Effect of RBP2 gene silencing on proliferation, migration and invasion of ovarian epithelial cancer SKOV3/DDP cells and its mechanism / 中华肿瘤杂志

Objective: To explore the effect of down-regulation of retinol binding protein 2 (RBP2) expression on the biological characteristics of ovarian cancer cells and its mechanism. Methods: Knockdown of RBP2 and cisplatin (DDP)-resistant ovarian cancer cell line SKOV3/DDP-RBP2i was established, the negative control group and blank control group were also set. Cell counting kit 8 (CCK-8) was used to detect the cell proliferation ability, flow cytometry was used to detect cell apoptosis, scratch test and Transwell invasion test were used to detect cell migration and invasion ability, real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) and western blot were used to detect the expressions of molecular markers related to epithelial-mesenchymal transition (EMT). The effect of RBP2 on the growth of ovarian cancer was verified through experiment of transplanted tumors in nude mice, and the relationships between RBP2 expression and tumor metastasis and patient prognosis were analyzed using the clinical data of ovarian cancer in TCGA database. Results: After down-regulating the expression of RBP2, the proliferation ability of SKOV3/DDP cell was significantly reduced. On the fifth day, the proliferation activities of SKOV3/DDP-RBP2i group, negative control group and blank control group were (56.67±4.16)%, (84.67±3.51) and (87.00±4.00)% respectively, with statistically significant difference (P<0.001). The apoptosis rate of SKOV3/DDP-RBP2i group was (14.19±1.50)%, higher than (8.77±0.75)% of the negative control group and (7.48±0.52)% of the blank control group (P<0.001). The number of invasive cells of SKOV3/DDP-RBP2i group was (55.20±2.39), lower than (82.60±5.18) and (80.80±7.26) of the negative control group and the blank control group, respectively (P<0.001). The scratch healing rate of SKOV3/DDP-RBP2i group was (28.47±2.72)%, lower than (50.58±4.06)% and (48.92±4.63)% of the negative control group and the blank control group, respectively (P<0.001). The mRNA and protein expressions of E-cadherin in the SKOV3/DDP-RBP2i group were higher than those in the negative control group (P=0.015, P<0.001) and the blank control group (P=0.006, P<0.001). The mRNA and protein expression of N-cadherin in SKOV3/DDP-RBP2i group were lower than those in the negative control group (P=0.012, P<0.001) and the blank control group (P=0.005, P<0.001). The mRNA and protein expressions of vimentin in SKOV3/DDP-RBP2i group were also lower than those in the negative control group (P=0.016, P=0.001) and the blank control group (P=0.011, P=0.001). Five weeks after the cells inoculated into the nude mice, the tumor volume of SKOV3/DDP-RBP2i group, negative control group and blank control group were statistically significant different. The tumor volume of SKOV3/DDP-RBP2i group was smaller than those of negative control group and blank control group (P=0.001). Bioinformatics analysis showed that the expression of RBP2 in patients with metastatic ovarian cancer was higher than that without metastasis (P=0.043), and the median overall survival of ovarian cancer patients with high RBP2 expression was 41 months, shorter than 69 months of low RBP2 expression patients (P<0.001). Conclusion: Downregulation of the expression of RBP2 in SKOV3/DDP cells can inhibit cell migration and invasion, and the mechanism may be related to the inhibition of EMT.

Numb activates the mTORC1 signaling pathway in proximal tubular epithelial cells by upregulating V1G1 expression / 南方医科大学学报

