RNA sequencing-based research on the immune regulation mechanism of C-MET in lung cancer / 实用医学杂志

Objective To analyze the immune regulation mechanism of C-MET expression in non-small cell lung cancer by transcriptome sequencing technology.Methods The C-MET expression of lung adenocarci-noma cell line(H1993)and lung squamous cell carcinoma cell line(EBC-1)with high C-MET expression was silenced using siRNA molecular interference technology.The differentially expressed genes(DEGs)before and after C-MET silencing were detected using transcriptome sequencing technology.The signal pathways and related genes of the immune microenvironment in which C-MET may participate in regulation were excavated through bioinformat-ics analysis.Finally,the co-culture technique of human immune cells with H1993 and EBC-1 was used to verify the effect of C-MET on immune factors such as INF-γ,INF-β and CXCL-10.Results We detected 505 DEGs in total using transcriptome sequencing.There were 38 differentially expressed genes in the C-MET regulation group before and after H1993,24 upregulated differentially expressed genes,and 14 downregulated differentially expressed genes,respectively.There are a total of 467 differentially expressed genes in the C-MET regulation group of EBC-1,347 upregulated differentially expressed genes,and 121 downregulated differentially expressed genes,respec-tively.KEGG analysis of differential genes suggested that C-MET expression might participate in the regulation of immune cell regulatory factors through the IL-17 signaling pathway,white blood cell differentiation,cytokine receptor activity,cell cycle,cytokine receptor activity,and cytokine-cytokine receptor interaction.The effect of C-MET on immune factor secretion was verified using the co-culture technique of lung cancer cells and human immune cells,and the results of Rt-qPCR assay suggested,the mRNA transcriptional level of INF-γ in PBMC co-cultured with the C-MET high expression group was 77 times that of the low expression group,and the mRNA transcriptional level of CXCL-10 was 1.6 times that of the low expression group.The mRNA transcriptional level of INF--β was twice as high as that of the low expression group.Conclusion C-MET expression may participate in the regulation of tumor surrounding immune microenvironment through IL-17 signaling pathway,leukocyte differen-tiation,and cytokine receptor activity pathway.

Meta-analysis of the efficacy of invisible orthodontic appliances for maxillary molar distalization in adult patients / 口腔疾病防治

Objective@#To evaluate the clinical efficacy of invisible orthodontic appliances without brackets for the distal movement of maxillary molars to improve the ability of orthodontists to predict treatment outcomes.@*Methods@#Web of Science, Cochrane Library, Embase, PubMed, Wanfang Database, CNKI Database, and VIP Database were searched for studies investigating the efficacy of invisible orthodontic appliances for distal movement of maxillary molars in adult patients and published from database inception to August 1, 2023. A total of three researchers screened the studies and evaluated their quality and conducted a meta-analysis of those that met quality standards.@*Results@#This study included 13 pre- and postcontrol trials with a total sample size of 281 patients. The meta-analysis revealed no significant differences in the sagittal or vertical parameters of the jawbone after treatment when compared with those before treatment (P>0.05). The displacement of the first molar was MD=-2.34, 95% CI (-2.83, -1.85); the displacement was MD=-0.95, 95% CI (-1.34, -0.56); and the inclination was MD=-2.51, 95% CI (-3.56, -1.46). There was a statistically significant difference in the change in sagittal, vertical, and axial tilt of the first molar before and after treatment. After treatment, the average adduction distance of the incisors was MD=-0.82, 95% CI (-1.54, -0.09), and the decrease in lip inclination was MD=-1.61, 95% CI (-2.86, -0.36); these values were significantly different from those before treatment (P<0.05).@*Conclusion@#Invisible orthodontic appliances can effectively move the upper molars in a distal direction and control the vertical position of the molars. When the molars move further away, there is some degree of compression and distal tilt movement, which is beneficial for patients with high angles. The sagittal movement of incisors is beneficial for improving the patient's profile.

