by 4% agarose gel. The difference between threshold cycle of a sample assay and threshold cycle of the corresponding endogenous reference (ΔCt) among parental U251 cells and cells transfected with different doses of siRNA cocktails were determined to be 3.06, 7.35, and 10.31 cycles, respectively. These results indicated effective silencing of EGFR expression by siRNA cocktails through transient transfection. CONCLUSION: The siRNA cocktails significantly suppressed exogenous expression of EGFR in U251 glioblastoma cells in a dose-dependent manner, thereby providing a more promising RNAi methodology for glioma therapy.展开更多
BACKGROUND: There is currently no effective medication to prevent stone recurrence after choledochoscopic lithotomy or to treat proliferative cholangitis(PC), which is the pathologic basis of hepatolithiasis. This ...BACKGROUND: There is currently no effective medication to prevent stone recurrence after choledochoscopic lithotomy or to treat proliferative cholangitis(PC), which is the pathologic basis of hepatolithiasis. This study aimed to investigate whether gefitinib, an epidermal growth factor receptor(EGFR) inhibitor, inhibited cholangio hyperplasia and lithogenesis in PC.METHODS: After cholangioscopic lithotomy, indwelling catheters were placed in the diseased bile duct lumens in 94 patients with hepatolithiasis. Subsequently, 49 of the 94 patients were treated with 250 mg gefitinib solution via a catheter twice a week, and they were subjected to choledochoscopic biopsy at 6 and 12 weeks. The rest 45 hepatolithiasis patients without gefitinib treatment served as controls.RESULTS: The expressions of EGFR, PCNA and procollagen I were significantly reduced in the patients treated with gefitinib in 12 weeks compared with those in the control group. Patients in the gefitinib group had a much lower degree of hyperplasia of the biliary epithelium, submucosal glands and collagen fibers compared with those in the control group. Gefitinib treatment significantly decreased mucin 3 expression and β-glucuronidase activity.CONCLUSION: Postoperative gefitinib treatment could significantly inhibit PC-mediated hyperplasia and lithogenesis, which might provide a novel strategy for the prevention of biliary restenosis and stone recurrence in patients with hepatolithiasis.展开更多
BACKGROUND For lung adenocarcinoma with epidermal growth factor receptor(EGFR)gene mutation,small molecule tyrosine kinase inhibitors are more effective.Some patients could not obtain enough histological specimens for...BACKGROUND For lung adenocarcinoma with epidermal growth factor receptor(EGFR)gene mutation,small molecule tyrosine kinase inhibitors are more effective.Some patients could not obtain enough histological specimens for EGFR gene mutation detection.Specific imaging features can predict EGFR mutation status to a certain extent.AIM To assess the associations of EGFR mutations with high-resolution computerized tomography(HRCT)features in ground-glass nodular lung adenocarcinoma.METHODS This study retrospectively assessed patients with ground-glass nodular lung adenocarcinoma diagnosed between January 2011 and March 2017.EGFR gene mutations in exons 18-21 were detected.The patients were classified into mutant EGFR and wild-type groups,and general data and HRCT image characteristics were assessed.RESULTS Among 98 patients,31(31.6%)and 67(68.4%)had mutated and wild-type EGFR in exons 18-21,respectively.Gender,age,smoking history,location of lesions,morphology,edges,borders,pleural indentations,and associations of nodules with bronchus and blood vessels were comparable in both groups(all P>0.05).Patients with mutant EGFR had larger nodules than those with the wild-type(17.19±6.79 and 14.37±6.30 mm,respectively;P=0.047).Meanwhile,the vacuole/honeycomb sign was more frequent in the mutant EGFR group(P=0.011).The logistic regression prediction model included the combination of nodule size and vacuole/honeycomb sign(OR=1.120,95%CI:1.023-1.227,P=0.014)revealed a sensitivity of 83.9%,a specificity of 52.2%and an AUC of 0.698(95%CI:0.589-0.806;P=0.002).CONCLUSION Nodule size and vacuole/honeycomb features could independently predict EGFR mutation status in ground-glass nodular lung adenocarcinoma.展开更多
文摘More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.