OBJECTIVE@#To investigate the role of Numb in regulating mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway.@*METHODS@#Male BALB/C mouse models of acute kidney injury (AKI) were subjected to intravenous injections of Numb-siRNA or NC-siRNA with or without intraperitoneal cisplatin injections. After the treatments, the expressions and distribution of Numb and megalin in the renal tissues of the mice were detected with immunohistochemistry, and the renal expressions of Numb, S6, p-S6, S6K1, p-S6K1, 4EBP1 and p-4EBP1 were examined with Western blotting. The proximal renal tubular epithelial cells were isolated from the mice transfected with Numb-siRNA for in vitro culture. In NRK-52E cells, the effects of amino acid stimulation, Numb knockdown, and V1G1 overexpression, alone or in combination, on expressions of Numb, S6 and p-S6 were detected with Western blotting; the expressions of AMPK and p-AMPK were also detected in transfected NRK-52E cells, mouse kidneys and cultured mouse renal tubular epithelial cells.@*RESULTS@#In BALB/C mice, injection of Numb-siRNA caused significant reductions of Numb and p-S6 expressions without affecting megalin expression in the renal proximal tubules (P < 0.05). Cisplatin treatment obviously upregulated p-S6K1 and p-4EBP1 expressions in the kidneys of the mice (P < 0.05), and this effect was significantly inhibited by treatment with Numb-siRNA (P < 0.05). In NRK-52E cells, amino acid stimulation significantly upregulated the expression of p-S6 (P < 0.05), which was strongly suppressed by transfection with Numb-siRNA (P < 0.05). Numb knockdown inhibited AMPK activation in NRK-52E cells, mouse kidneys and primary proximal tubular epithelial cells (P < 0.05). Numb knockdown significantly downregulated V1G1 expression in NRK-52E cells (P < 0.05), and V1G1 overexpression obviously reversed the inhibitory effect of Numb-siRNA on S6 phosphorylation (P < 0.05).@*CONCLUSION@#Numb promotes the activation of mTORC1 signaling in proximal tubular epithelial cells by upregulating V1G1 expression.

Autophagy promotes recurrence of nasopharyngeal carcinoma via inducing the formation of dormant polyploid giant cancer cells / 中华耳鼻咽喉头颈外科杂志

Objective: To explore the effect of dormant polyploid giant cancer cells (PGCC) on nasopharyngeal carcinoma (NPC) recurrence and to clarify the role of inhibition of autophagy in inhibiting NPC-PGCC formation and preventing NPC recurrence. Methods: NPC cells-derived PGCC (NPC-PGCC) were induced by paclitaxel (PTX), and the morphology, polyploid characteristics and cell activity of PGCC were identified by light microscopy, immunofluorescence and Live/Dead cell double staining assays. RNA-seq was used to analyze the differentially expressed genes between NPC-PGCC and diploid nasopharyngeal carcinoma cells CNE2. Functional enrichment and pathway annotation analysis of differentially expressed genes were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG). The level of autophagy in NPC-PGCC cells was assessed by Western Blot and transmission electron microscopy analysis. The role of autophagy in the formation of NPC-PGCC and the effect of NPC-PGCC on the recurrence of nasopharyngeal carcinoma were studied using a highly clinically relevant mouse nasopharyngeal carcinoma recurrence model. Statistical analysis was performed using GraphPad Prism 6 and P-values<0.05 were considered statistically significant. Results: NPC-PGCC induced by paclitaxel had the characteristics of burst-like division after dormancy. GO enrichment and KEGG pathway analyses identified the significant biological processes and pathways mainly concentrated in autophagy and related pathways involving the differentially expressed genes between NPC-PGCC and diploid nasopharyngeal carcinoma cells CNE2. The autophagy level was significantly enhanced in NPC-PGCC cells. In a highly clinically relevant mouse nasopharyngeal carcinoma recurrence model, the number of PGCC in the primary tumor of the nude mice treated with cisplatin were higher than those of the other groups. In nude mice pretreated with autophagy inhibitor and then co-treatment with autophagy inhibitor and cisplatin, the number of PGCC in primary tumors was less and the recurrence rate was significantly lower than in other groups. Conclusions: The mechanism of dormant polyploid giant cancer cells formation is related to autophagy. Inhibition of autophagy can inhibit the formation of PGCC and thus prevent the recurrence of nasopharyngeal carcinoma.