Chinese multidisciplinary expert consensus on the management of adverse drug reactions associated with savolitinib / 中华肿瘤杂志

MET gene is a proto-oncogene, which encodes MET protein with tyrosine kinase activity. After binding to its ligand, hepatocyte growth factor, MET protein can induce MET dimerization and activate downstream signaling pathways, which plays a crucial role in tumor formation and metastasis. Savolitinib, as a specific tyrosine kinase inhibitor (TKI) targeting MET, selectively inhibits the phosphorylation of MET kinase with a significant inhibitory effect on tumors with MET abnormalities. Based on its significant efficacy shown in the registration studies, savolitinib was approved for marketing in China on June 22, 2021 for the treatment of advanced non-small cell lung cancer with MET 14 exon skipping mutations. In addition, many studies have shown that MET TKIs are equally effective in patients with advanced solid tumors with MET gene amplification or MET protein overexpression, and relevant registration clinical studies are ongoing. The most common adverse reactions during treatment with savolitinib include nausea, vomiting, peripheral edema, pyrexia, and hepatotoxicity. Based on two rounds of extensive nationwide investigations to guide clinicians, the consensus is compiled to use savolitinib rationally, prevent and treat various adverse reactions scientifically, and improve the clinical benefits and quality of life of patients. This consensus was prepared under the guidance of multidisciplinary experts, especially including the whole-process participation and valuable suggestions of experts in Traditional Chinese Medicine, thus reflecting the clinical treatment concept of integrated Chinese and western medicines.

Study on construction of c-Met specific CAR-T cells and its killing effect on non-small cell lung carcinoma / 中华肿瘤杂志

Objective: To produce chimeric antigen receptor T cells (CAR-T) targeting human hepatocyte growth factor/c-Met (HGF/c-Met) protein and detect its cytotoxicity against non-small cell lung cancer (NSCLC) cells H1975 in vitro. Methods: The whole gene sequence of c-Met CAR containing c-Met single-chain fragment variable was synthesized and linked to lentiviral vector plasmid, plasmid electrophoresis was used to detect the correctness of target gene. HEK293 cells were transfected with plasmid and the concentrated solution of the virus particles was collected. c-Met CAR lentivirus was transfected into T cells to obtain second-generation c-Met CAR-T and the expression of CAR sequences was verified by reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and western blot, and the positive rate and cell subtypes of c-Met CAR-T cells were detected by flow cytometry. The positive expression of c-Met protein in NSCLC cell line H1975 was verified by flow cytometry, and the negative expression of c-Met protein in ovarian cancer cell line A2780 was selected as the control. The cytotoxicity of c-Met CAR-T to H1975 was detected by lactate dehydrogenase (LDH) cytotoxicity assay at 1∶1, 5∶1, 10∶1 and 20∶1 of effector: target cell ratio (E∶T). Enzyme-linked immunosorbent assay (ELISA) was used to detect the release of cytokines such as TNF-α, IL-2 and IFN-γ from c-Met CAR-T co-cultured with H1975. Results: The size of band was consistent with that of designed c-Met CAR, suggesting that the c-Met CAR plasmid was successfully constructed. The results of gene sequencing were consistent with the original design sequence and lentivirus was successfully constructed. CAR molecules expression in T cells infected with lentivirus was detected by western blot and RT-qPCR, which showed c-Met CAR-T were successfully constructed. Flow cytometry results showed that the infection efficiency of c-Met CAR in T cells was over 38.4%, and the proportion of CD8(+) T cells was increased after lentivirus infection. The NSCLC cell line H1975 highly expressed c-Met while ovarian cancer cell line A2780 negatively expressed c-Met. LDH cytotoxicity assay indicated that the killing efficiency was positively correlated with the E∶T, and higher than that of control group, and the killing rate reached 51.12% when the E∶T was 20∶1. ELISA results showed that c-Met CAR-T cells released more IL-2, TNF-α and IFN-γ in target cell stimulation, but there was no statistical difference between c-Met CAR-T and T cells in the non-target group. Conclusions: Human NSCLC cell H1975 expresses high level of c-Met which can be used as a target for immunotherapy. CAR-T cells targeting c-Met have been successfully produced and have high killing effect on c-Met positive NSCLC cells in vitro.

Treatment status of non-small cell lung cancer with METexon14 skipping mutation / 国际肿瘤学杂志

MET exon14 (METex14) skipping mutation is an independent driver gene in non-small cell lung cancer (NSCLC) . About 3%-4% of NSCLC patients carry METex14 skipping mutation. These patients have poor prognoses and poor responses to traditional chemotherapy and immunotherapy. Highly selective MET inhibitors such as capmatinib, tepotinib, savolitinib have shown good efficacy and safety data in clinical trials, which bring new treatment options for patients with METex14 skipping mutations.