基金the Suzhou Medical Center,No.Szlcyxzx202103the National Natural Science Foundation of China,No.82171828+9 种基金the Key R&D Plan of Jiangsu Province(Social Development),No.BE2021652the Subject Construction Support Project of The Second Affiliated Hospital of Soochow University,No.XKTJHRC20210011Wu Jieping Medical Foundation,No.320.6750.2021-01-12the Special Project of“Technological Innovation”Project of CNNC Medical Industry Co.Ltd,No.ZHYLTD2021001Suzhou Science and Education Health Project,No.KJXW2021018Foundation of Chinese Society of Clinical Oncology,No.Y-pierrefabre202102-0113Beijing Bethune Charitable Foundation,No.STLKY0016Research Projects of China Baoyuan Investment Co.,No.270004Suzhou Gusu Health Talent Program,No.GSWS2022028Open Project of State Key Laboratory of Radiation Medicine and Protection of Soochow University,No.GZN1202302.
文摘BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.
文摘Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.
基金Supported by the Science and Technology Innovation Development Project of Tai’an,No.2021NS160the Medical and Health Science and Technology Development Plan of Shandong Province,No.202102010647。
文摘BACKGROUND Human epidermal growth factor receptor-2(HER-2)plays a vital role in tumor cell proliferation and metastasis.However,the prognosis of HER2-positive gastric cancer is poor.Inetetamab,a novel anti-HER2 targeting drug independently developed in China,exhibits more potent antibody-dependent cell-mediated cytotoxicity than trastuzumab,which is administered as the first-line treatment for HER2-positive gastric cancer in combination with chemotherapy.In this case,the efficacy and safety of inetetamab combined with tegafur was investigated as a second-line treatment for HER2-positive gastric cancer.CASE SUMMARY A 52-year-old male patient with HER2-positive gastric cancer presented with abdominal distension,poor appetite,and fatigue two years after receiving six cycles of oxaliplatin combined with tegafur as first-line treatment after surgery,followed by tegafur monotherapy for six months.The patient was diagnosed with postoperative recurrence of gastric adenocarcinoma.He received 17 cycles of a combination of inetetamab,an innovative domestically developed anti-HER2 monoclonal antibody,and tegafur chemotherapy as the second-line treatment(inetetamab 200 mg on day 1,every 3 wk combined with tegafur twice daily on days 1–14,every 3 wk).Evaluation of the efficacy of the second-line treatment revealed that the patient achieved a stable condition and progression-free survival of 17 months.He tolerated the treatment well without exhibiting any grade 3-4 adverse events.CONCLUSION Inetetamab combined with chemotherapy for the treatment of metastatic HER2-positive gastric cancer demonstrates significant survival benefits and acceptable safety.
基金Supported by Beijing CSCO Clinical Oncology Research Foundation,No.Y-HH202102-0314。
文摘BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.
基金Supported by the Elsa U.Pardee Foundation Grant,No.671432(to Sahu RP)NIH R21 Grant,No.ES033806(to Sahu RP).
文摘The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.
文摘Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.
文摘Patients with early-stage non-small-cell lung cancer(NSCLC)are candidates for curative surgery;however,despite multiple advances in lung cancer management,recurrence rates remain high.Adjuvant chemotherapy has been demonstrated to significantly prolong overall survival(OS),but this benefit is modest and there is an urgent need for effective new therapies to provide a cure for more patients.The high efficacy of tyrosine kinase inhibitors(TKIs)against epidermal growth factor receptor-mutated(EGFR)in patients with advanced EGFR-mutated NSCLC has led to the evaluation of these agents in early stages of the disease.Multiple clinical trials have evaluated the safety and efficacy of EGFR TKIs as an adjuvant treatment,in patients with resected EGFR-mutated NSCLC,and shown that they significantly prolong disease-free survival(DFS),but this benefit does not translate to OS.Recently,an interim analysis of the ADAURA trial demonstrated that,surprisingly,osimertinib improved DFS.This led to the study being stopped early,leaving many unanswered questions about its potential effect on OS and its incorporation as a standard adjuvant treatment in this patient subgroup.These targeted agents are also being evaluated in locally-advanced disease,with promising results,although prospective studies with larger sample sizes are needed to confirm these results.In this article,we review the most relevant studies on the role of EGFR TKIs in the management of early-stage EGFR-mutated NSCLC.