Atezolizumab therapy in Chinese patients with locally advanced or metastatic solid tumors: An open-label, phase Ⅰ study / 北京大学学报(医学版)

OBJECTIVE@#To evaluate pharmacokinetics (PK), efficacy, and safety of atezolizumab (anti-PD-L1) in high interest cancers in China, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), nasopharyngeal cancer (NPC), and non-small cell lung can-cer (NSCLC).@*METHODS@#This phase I, open-label study was conducted at 6 Chinese sites from August 4, 2016 to April 15, 2019. The patients were ≥18 years old with a histologically documented incurable or metastatic solid tumor that was advanced or recurrent and had progressed since the last anti-tumor the-rapy. The PK phase characterized PK and safety of atezolizumab following multiple-dose administration when atezolizumab was administered as a single agent. The extension phase studied safety and efficacy of atezolizumab, as monotherapy (EC, GC, HCC, NPC) and with chemotherapy (NSCLC).@*RESULTS@#This study enrolled 120 patients (PK phase: n=20; extension phase: n=20/cohort). Fourty-two patients (42.0%) were PD-L1 positive in atezolizumab monotherapy group (100 patients), of the 9 patients (9.0%) with microsatellite instability-high (MSI-H) tumors. Atezolizumab clearance was 0.219 L/d, and steady state was reached after 6 to 9 weeks (2-3 cycles) of repeated dosing. Objective response rates (ORRs) in EC, GC, HCC, NPC, and NSCLC were 10.0%, 15.0%, 10.0%, 5.0%, and 40.0%, respectively. In the patients with PD-L1 positive tumors, ORR was 11.9% with atezolizumab and 46.2% with atezolizumab plus gemcitabine and cisplatin. Two GC patients achieved durable response after pseudo-progression. The most common treatment-related adverse events in the atezolizumab monotherapy group were fatigue, anemia, fever, and decreased white blood cell count. The most common treatment-related adverse events in the combination group were anemia, decreased white blood cell count, and decreased appetite. No new safety signals were identified.@*CONCLUSION@#Atezolizumab's PK, efficacy, and safety were similar in Chinese patients vs. global patients in previous studies.

Carbenoxolone enhances inhibitory effect of RSL3 against cisplatin-resistant testicular cancer cells by promoting ferroptosis / 南方医科大学学报

OBJECTIVE@#To investigate the inhibitory effect of RSL3 on the proliferation, invasion and migration of cisplatinresistant testicular cancer cells (I-10/DDP) and the effect of carbenoxolone on the activity of RSL3 against testicular cancer.@*METHODS@#MTT assay was used to evaluate the survival rate of I-10/DDP cells following treatment with RSL3 (1, 2, 4, 8, 16 or 32 μmol/L) alone or in combination with carbenoxolone (100 μmol/L) or after treatment with Fer-1 (2 μmol/L), RSL3 (4 μmol/L), RSL3+Fer-1, RSL3+carbenoxolone (100 μmol/L), or RSL3+Fer-1+carbenoxolone. Colony formation assay was used to assess the proliferation ability of the treated cells; wounding-healing assay and Transwell assay were used to assess the invasion and migration ability of the cells. The expression of GPX4 was detected using Western blotting, the levels of lipid ROS were detected using C11 BODIPY 581/591 fluorescent probe, and the levels of Fe2+ were determined with FerroOrange fluorescent probe.@*RESULTS@#RSL3 dose-dependently decreased the survival rate of I-10/DDP cells, and the combined treatment with 2, 4, or 8 μmol/L RSL3 with carbenoxolone, as compared with RSL3 treatment alone, resulted in significant reduction of the cell survival rate. The combination with carbenoxolone significantly enhanced the inhibitory effect of RSL3 on colony formation, wound healing rate (P=0.005), invasion and migration of the cells (P < 0.001). Fer-1 obviously attenuated the inhibitory effects of RSL3 alone and its combination with carbenoxolone on I-10/DDP cells (P < 0.01). RSL3 treatment significantly decreased GPX4 expression (P=0.001) and increased lipid ROS level (P=0.001) and Fe2+ level in the cells, and these effects were further enhanced by the combined treatment with carbenoxolone (P < 0.01).@*CONCLUSION@#Carbenoxolone enhances the inhibitory effect of RSL3 on the proliferation, invasion and migration of cisplatin-resistant testicular cancer cells by promoting RSL3-induced ferroptosis.