Clinical features of transthyretin amyloid polyneuropathy caused by Ser77Tyr mutation / 中华神经医学杂志

Objective:To study the clinical features of transthyretin amyloid polyneuropathy (ATTR-PN) caused by Ser77Tyr mutation.Methods:The clinical data of a patient with ATTR-PN caused by Ser77Tyr mutation, admitted to our hospital from Department of Neurology, Mindong Hospital Affiliated to Fujian Medical University, were retrospectively analyzed. Literature on patients with ATTR-PN caused by Ser77Tyr mutation in Pubmed, Web of Science, CNKI and Wanfang databases and those with ATTR-PN caused by Val30Met mutation in Pubmed and Web of Science were searched and screened, and clinical characteristics of these patients were extracted. The differences of clinical characteristics among patients with ATTR-PN caused by Ser77Tyr or Val30Met mutations were compared.Results:(1) Transthyroxin ( TTR) gene Sanger sequencing results showed Ser77Tyr heterozygous pathogenic mutation; Congo red staining of biopsy sample in the patient 2.5 years after onset showed amyloid deposition. (2) Seventy-eight patients with ATTR-PN caused by Ser77Tyr mutation were summarized, they mostly had onset at 50-60 years old; male patients had higher incidence (74.4%); most patients (78.0%) had positive family history; most patients had sensory symptoms as initial symptom (72.0%), which gradually progressed to extensive peripheral nerve involvement and combined with widespread heart damage (96.4%) over several years; electrophysiological examination mainly showed axonal damage and carpal tunnel syndrome; the tissue biopsy had high positive rate(84.8%). (3) There were 192 and 96 patients with ATTR-PN caused by early-onset and late-onset Val30Met mutations, respectively; compared with patients with ATTR-PN caused by early-onset Val30Met mutation, patients with ATTR-PN caused by Ser77Tyr mutation had significantly higher incidence of deep sensory disturbance (28.6% vs. 58.5%, P<0.05). Compared with patients with ATTR-PN caused by late-onset Val30Met mutation, patients with ATTR-PN caused by Ser77Tyr mutation had increased incidence of mild sensory disturbance (56.3% vs. 75.0%) and decreased incidence of limb weakness (65.6% vs. 48.3%), with significant differences ( P<0.05). ATTR-PN patients caused by Ser77Tyr mutation had significantly higher incidence of carpal tunnel syndrome than ATTR-PN patients caused by early-onset and late-onset Val30Met mutations (75.4% vs. 10.8% and 25.0%) and significantly higher incidence of cardiac damage than ATTR-PN patients caused by early-onset Val30Met mutation (96.4% vs. 80.5%, P<0.05). Conclusion:Ser77Tyr mutation has some distinctive clinical features: relatively balanced damage of large and small fibers, prominent carpal tunnel syndrome, and obvious heart disease; early identification of these features and administration of tissue biopsy and gene detection are helpful for early diagnosis.

Kaempferol promotes cell autophagy and affects cell proliferation of non-small cell lung cancer H1650 cells via regulating Met/PI3K/Akt/mTOR pathway / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨山柰酚诱导人非小细胞肺癌（NSCLC）NCI-H1650细胞发生自噬及其机制。方法：常规培养NCI-H1650细胞，用不同浓度山柰酚处理细胞，用CCK-8法、MTT法以及EdU法检测山柰酚对NCI-H1650细胞增殖能力的影响，用自噬双标记腺病毒mCherry-EGFR-LC3感染实验检测山柰酚对NCI-H1650细胞发生自噬的影响，用WB法检测山柰酚处理后NCI-H1650细胞中自噬相关蛋白及Met/PI3K/Akt/mTOR信号通路相关蛋白的表达，用qPCR法检测山柰酚处理后NCI-H1650细胞中Met mRNA的表达。采用荧光素酶标记A549-luc细胞建立裸鼠移植瘤模型后用山柰酚进行处理，用活体动物成像技术观察移植瘤生长情况，用WB法检测移植瘤组织中自噬相关蛋白以及Met/PI3K/Akt/mTOR信号通路相关蛋白的表达。结果：山柰酚能显著抑制NCI-H1650细胞的增殖能力（P<0.05），山柰酚处理后NCI-H1650细胞内的自噬小体数量明显增加（P<0.05）、自噬标志蛋白LC3B和beclin1表达均明显上调（均P<0.05）、P62表达明显下调（P<0.05），山柰酚可明显抑制NCI-H1650细胞中Met mRNA和蛋白的表达（均P<0.05）、抑制p-PI3K p85、PI3K p85、p-Akt和p-mTOR蛋白表达（均P<0.05）。山柰酚抑制A549细胞裸鼠移植瘤的生长（P<0.05）和影响其体内自噬、Met/PI3K/Akt/mTOR通路相关蛋白的表达（均P<0.05）。结论：山柰酚通过影响Met/PI3K/Akt/mTOR通路诱导NSCLC NCI-H1650细胞发生自噬，进而抑制其增殖能力。