文摘Aim: To investigate mechanisms of tryptase-induced reduction of sperm motility and explore whether epidermal growth factor receptor (EGF-R) and protease activated receptor 2 (PAR-2)- associated pathways are involved. Methods: Fresh semen was collected from healthy donors (n = 15). Semen parameters and quality were assessed in accordance with the World Health Organization (WHO) criteria. Swim-up sperm were fixed and subjected to immunocytochemistry and immunoelectronmicroscopy with specific antibodies directed against PAR-2 and EGF-R. Protein extractions from swim-up spermatozoa were analyzed by Western blotting with antibodies for both receptors. Motility of spermatozoa was evaluated by computer-assisted semen analysis. Results: Immunocytochemistry found PAR-2 and EGF-R in approximately 30% of examined human ejaculated spermatozoa. Both receptors were localized in the plasma membrane. Like tryptase, the PAR-2 synthetic agonist SLIGKV reduced sperm motility, and this effect was inhibited by application of two specific EGF-R pathway blockers (AG1478 and PD168393). Conclusion: The observed reduction of sperm motility by tryptase through the PAR-2 receptor involves EGF-R pathways.
基金the National Nature Science Foundation of China (39670736).
文摘Objective: To explore the role of growth factor autocrine stimulation in the pathogenesis of human pituitary tumors. Methods: The expression of EGF, TGF-( and EGFR were studied by immunohisto-chemical method on paraffin-embedded sections of 30 cases pituitary tumor. Results: EGFR and its ligands EGF, TGF-( expressed in majority of pituitary tumors. The expression of EGFR and its ligands varied with cells' intensity, density and type. Conclusion: The EGF autocrine stimulating exerted in the pituitary tumor development process, that tyrosine kinases inhibitors may be useful for pituitary tumors treatment.
基金Supported by National Natural Science Foundation of China,No. 81502556Yunnan Digestive Endoscopy Clinical Medical Center Foundation for Health Commission of Yunnan Province,No. 2X2019-01-02
文摘BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal growth factor receptor(EGFR)pathway.AIM To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor(HB-EGF)/EGFR pathway.METHODS We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis(GEPIA)website(http://gepia.cancer-pku.cn/index.html).Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues,and we constructed a stable lowexpressing FOXQ1 cell line and verified it with the above method.The expression changes of membrane-bound HB-EGF(proHB-EGF)and soluble HB-EGF(sHB-EGF)in the lowexpressing FOXQ1 cell line were detected by flow cytometry and ELISA.Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells.Proliferation experiments,transwell migration experiments,and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF,and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.RESULTS GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate.PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways.Knockdown of FOXQ1 suppressed the expression of HB-EGF,and led to a decrease in EGFR and its downstream genes AKT,RAF,KRAS expression levels.After knockdown of FOXQ1 in CRC cell lines,cell proliferation,migration and invasion were attenuated.Adding HB-EGF restored the migration and invasion ability of CRC,but not the cell proliferation ability.Kaplan–Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.CONCLUSION Based on these collective data,we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.
基金Supported by the National Natural Science Foundation of China(N o.81570875No.31170685)+4 种基金the China Postdoctoral Science Foundation Funded Project(No.2015M582044)the Health Systems Young Personnel Training Projects Foundation of Fujian Province,China(No.2013-ZQN-JC-37)the Science and Technology Program Foundation of Xiamen City in China(No.3502720144044)the Scientific Research Foundation of the State Human Resource Ministrythe Scientific Research Staring Foundation for the Returned Overseas Chinese Scholars,Ministry of Education of China
文摘AIM:To investigate the cross-talk between oxidative stress and the epidermal growth factor receptor(EGFR)/AKT signaling pathway in retinal pigment epithelial( RPE) cells.METHODS:Human RPE cell lines(ARPE-19 cell) were treated with different doses of epidermal growth factor(EGF) and hydrogen peroxide(H2O2).Cell viability was determined by a methyl thiazolyl tetrazolium assay.Cell proliferation was examined by a bromodeoxyuridine(Brd U) incorporation assay.EGFR/AKT signaling was detected by Western blot.EGFR localization was also detected by immunofluorescence.In addition,EGFR/AKT signaling was intervened upon by EGFR inhibitor(erlotinib),PI3 K inhibitor(A66) and AKT inhibitor(MK-2206),respectively.H2O2-induced oxidative stress was blocked by antioxidant N-acetylcysteine(NAC).RESULTS:EGF treatment increased ARPE-19 cell viabili ty and proliferation through inducing phosphorylation of EGFR and AKT.H2O2 inhibited ARPE-19 cell viability and proliferation and also suppressed EGF-stimulated increase of RPE cell viability and proliferation by affecting the EGFR/AKT signaling pathway.EGFR inhibitor erlotinib blocked EGF-induced phosphorylation of EGFR and AKT,while A66 and MK-2206 only blocked EGF-induced phosphorylation of AKT.EGF-induced phosphorylation andendocytosis of EGFR were also affected by H2O2 treatment.In addition,antioxidant NAC attenuated H2O2-induced inhibition of ARPE-19 cell viability through all eviating reduction of EGFR,and phosphorylated and total AKT proteins.CONCLUSION:Oxidative stress affects RPE cell viability and proliferation through interfering with the EGFR/AKT signaling pathway.The EGFR/AKT signaling pathway may be an important target in oxidative stress-induced RPE cell dysfunction.