Molecular mechanisms of Gupi Xiaoji decoction inducing apoptosis of human hepatoma HepG2 cells / 中国应用生理学杂志

Objective: To investigate the molecular mechanisms of Gupi Xiaoji decoction on apoptosis of human hepatoma cells HepG2. Methods: HepG2 cells were divided into 4 groups: control group (Control), blank serum group (Blank), Gupi Xiaoji Yin serum group (GPXJY) and cisplatin group (Positive). Eight duplicate holes were set in each group. After treated with Gupi Xiaoji Decoction-containing serum or cisplatin for 24 hours, the cell viability, the number of viable cells, the state of apoptosis, the cell cycle and the mitochondrial membrane potential were detected, and the level of lipid peroxidation (MDA) and glycolysis rate of the cells were detected. The expressions of apoptotic Bax, Bcl-2, and Caspase-3 proteins, and the contents of triacylglycerol (TG), cholesterol (TC), pyruvate and glucose in the cell supernatant were detected. Results: Compared with the control group, in the GPXJY group, the inhibition rate was increased (P＜0.05), the number of cells was decreased, the number of apoptosis-positive cells was increased (P＜0.01), the number of cells in the G1 phase was increased significantly (P＜0.05), and the cell membrane potential was decreased (P＜0.05,P＜0.01), the glycolytic function was inhibited significantly, the MDA level was increased, the expressions of Bax and Caspase-3 in the GPXJY group were increased, and the expression of Bcl-2 was decreased (P＜0.05, P＜0.01). In cell supernatant, the TC, TG and glucose contents were decreased significantly, and the pyruvate content was increased significantly (P＜0.05,P＜0.01). Conclusion: Gupi Xiaoji Decoction can induce apoptosis of HepG2 cells and may play a role in energy metabolism.

Analysis of the Efficacy of Pemetrexed Maintenance Therapy in Patients with Malignant Pleural Mesothelioma / 中国肺癌杂志

BACKGROUND@#Malignant pleural mesothelioma (MPM) is a highly aggressive disease arising from pleural mesothelial cells. Advanced pleural mesothelioma has a poor prognosis, with a median survival of no more than 15 months. First line standard chemotherapy regimen recommended is Pemetrexed based chemotherapy regimen, with or without bevacizumab. There is no consensus on whether patients who have received first-line standard chemotherapy can benefit from pemetrexed maintenance chemotherapy. The study aimed to investigate the efficacy and safety of pemetrexed maintenance therapy (PMT) after treatment with a pemetrexed and platinum regimen for patients with MPM.@*METHODS@#A total of 40 MPM patients were collected from Cancer Hospital Chinese Academy of Medical Sciences from January 2013 to January 2018, eligible patients were unresectable MPM, without disease progression following 4 to 6 cycles of pemetrexed and platinum, including pemetrexed maintenance therapy group (22 cases) and observation group (18 cases). The last follow-up was conducted in January 2020. The primary endpoint were progression free survival (PFS), and the secondary end points were overall survival (OS), the efficacy, adverse reactions of PMT.@*RESULTS@#The median PFS in the PMT arm was longer than that in the observation arm (8.5 mon vs 3 mon, P=0.008), but there was no significant difference in median OS (26.4 mon vs 15.7 mon, P=0.177). Objective response rate (ORR) of two group were 22.7% and 0%, respectively. The grade 3-4 toxicity in PMT group included grade 4 neutropenia in 1 patient (4.5%), grade 3 neutropenia in 1 patient (4.5%), grade 4 anemia in 1 patient (4.5%) and grade 3 nausea and anorexia in 1 patient (4.5%).@*CONCLUSIONS@#Pemetrexed maintenance therapy following initial pemetrexed and platinum chemotherapy improve PFS in patients with MPM, and is well tolerated.