Clinicopathological Features and Prognosis of Patients Newly Diagnosed With Lung Adenocarcinoma With Both EGFR Mutation and C-MET Amplification / 中国医学科学院学报

Objective To explore the clinicopathological features and prognosis of the patients newly diagnosed with lung adenocarcinoma with both EGFR mutation and C-MET amplification.Methods The pathological sections were reviewed.EGFR mutation was detected by amplification refractory mutation system-quantitative real-time polymerase chain reaction,and C-MET amplification by fluorescence in situ hybridization.The clinicopathological features and survival data of the patients newly diagnosed with lung adenocarcinoma with both EGFR mutation and C-MET amplification were analyzed retrospectively.Results In 11 cases of EGFR mutation combined with C-MET amplification,complex glands and solid high-grade components were observed under a microscope in 10 cases except for one case with a cell block,the tissue structure of which was difficult to be evaluated.The incidence of lung adenocarcinoma in the patients with EGFR mutation combined with C-MET amplification at clinical stage Ⅳ was higher than that in the EGFR mutation or C-MET amplification group (all P<0.001),whereas the difference was not statistically significant between the EGFR mutation group and C-MET amplification group at each clinical stage (all P>0.05).There was no significant difference in the trend of survival rate between EGFR gene group and C-MET amplification group (χ2=0.042,P=0.838),while the survival of the patients with EGFR mutation combined with C-MET amplification was worse than that of the patients with EGFR mutation (χ2=246.72,P<0.001) or C-MET amplification (χ2=236.41,P<0.001).Conclusions The patients newly diagnosed with lung adenocarcinoma with EGFR mutation plus C-MET amplification demonstrate poor histological differentiation,rapid progress,and poor prognosis.The patients are often in the advanced stage when being diagnosed with cancer.Attention should be paid to this concurrent adverse driving molecular event in clinical work.With increasing availability,the inhibitors targeting C-MET may serve as an option to benefit these patients in the near future.

Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation / 中国肺癌杂志

The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians.
.

Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC50 values and achieved picomolar DC50 values and >99% of maximum degradation (Dmax) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-METY1230H and c-METD1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

c-MET positivity and its relationship with histopathological findings in gastric carcinomas exhibiting HER2 gene expression

Context: Co-expressions of receptor tyrosine kinases such as c-MET and HER2 were reported in many studies. The concomitant expression is associated with more aggressive clinical course. Aims: In this study, it was intended to investigate the correlation of the positivity of c-MET and HER2 with histopathologic findings and their impacts on prognosis. Subjects and Methods: After the decision of the ethics committee, a total of 64 cases, whose HER 2 status was studied by dual silver in situ hybridization/immunohistochemistry method, were included in the study. Immunohistochemical staining for c-MET was performed to all cases and the evaluation was performed similarly to the criteria for HER2 evaluation, but cytoplasmic staining was also considered significant. Statistical Analysis Used: The data were analyzed using SPSS 20 for Windows. Results: c-MET positivity which is considered by the score of 2+ and 3+ was found only in 34.4% of HER2 positive cases while it was 59.3% in HER2 negative cases (P = 0.045). The sole histopathological feature associated with c-MET positivity was distal gastric localization (P = 0.016). Conclusions: Even though higher rates of c-MET positivity in HER2 positive cases were stated in the literature, contrary results were obtained in this study. Comparing the HER2+/c-MET + co-expression group with the other groups, no difference was found about age, sex, macroscopic and microscopic characteristics. The presence of c-MET positivity in cases with HER2 expression suggests that c-MET expression might be associated with the resistance to Trastuzumab.