文摘Aim: To investigate the expression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) and the possible mechanism in the development in androgen independent prostate cancer (AIPC). Methods: Immunohistochemistry was performed on paraffin-embedded sections with goat polyclonal against COX-2 and mouse monoclonal antibody against EGFR in 30 AIPC and 18 androgen dependent prostate cancer (ADPC) specimens. The effect of epidermal growth factor (EGF) treatments on the expression of COX-2 and signal pathway in PC-3 and DU-145 cells was studied using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. ELISA was used to measure prostaglandin E2 (PGE2) levels in the media of PC-3 and DU-145 incubated with EGF for 24 h. Results: COX-2 was positively expressed in AIPC and ADPC, which were predominantly in endochylema of prostate cancer (PCa) cells. Intense staining was seen in AIPC (80%) and in ADPC (55.5%), but there was no significant association between the two groups. EGFR expression was also positive in the two groups (61.8% in ADPC and 90% in AIPC, P 〈 0.01). A significant association was found between EGFR expression and a higher Gleason score (P 〈 0.05) or tumor stage (P 〈 0.05). The expression of PGE2 was increased in PC-3 and DU-145 cells after being incubated with EGF. Both p38MAPK and PI-3K pathway were involved in the PC-3 cell COX-2 upregulation course. In DU- 145, only p38MAPK pathway was associated with COX-2 upregulation. Conclusion: EGFR activation induces COX-2 expression through PI-3K and/or p38MAPK pathways. COX-2 and EGFR inhibitors might have a cooperative anti-tumor effect in PCa.
文摘Background: Epidermal growth factor receptor(EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors(TKIs) efficacy in non-small cell lung cancer(NSCLC). We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.Methods: A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system(ARMS). We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate(ORR), disease control rate(DCR) and progression free survival(PFS).Results: Of all patients, EGFR mutation rate was 28.6%(60/210) by direct sequencing and 45.2%(95/210) by ARMS(P〈0.001) respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR(48.0% vs. 80.9%, P=0.004) and shorter median PFS(7.4 vs. 10.5 months, P=0.009) as compared with that of EGFR mutation positive patients by both detection methods. Conclusions: Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.
基金This study was supported by grants from National Natural Science Foundation of China (No. 30772162).
文摘Aim: To investigate human epidermal growth factor receptor type 2 (HER2) protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Methods: Immunohistochemistry (IHC) was performed to investigate HER2 protein expression in prostate biopsy specimens from 104 Chinese metastatic prostate cancer patients. After 3-11 months of hormonal therapy, 12 patients underwent transurethral resection of the prostate (TURP). HER2 protein expression of TURP specimens was compared with that of the original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores ≥ 2+ were investigated for HER2 gene amplification status by fluorescent in situ hybridization (FISH). Results: Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1+, 2+ and 3+ in 49 (47.1%), 45 (43.3%), 8 (7.7%) and 2 (1.9%) cases, respectively. There was a significant association between HER2 expression and Gleason score (P = 0.026). HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal therapy. None of the 14 specimens with HER2 IHC scores 〉 2+ showed HER2 gene amplification. Patients with HER2 scores 〉 2+ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0 (P = 0.004) and 1+ (P = 0.034). Multivariate Cox regression analysis showed that HER2 protein expression intensity was an independent predictor of cancer-related death (P = 0.039). Conclusion: An HER2 IHC score 〉 2+ should be defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual patients after hormonal therapy.