Knockout of farnesoid X receptor gene aggravates cisplatin-induced kidney injury / 中南大学学报(医学版)

OBJECTIVES@#Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand activated transcription factors and belongs to bile acid receptor. Studies have shown that the expression of FXR in renal tissue can reduce renal injury via regulation of glucose and lipid metabolism, inhibition of inflammatory response, reduction of oxidative stress and renal fibrosis. However, it is unclear whether FXR is involved in autophagy in renal diseases. This study aims to investigate the role of FXR in cisplatin-induced acute renal injury and whether its mechanism is related to autophagy regulation.@*METHODS@#Twelve male WT or FXR-KO mice at 12 weeks were randomly divided into a WT group, a WT+cisplatin group, a FXR-KO group, and a FXR-KO+cisplatin group, with 6 mice in each group. The WT+cisplatin group and the FXR-KO+cisplatin group were intraperitoneally injected with cisplatin (20 mg/kg), and the WT group and the FXR-KO group were intraperitoneally injected with equal volume of cisplatin solvent. Seventy-two hours later, the mice were killed and blood and renal tissue samples were collected. The levels of SCr and BUN were detected by immunoturbidimetry. After the staining, the pathological changes of renal tissue were observed under optical microscope. The protein levels of LC3 and p62 were detected by Western blotting and immunohistochemistry. The clearance of damaged mitochondria and the accumulation of lysosomal substrate were observed under electron microscope. The apoptosis of renal tubular epithelial cells was detected by TUNEL.@*RESULTS@#Compared with the WT group or the FXR-KO group, both SCr and BUN levels in the WT+cisplatin group or the FXR-KO+cisplatin group were significantly increased (P<0.01 or P<0.001), and SCr and BUN levels in the FXR-KO+cisplatin group were significantly higher than those in the WT+cisplatin group (both P<0.05). Under the light microscope, there were no obvious pathological changes in the renal tissue of mice in the WT group and the FXR-KO group. Both the WT+cisplatin group and the FXR-KO+cisplatin group had vacuolar or granular degeneration of renal tubular epithelial cells, flat cells, lumen expansion, brush edge falling off, and even exposed basement membrane and tubular formation. The scores of renal tubular injury in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the score in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). Under the transmission electron microscope, the mitochondria of mouse tubular epithelial cell in the WT+cisplatin group and the FXR-KO+cisplatin group was swollen, round, vacuolated, cristae broken or disappeared; the lysosome was uneven and high-density clumps, and the change was more obvious in the FXR-KO+cisplatin group. Western blotting showed that the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased in the WT+cisplatin group compared with the WT group and the FXR-KO+cisplatin group compared with FXR-KO group (P<0.05 or P<0.01); compared with the FXR-KO group, the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased significantly in the FXR-KO+cisplatin group (both P<0.05). Immunohistochemistry results showed that the expression of total LC3 and p62 in renal cortex of the WT+cisplatin group and the FXR-KO+cisplatin group was increased significantly, especially in the FXR-KO+cisplatin group. TUNEL results showed that the mice in the WT group and the FXR-KO group had negative staining or only a few apoptotic tubular epithelial cells, and the number of apoptotic cells in the WT+cisplatin group and the FXR-KO+cisplatin group were increased. The apoptosis rates of renal tubular epithelial cells in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the apoptosis rate in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05).@*CONCLUSIONS@#Knockout of FXR gene aggravates cisplatin induced acute renal injury, and its mechanism may be related to inhibiting autophagy and promoting apoptosis.