FISH patterns of ROS1, MET, and ALK with a correlation of ALK immunohistochemistry in lung cancer: a case for introducing ALK immunohistochemistry ‘Equivocal’ interpretation category in the Ventana anti?ALK (D5F3) CDx assay ? A tertiary cancer center experience

Background: Mutations in ROS1, ALK, and MET genes are targetable alterations in non-small cell lung cancer (NSCLC). They can be evaluated by different techniques, most commonly fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Methods: We explored the prevalence of ROS1, ALK, MET mutations, discuss clinicopathological associations and FISH signal patterns on 413 consecutive cases of EGFR negative lung carcinoma from March 2016 to April 2017 using FISH for ALK, ROS1, and MET along with ALK (D5F3) IHC. Results: ROS1 gene rearrangement, ALK positivity (IHC and/or FISH), and MET amplification were seen in 18/358 (5%) cases, 76/392 cases (19.4%), and 10/370 (2.7%) cases, respectively. ALK FISH and ALK IHC were positive in 51/300 (17%) and 58/330 cases (17.57%), respectively, while 8/330 (2.4%) cases were ALK IHC “equivocal” of which 3/8 (37.5%) were ALK FISH positive. Of ALK FISH and IHC co-tested cases, 43/238 (18.07%) cases were positive by both techniques, while 15/43 (34.88%) of ALK positive cases showed discordant ALK FISH and IHC results. All ROS1 rearranged and MET amplified cases were adenocarcinoma. Signet ring cell histology was associated with 78.57% likelihood of being either ALK or ROS1 positive. Genomic heterogeneity was seen in 30% of MET amplified cases. Conclusions: ALK/ROS1/MET gene alterations were found in 25.18% of NSCLC cases. An ALK IHC “equivocal” interpretation category should be incorporated into practice. Atypical patterns of ROS1 and genomic heterogeneity need to be evaluated further for any clinical relevance.

MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.

Effects of propofol on malignant biological behaviors of prostate cancer DU145 cells and its mechanism / 国际肿瘤学杂志

Objective:To investigate the effects of propofol on malignant biological behaviors of prostate cancer DU145 cells and its possible mechanism.Methods:Control group, 5-fluorouracil group (200 ng/ml) , low-dose propofol group (100 ng/ml) and high-dose propofol group (400 ng/ml) were set up. CCK-8 kit was used to measure the level of cell proliferation, Transwell method was used to measure the abilities of cell invasion and migration, flow cytometry was used to measure the level of apoptosis, and qRT-PCR and Western blotting were used to measure hepatocyte growth factor (HGF) and c-Met mRNA and protein levels.Results:The survival rates of the control group, 5-fluorouracil group, low-dose propofol group and high-dose propofol group were (83.32±3.02) %, (36.29±3.54) %, (62.01±4.69) % and (40.20±5.48) % ( F=8.65, P=0.006) ; the apoptosis rates were (2.36±0.41) %, (12.47±0.40) %, (6.28±0.39) % and (10.24±0.37) % ( F=26.73, P=0.001) . Further pairwise comparison showed that there were statistically significant differences (all P<0.05) . The numbers of penetrating membranes of the four groups were 617.45±29.86, 125.27±24.38, 407.02±32.27 and 230.74±31.59 ( F=18.33, P=0.002) ; the migration distances were (603.85±27.74) μm, (121.69±25.85) μm, (395.59±28.37) μm and (233.52±30.42) μm ( F=27.02, P=0.001) . Further pairwise comparison showed that there were statistically significant differences (all P<0.05) . HGF mRNA expression levels of the four groups were 6.26±0.39, 1.94±0.35, 4.15±0.37 and 2.90±0.33 ( F=25.31, P=0.001) ; c-Met mRNA expression levels were 5.85±0.30, 2.04±0.32, 3.89±0.31 and 2.94±0.32 ( F=12.12, P=0.003) ; HGF protein expression levels were 1.43±0.04, 0.34±0.08, 0.86±0.06 and 0.63±0.09 ( F=17.02, P=0.001) ; c-Met protein expression levels were 1.63±0.14, 0.39±0.15, 0.93±0.11 and 0.64±0.17 ( F=19.89, P=0.001) . Further pairwise comparison showed that there were statistically significant differences (all P<0.05) . Conclusion:Propofol has obvious inhibitory effects on the malignant biological behaviors of prostate cancer DU145 cells, and the inhibitory effect of high-dose propofol is more obvious. The mechanism may be related to the inhibition of HGF and c-Met mRNA and protein expressions of DU145 cells by propofol, which inhibits the activation of HGF/c-Met pathway.