基金supported by National Nature Science Foundation of China(U1303221)National Natural Science Foundation of China(81373439,81473234)Construction of Technique Plate for Evaluation of the Pharmacodynamics of New Drugs in Xinjiang from the Department of Science and Technology of Xinjiang Province(201233150)
文摘OBJECTIVE To investigate the role of connexin proteins(Cx),which form gap junctions(GJ),in progression and chemotherapeutic sensitivity of cervical cancer(CaC x).METHODS We analyze the expression of Cx26,Cx30,Cx32 and Cx43 in human specimens consisting of:Normal cervix(n=78),CaCx FIGO stageⅠ(n=148),CaCx FIGO stageⅡ(n=165).In CaCx cell lines,Hela-Cx32(induced expression by doxycycline),C-33A(endogenously express Cx32)and si Ha(transiently transfected plasmid with Cx32),we detected the role of Cx32 against tostreptonigrin/cisplatin-induced apopotosisin presence or absence of functional GJ through using GJ inhibitors or low density cultural.Furtherly,we observed the relativity of Cx32 and EGFR expression in human specimens.Also,we detected the role of EGFR signaling pathway in the process of Cx32 anti-apoptosis through suppressed EGFR expression by inhibitors or si RNA sequences in cell lines.RESULTS We firstly demonstrated the expression of Cx32 was highly upregulated and accumulated in cytoplasm in the CaCx specimens,and the degree of upregulation correlated with advanced FIGO stages.Thus,in three human cervical cell lines,Cx32 was shown to suppress apoptosis when GJ formation is inhibited.No matter in cases of CaCx or cell lines,Cx32 expression was highly correlated with expression of EGFR and the EGFR pathway is an essential component of the Cx32-induced anti-apoptotic effect.CONCLUSION Cx32,traditionally tumor suppressive protein,was shown to be tumor protective against chemotherapy through EGFR pathway in a GJ-independent way.
基金supported by the National Key R&D Program of China(No.2017YFC1309100)the National Science Fund for Distinguished Young Scholars(No.81925023)+1 种基金the National Natural Science Foundation of China(No.81771912,81701662,81701782,81601469,and 81702322)Science and Technology Planning Project of Guangdong Province(No.2017B020227012)。
文摘Objective:To evaluate the human epidermal growth factor receptor 2(HER2)status in patients with breast cancer using multidetector computed tomography(MDCT)-based handcrafted and deep radiomics features.Methods:This retrospective study enrolled 339 female patients(primary cohort,n=177;validation cohort,n=162)with pathologically confirmed invasive breast cancer.Handcrafted and deep radiomics features were extracted from the MDCT images during the arterial phase.After the feature selection procedures,handcrafted and deep radiomics signatures and the combined model were built using multivariate logistic regression analysis.Performance was assessed by measures of discrimination,calibration,and clinical usefulness in the primary cohort and validated in the validation cohort.Results:The handcrafted radiomics signature had a discriminative ability with a C-index of 0.739[95%confidence interval(95%CI):0.661-0.818]in the primary cohort and 0.695(95%CI:0.609-0.781)in the validation cohort.The deep radiomics signature also had a discriminative ability with a C-index of 0.760(95%CI:0.690-0.831)in the primary cohort and 0.777(95%CI:0.696-0.857)in the validation cohort.The combined model,which incorporated both the handcrafted and deep radiomics signatures,showed good discriminative ability with a C-index of 0.829(95%CI:0.767-0.890)in the primary cohort and 0.809(95%CI:0.740-0.879)in the validation cohort.Conclusions:Handcrafted and deep radiomics features from MDCT images were associated with HER2 status in patients with breast cancer.Thus,these features could provide complementary aid for the radiological evaluation of HER2 status in breast cancer.
基金the National Natural Science Foundation of China, No.30400461Committee of Tianjin Science and Technology, No 05YFJZJC1002
文摘BACKGROUND: Dicer, a large multidomain ribonuclease, is responsible for processing double-stranded RNAs (dsRNAs) to 20-bp-long small interfering RNAs (siRNAs), which act as effectors during RNA interference (RNAi). OBJECTIVE: To observe the efficacy of siRNA cocktails generated by recombinant human Dicer on the down-regulation of epidermal growth factor receptor (EGFR) expression in human glioma cells. DESIGN, TIME AND SETTING: The following in vitro experiment was performed at the Department of Neurosurgery, Tianjin Medical University General Hospital and Laboratory of Neuro-Oncology, Tianjin Neurological Institute. MATERIALS: Mini-RNA isolation kit, human placenta complimentary DNA (cDNA) was produced by Tiangen Biotech (Beijing, China), human glioblastoma U251-MG cells were produced by the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences. METHODS: A PCR product from the human EGFR, which corresponded to the tyrosine kinase domain of the 3'-end fragment, was used as the T7-promotor for in vitro transcription. siRNA cocktails were generated by in vitro dicing of double stranded RNA. A total of 500, 250 and 125 μg siRNA cocktails were transiently transfected into U251 glioma cells through the use of the GeneSilencer. MAIN OUTCOME MEASURE: Expression of EGFR was detected by real-time PCR. RESULTS: The total PCR product of the human EGFR, corresponding to the tyrosine kinase domain, is approximately 680 bp in length. The PCR transcriptants included GCC leader sequences and a T7 promoter sequence, with a fragment of EGFR cDNA at the center. The T7 promoter was prepared for in vitro transcription of dsRNA. After dicing for 24 hours, the 21-nt siRNA cocktails were verified by 4% agarose gel. The difference between threshold cycle of a sample assay and threshold cycle of the corresponding endogenous reference (ΔCt) among parental U251 cells and cells transfected with different doses of siRNA cocktails were determined to be 3.06, 7.35, and 10.31 cycles, respectively. These results indicated effective silencing of EGFR expression by siRNA cocktails through transient transfection. CONCLUSION: The siRNA cocktails significantly suppressed exogenous expression of EGFR in U251 glioblastoma cells in a dose-dependent manner, thereby providing a more promising RNAi methodology for glioma therapy.