Ethoxysanguinarine directly targets CIP2A to inhibit proliferation and induce autophagy of SGC7901/DDP cells / 中国中药杂志

This study aims to investigate the effect of ethoxysanguinarine(Eth) on cisplatin(DDP)-resistant human gastric cancer cells and decipher the underlying mechanism. The human gastric cancer cell line SGC7901 and the DDP-resistant cell line SGC7901/DDP were used as the cell models. Western blot was employed to determine the expression levels of multidrug resistance-related proteins, and methyl thiazolyl tetrazolium(MTT) assay to detect the proliferation of SGC7901 and SGC7901/DDP cells exposed to DDP. After treatment with different concentrations of Eth, the proliferation of SGC7901 and SGC7901/DDP cells was detected by MTT assay, trypan blue exclusion assay, colony formation assay, and high-content imaging and analysis system. The apoptosis of SGC7901/DDP cells was detected by flow cytometry with Annexin V-FITC/PI staining. GFP-LC3 transfection was carried out to detect the effect of Eth on the autophagy of SGC7901/DDP cells. The expression levels of the multidrug resistance-related protein P-glycoprotein(P-gp), the apoptosis-related proteins [caspase-9, caspase-3, and poly(ADP-ribose) polymerase(PARP)], the autophagy-related protein light chain 3-Ⅱ(LC3-Ⅱ), the key effectors [mammalian target of rapamycin(mTOR), 70 kDa ribosomal protein S6 kinase(P70 S6 K), and 4 E binding protein 1(4 E-BP1)] of the mammalian target of rapamycin complex 1(mTORC1) signaling pathway, cancerous inhibitor of protein phosphatase 2A(CIP2A), and protein kinase B(Akt) were measured by Western blot. The mRNA level of CIP2A in the SGC7901/DDP cells exposed to Eth for 24 h was analyzed by RT-qPCR. After SGC7901/DDP cells were transfected with CIP2A expression vector pcDNA3.1-HA-CIP2A and treated with different concentrations of Eth, MTT assay was used to determine the prolife-ration of SGC7901/DDP cells and Western blot to detect the expression levels of related proteins. The interaction sites of Eth and CIP2A were predicted by molecular docking. The affinity between Eth and CIP2A was determined by drug affinity responsive target stability(DARTS) assay. The pharmacokinetic properties and drug-like activity of Eth were predicted by SwissADME. The results indicated that SGC7901/DDP cells were more sensitive to Eth than SGC7901 cells. Eth significantly inhibited proliferation and colony formation and changed the morphology, roundness, and area of SGC7901/DDP cells. Eth treatment caused the nucleus shrinking and significantly increased the apoptosis rate of the cells. Furthermore, Eth down-regulated the expression of caspase-9 and caspase-3 precursors and promoted the cleavage of PARP, which suggested that Eth induced the apoptosis of SGC7901/DDP cells. The GFP-LC3 in Eth-treated cells showed speckled aggregation. The up-regulated expression of LC3-Ⅱ by Eth indicated that Eth activated the autophagy of SGC7901/DDP cells. Eth down-regulated the expression of P-gp, the phosphorylation of mTOR, P70 S6K, and 4E-BP1, the expression of CIP2A, and the phosphorylation of Akt. Additionally, it increased the activity of PP2A, and had no significant effect on the expression of CIP2A in SGC7901/DDP cells. CIP2A overexpression antagonized the inhibition of cell proliferation and the activation of autophagy by Eth. Molecular docking suggested that Eth bound to CIP2A. The results of DARTS assay further proved the above binding effect. Eth has potential drug-like activity. The above results demonstrated that Eth inhibited the proliferation, induced the apoptosis, and activated the autophagy of SGC7901/DDP cells by targeting CIP2A and then down-regulating PP2A/mTORC1 signaling pathway. This study provided a new target for the treatment of cisplatin-resistant gastric cancer.