Analysis of the Effcacy and Safety of Amivantamab in Non-small Cell Lung Cancer Patients with EGFR/MET Gene Abnormalities: A Single Center's Experience / 中国肺癌杂志

BACKGROUND@#Epidermal growth factor receptor (EGFR) and cellular-mesenchymal to epithelial transition factor (c-Met) are widely expressed on cancer cells. There is a synergistic effect of EGFR and HGF/c-Met pathways on proliferation, downstream activation of signal transduction and an additive effect. Studies show that combination of both signaling pathways could potentially be targeted in a synergistic fashion. Amivantamab, a bispecific monoclonal antibody targeting EGFR and c-Met, yielded robust and durable responses in a variety of clinicals trials. However, few researches have reported its efficacy in Chinese non-small cell lung cancer (NSCLC) patients. This study was conducted to evaluate the effectiveness and tolerance of Amivantamab in NSCLC patients with EGFR/MET gene abnormalities at Peking University Cancer Hospital.@*METHODS@#The study enrolled NSCLC patients who received Amivantamab in our hospital between August 2020 and December 2021, and analyzed the response, survival, and treatment-related adverse events.@*RESULTS@#Fifteen patients were enrolled in this research, and six of them received Amivantamab treatment and the other nine patients received Amivantamab plus Lazertinib treatment. The rates of partial response (PR), stable disease (SD), and progressive disease (PD) were 46.7% (7/15), 46.7% (7/15) and 6.7% (1/15), respectively. The overall response rate (ORR) and disease control rate (DCR) were 28.6% (2/7) and 100.0% (7/7) in seven patients with EGFR exon 20 insertion, respectively. The ORR and DCR were 40.0% (2/5) and 100.0% (5/5) in five post-osimertinib EGFR-mutant patients, respectively. After a median follow-up of 8.7 months, the median progression-free survival and overall survival were not reached. The most common treatment-related adverse events were rash (86.7%), paronychia (80.0%), and infusion-related reactions (60.0%), and most of them were graded as 1 to 2. Grade 3 to 4 adverse events included rash (33.3%), alanine aminotransferase elevation (13.3%), gamma-glutamyl transpeptidase elevation (13.3%), peripheral edema (6.7%), thromboembolism (6.7%), interstitial lung disease (6.7%), and thrombocytopenia (6.7%).@*CONCLUSIONS@#Amivantamab was effective in Chinese NSCLC patients with EGFR exon 20 insertion and post-Osimertinib EGFR-mutant patients, similar to the results of clinical trials conducted in western countries. Amivantamab was well tolerated and emphases should be put on adverse events such as rash, paronychia, and infusion-related reactions.