基金supported by grants from the National Nature Science Foundation of China(30801111 and 30972923)Science&Technology Support Project of Sichuan Province(10SZ0166,14ZC1337 and 14ZC1335)
文摘BACKGROUND: There is currently no effective medication to prevent stone recurrence after choledochoscopic lithotomy or to treat proliferative cholangitis(PC), which is the pathologic basis of hepatolithiasis. This study aimed to investigate whether gefitinib, an epidermal growth factor receptor(EGFR) inhibitor, inhibited cholangio hyperplasia and lithogenesis in PC.METHODS: After cholangioscopic lithotomy, indwelling catheters were placed in the diseased bile duct lumens in 94 patients with hepatolithiasis. Subsequently, 49 of the 94 patients were treated with 250 mg gefitinib solution via a catheter twice a week, and they were subjected to choledochoscopic biopsy at 6 and 12 weeks. The rest 45 hepatolithiasis patients without gefitinib treatment served as controls.RESULTS: The expressions of EGFR, PCNA and procollagen I were significantly reduced in the patients treated with gefitinib in 12 weeks compared with those in the control group. Patients in the gefitinib group had a much lower degree of hyperplasia of the biliary epithelium, submucosal glands and collagen fibers compared with those in the control group. Gefitinib treatment significantly decreased mucin 3 expression and β-glucuronidase activity.CONCLUSION: Postoperative gefitinib treatment could significantly inhibit PC-mediated hyperplasia and lithogenesis, which might provide a novel strategy for the prevention of biliary restenosis and stone recurrence in patients with hepatolithiasis.
基金by the Zhejiang Province Traditional Chinese Medicine Science and Technology Plan-Zhejiang Province Traditional Chinese Medicine Project for Traditional Chinese Medicine Scientific Research(2020)(Class B),No.2020ZB117。
文摘BACKGROUND For lung adenocarcinoma with epidermal growth factor receptor(EGFR)gene mutation,small molecule tyrosine kinase inhibitors are more effective.Some patients could not obtain enough histological specimens for EGFR gene mutation detection.Specific imaging features can predict EGFR mutation status to a certain extent.AIM To assess the associations of EGFR mutations with high-resolution computerized tomography(HRCT)features in ground-glass nodular lung adenocarcinoma.METHODS This study retrospectively assessed patients with ground-glass nodular lung adenocarcinoma diagnosed between January 2011 and March 2017.EGFR gene mutations in exons 18-21 were detected.The patients were classified into mutant EGFR and wild-type groups,and general data and HRCT image characteristics were assessed.RESULTS Among 98 patients,31(31.6%)and 67(68.4%)had mutated and wild-type EGFR in exons 18-21,respectively.Gender,age,smoking history,location of lesions,morphology,edges,borders,pleural indentations,and associations of nodules with bronchus and blood vessels were comparable in both groups(all P>0.05).Patients with mutant EGFR had larger nodules than those with the wild-type(17.19±6.79 and 14.37±6.30 mm,respectively;P=0.047).Meanwhile,the vacuole/honeycomb sign was more frequent in the mutant EGFR group(P=0.011).The logistic regression prediction model included the combination of nodule size and vacuole/honeycomb sign(OR=1.120,95%CI:1.023-1.227,P=0.014)revealed a sensitivity of 83.9%,a specificity of 52.2%and an AUC of 0.698(95%CI:0.589-0.806;P=0.002).CONCLUSION Nodule size and vacuole/honeycomb features could independently predict EGFR mutation status in ground-glass nodular lung adenocarcinoma.