Mechanism of Cordyceps militaris against non-small cell lung cancer: based on serum metabolomics / 中国中药杂志

This study investigated the potential mechanism of Cordyceps militaris(CM) against non-small cell lung cancer(NSCLC) based on serum untargeted metabolomics. Specifically, Balb/c nude mice were used to generate the human lung cancer A549 xenograft mouse model. The tumor volume, tumor weight, and tumor inhibition rate in mice in the model, cisplatin, Cordyceps(low-, medium-, and high-dose), and CM(low-, medium-, and high-dose) groups were compared to evaluate the influence of CM on lung cancer. Gas chromatography-mass spectrometry(GC-MS) was used for the analysis of mouse serum, SIMCA 13.0 for the compa-rison of metabolic profiles, and MetaboAnalyst 5.0 for the analysis of metabolic pathways. According to the pharmacodynamic data, the tumor volume and tumor weight of mice in high-dose CM group and cisplatin group decreased as compared with those in the model group(P<0.05 or P<0.01). The results of serum metabolomics showed that the metabolic profiles of the model group were significantly different from those of the high-dose CM group, and the content of endogenous metabolites was adjusted to different degrees. A total of 42 differential metabolites and 7 differential metabolic pathways were identified. In conclusion, CM could significantly inhibit the tumor growth of lung cancer xenograft mice. The mechanism is the likelihood that it influences the aminoacyl-tRNA biosynthesis, the metabolism of D-glutamine and D-glutamate, metabolism of alanine, aspartate, and glutamate, metabolism of glyoxylate and dicarboxylic acid, biosynthesis of phenylalanine, tyrosine, and tryptophan, arginine biosynthesis as well as nitrogen metabolism. This study elucidated the underlying mechanism of CM against NSCLC from the point of metabolites. The results would lay a foundation for the anticancer research and clinical application of CM.

Utility of GPR68 and TIL in TPF-induced chemotherapy and prognosis evaluation in middle-advanced hypopharyngeal squamous cell carcinoma / 中华耳鼻咽喉头颈外科杂志

Objective: To evaluate the roles of G Protein-Coupled Receptor 68 (GPR68) and tumor infiltrating lymphocytes (TIL) in TPF-(paclitaxel, cisplatin and 5-fluorouracil) induced chemotherapy for middle-advanced hypopharyngeal squamous cell carcinomas. Methods: A total of 31 patients with middle-advanced hypopharyngeal squamous cell carcinoma before TPF-inducted chemotherapy were enrolled from September 2012 to November 2017 in Beijing Tongren Hospital, Capital Medical University, including 28 males and 3 females, aged 43 to 71 years old. The expression of GPR68 and tumor infiltrating CD4+and CD8+T cells before chemotherapy was detected by immunohistochemical staining, and the relationships between GPR68 expression and clinical features, chemotherapy efficacy and overall survival (OS) were analyzed using t-test. Results: After 3 cycles of chemotherapy, there were 4, 14, 10 and 3 patients respectively with complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The positive rates of GPR68 and CD8 were 25% and 40% respectively in the effective group (CR+PR), while 50% and 15% in the ineffective group (SD+PD), with statistically significant differences between two groups (t=5.17 and 12.86,P<0.001). Linear regression analysis showed that GPR68 was negatively correlated with CD8+T cells (r=-0.64,P<0.001). There was no significant correlation between the CD4 expression and TPF efficacy (P>0.05). The mean OS was 12.5 months in patients with high-expressed GPR68 and 25.0 months in patients with low-expressed GPR68, with a statistically significant difference (P=0.005). And mean OS was 25.0 months in patients with high-expressed CD8 and 14.5 months in low-expressed CD8, with a statistically significant difference (HR=2.58, P=0.019). Cox regression analysis showed that GPR68 and CD8+T cells were significant prognostic factors (OR(95%CI)=3.27(2.46-5.97) and 1.53(0.78-1.82), all P<0.05), while CD4 had no significant effect on prognosis (P>0.05). Conclusion: GPR68 and CD8+T cells are expected to be biomarkers for evaluating the efficacy and prognosis of TPF-induced chemotherapy in patients with middle-advanced hypopharyngeal squamous cell carcinoma.