Effect and Mechanism of Wumeiwan Against Lewis Lung Cancer in Mice with Syndrome of Cold and Heat in Complexity Based on HGF/C-Met Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect and mechanism of Wumeiwan against Lewis lung cancer in mice with syndrome of cold and heat in complexity based on hepatocyte growth factor/mesenchymal-epithelial transition factor （HGF/C-Met） signaling pathway. MethodTwenty healthy male mice were classified into blank group， model group （equivalent volume of distilled water， ig）， cisplatin group （4.0 mg·kg-1 cisplatin， ip）， and Wumeiwan group （12.5 mL·kg-1 Wumeiwan， ig）， with 5 in each group. Lewis lung cancer with the syndrome of cold and heat in complexity was induced in mice except the blank group by gavage of propylthiouracil， Zhimu Shigaotang， and Fanxieye， ice-water swimming， and subcutaneous injection of dry yeast suspension and Lewis cell suspension under the right armpit. After modeling， administration began and lasted 6 weeks. After the experiment， the tumor weight， tumor volume， tumor inhibition rate， and lung cancer metastasis-inhibiting proportion were measured and calculated. The pathological morphology of lung tissue was observed based on hematoxylin and eosin （HE） staining. The growth state of tumor tissue was analyzed by immunohistochemistry. The mRNA expression of HGF and C-Met was detected by Real-time polymerase chain reaction （PCR）， and the protein expressions of HGF， C-Met， survivin， and X-linked inhibitor of apoptosis protein （XIAP） by Western blot. ResultCompared with the blank group， the model group showed high mRNA expression of HGF and C-Met and protein expression of HGF， C-Met， surviving， and XIAP （P<0.01）. Compared with the model group， Wumeiwan group displayed low proportion of positive cells， positive cell density， positive score （P<0.05）， histochemical score， tumor weight， tumor volume （P<0.01）， mRNA expression of HGF and C-Met （P<0.01）， and protein expression of HGF， C-Met， surviving， and XIAP （P<0.01）. Compared with the model group， the cisplatin group displayed decrease in the proportion of positive cells， density of positive cells （P<0.05）， positive score， tumor weight， tumor volume （P<0.01）， mRNA expression of HGF and C-Met （P<0.01）， and protein expression of HGF， C-Met， surviving， and XIAP （P<0.01）， and insignificant variation in the histochemical score. Wumeiwan group had high mRNA expression of HGF （P<0.01）， and insignificant variation in the proportion of positive cells， positive cell density， histochemical score， positive score， tumor weight， tumor volume， mRNA expression of C-Met， and protein expression of HGF， C-Met， surviving， and XIAP. ConclusionWumeiwan can slow down the progression of Lewis lung cancer in mice with syndrome of cold and heat I complexicity by inhibiting HGF/C-Met signaling pathway.

6-desulfated heparin inhibits heparan sulfate shedding and epithelial cell damage during bleomycin induced pulmonary injury / 中国药理学通报

Aim To study the effect of different hepa- ry.Methods First, heparin derivatives with different rin sulfation patterns on bleomycin induced lung inju- sulfation patterns,6-desulfated heparin (6-DeH) and N-acetvlated heparin ( N-AcH ) , were synthesized.Secondly, the effect of these compounds on BLM-in¬duced bronchial epithelial cell ( BEARS-2B) injury was evaluated via lactate dehydrogenase activity, MTT experiment, Annexin V/ PI staining and Hoechst 33258 staining.Then , immunofluorescence staining and West¬ern blotting were used to investigate the shedding of Svndecan-1 and the activation of c-Met by 6-DeH/Akt j j signaling pathway.Finally, a BLM-induced lung injury mouse model was used to further verify the protective effect of 6-DeH by HE staining, Svndecan-1 immunos- taining,bodv weight change,and survival rate.Results In the BLM-induced BEARS-2B injury model, 6- DeH was selected as the best candidate, which exerted their effect by competitively binding to BLM, thereby reducing the damage of heparan sulfate barrier (Svnde- can-1 ) on cell surface, and improving cell survival by activating the downstream c-Met/Akt pathway.In the BLM-induced lung injury mouse model, it was further confirmed that 6-DeH reduced the shedding of Svnde- can-1 in the early stage, and delayed the lung injury and fibrosis process.Conclusions 6-DeH protects the bronchial epithelial cells against BLM-induced lung in¬jur)' through inhibiting the shedding of Svndecan-1 and activating the c-Met/Akt signaling pathway.

Correlation between serum BDNF，Val66Met gene polymorphism and clinical symptoms in early Parkinson’s disease / 中风与神经疾病杂志

@#To investigate the correlation between serum Brain-derived neurotrophic factor （BDNF），Val66Met gene polymorphism and clinical symptoms in patients with newly diagnosed Parkinson’s disease （PD）. Methods A total of 62 early PD patients and 46 healthy controls were collected from Ningbo First Hospital. General demographics，Hamilton Anxiety Scale （HAMA），Hamilton Depression Scale （HAMD），Orthostatic Hypotension （OH） or not，serum BDNF levels，Val66Met genotype were examined in all subjects，duration of disease，Hoehn-Yahr （HY） Rating Scale，Unified Parkinson’s Disease Rating Scale motor scores （UPDRS-Ⅲ），symptom classification （tremor type，rigid type or mixed type） were also assessed in patients. Results PD patients had significantly higher HAMA，HAMD scores，incidence of OH and lower BDNF levels than controls，there was no significant difference in the distribution of Val66Met gene polymorphism between the two groups. Multiple linear regression revealed that BDNF levels were negatively associated with HAMA （P=0.014） and HAMD （P=0.013） scores in PD patients，however，no significant correlation were found between Val66Met polymorphism and clinical symptoms. Conclusion Evident non-motor symptoms can occur in early PD patients，serum BNDF levels were correlated with the degree of anxiety and depression in patients，and Val66Met gene polymorphism may not play an important role in the course of disease.

BDNF Val66Met polymorphism and resilience in major depressive disorder: the impact of cognitive psychotherapy

Objective: Clinical and biological correlates of resilience in major depressive disorder are scarce. We aimed to investigate the effect of the Val66Met polymorphism in the BDNF gene on resilience scores in major depressive disorder patients and evaluate the polymorphism's moderation effect on resilience scores in response to cognitive therapy. Method: A total of 106 major depressive disorder patients were enrolled in this clinical randomized study. The Resilience Scale and the Hamilton Rating Scale for Depression were applied at baseline, post-treatment, and at six months of follow-up. Blood samples were obtained at baseline for molecular analysis. Results: The baseline resilience scores were higher in patients with the Met allele (114.6±17.6) than in those with the Val/Val genotype (104.04±21.05; p = 0.037). Cognitive therapy treatment increased resilience scores (p ≤ 0.001) and decreased depressive symptoms (p ≤ 0.001). In the mixed-effect model, the Val/Val genotype represented a decrease in resilience scores (t218 = -1.98; p = 0.048), and the Val66Met polymorphism interacted with sex to predict an increase in total resilience scores during cognitive treatment (t218 = 2.69; p = 0.008). Conclusion: Our results indicate that cognitive therapy intervention could improve resilience in follow-up, considering that gender and genetic susceptibility are predicted by the Val66Met polymorphism.

Correlation of c-MET and CXCR4 proteins and microvessel density with liver metastasis in colorectal cancer / 肿瘤研究与临床

Objective:To explore the correlation of c-MET and CXCR4 proteins and microvessel density (MVD) with liver metastasis in colorectal cancer tissues.Methods:A total of 40 colorectal cancer tissue samples and 10 paracancerous (5 cm from the edge of the tumor) normal colorectal tissue samples were collected from March 2015 to December 2020 in Shanxi Traditional Chinese Medical Hospital. Among 40 patients with colorectal cancer, 15 patients had liver metastasis. Immunohistochemistry was used to detect c-MET protein, CXCR4 protein and CD34-labeled MVD in various tissues, and the relationships between them and liver metastasis and between the three were analyzed.Results:The positive rates of c-MET protein [72.5% (29/40) vs. 30.0% (3/10)], CXCR4 protein [47.5% (19/40) vs. 10.0% (1/10)] and MVD (20.1±5.2 vs. 11.5±4.3) in colorectal cancer tissues were higher than those in paracancerous tissues, and the differences were statistically significant (all P < 0.05). The positive rates of c-MET protein [86.7% (13/15) vs. 64.0% (16/25)] and CXCR4 protein [66.7% (10/15) vs. 36.0% (9/25)] in colorectal cancer liver metastasis group were significantly higher than those in non-liver metastasis group, and the differences were statistically significant (both P < 0.05). MVD in colorectal cancer liver metastasis group was significantly higher than that in non-liver metastasis group (21.5±5.3 vs. 12.4±5.7), and the difference was statistically significant ( P < 0.05). In colorectal cancer tissues, c-MET protein expression was positively correlated with CXCR4 protein expression ( r = 0.568, P < 0.05), and MVD in c-MET-positive patients or CXCR4-positive patients was higher than that in negative ones (both P < 0.05). Conclusions:The c-MET protein, CXCR4 protein and MVD may play important roles in the liver metastasis of colorectal cancer. The three indicators can provide a certain reference for the early diagnosis and prognosis prediction of liver metastasis of colorectal cancer.