Protective effects of melatonin in cisplatin-induced cardiac toxicity: possible role of BDNF-TNF-α signaling pathway

Purpose: The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects. Methods: Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg). Results: Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury. Conclusions: Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.

Effect of kefir on increased apoptosis in liver and kidney in cisplatin toxicity / Efecto del kéfir sobre el aumento de la apoptosis en el hígado y los riñones en la toxicidad del cisplatino

SUMMARY: Cisplatin is a chemotherapeutic agent inducing liver and kidney damage. In this study, we intended to investigate the impact of kefir beverage, an essential probiotic and functional food, on liver and kidney damage induced by cisplatin. Wistar albino rats were divided into four groups: Control, Cisplatin (single dose of 7 mg/kg, intraperitoneal), Kefir (2 ml/d, 7 d, oral gavage), and Cisplatin+Kefir (CK). At the end of day 7, animals were euthanized. Blood, kidney, and liver tissue samples were collected. For both tissues, biochemically ALT, AST, Urea, Creatine; histomorphologically, hematoxylin-eosin, Masson's Trichrome, and immunohistochemical staining of caspase-3, a marker of apoptosis, were performed. Serum urea and creatinine levels of the Cisplatin group were significantly higher than the Control group (p<0.05). In the CK group, kefir consumption decreased urea and creatinin levels approached to Control and Kefir groups. Cisplatin resulted in higher ALT and AST activities, indicating hepatocellular damage, compared to the Control group (p<0.05). Kefir consumption decreased ALT activities approached to both the Control and Kefir group. Histomorphological observations were in agreement biochemical results. In liver and kidney tissues, structural damage was observed with an increase in collagen fibers in the Cisplatin group, and Caspase-3 activity was immunohistochemically higher than in the other groups. In the CK group, collagen fiber increase, structural damage, and Caspase-3 activities were less than in the Cisplatin group. Kefir consumption alleviated liver and kidney damage. However, more research is required to understand such effect of kefir better.

RESUMEN: El cisplatino es un agente quimioterapéutico que induce daño hepático y renal. En este estudio, intentamos investigar el efecto del kéfir, un alimento funcional y probiótico esencial, en el daño hepático y renal inducido por el cisplatino. Se dividieron ratas albinas Wistar en cuatro grupos: control, cisplatino (dosis única de 7 mg/kg, intraperitoneal), kéfir (2 ml/día, 7 días, sonda oral) y cisplatino + kéfir (CK). Al final del día 7, los animales fueron sacrificados. Se recolectaron muestras de sangre, riñón y tejido hepático. Se determinó ALT, AST, Urea y Creatina; Para el análisis histomorfológico, se realizaron tinciones con hematoxilina-eosina, tricrómico de Masson y para inmunohistoquímica, caspasa-3, un marcador de apoptosis. Los niveles séricos de urea y creatinina del grupo de cisplatino fueron significativamente más altos que los del grupo de control (p<0,05). En el grupo CK, el consumo de kéfir disminuyó los niveles de urea y creatinina acercándose a los grupos Control y Kéfir. El cisplatino resultó en actividades más altas de ALT y AST, lo que indica daño hepatocelular, en comparación con el grupo Control (p<0.05). El consumo de kéfir disminuyó las actividades de ALT tanto en el grupo Control como en el de Kéfir. Las observaciones histomorfológicas coincidieron con los resultados bioquímicos. En tejidos hepáticos y renales se observó daño estructural con aumento de fibras colágenas en el grupo de Cisplatino, y la actividad de Caspasa-3 fue inmunohistoquímicamente mayor que en los otros grupos. En el grupo de CK, el aumento de las fibras colágenas, el daño estructural y las actividades de Caspasa-3 fueron menores que en el grupo Cisplatino. El consumo de kéfir mejoró el daño hepático y renal. Sin embargo, se requiere más investigación para comprender mejor el efecto del kéfir.

Voltammetric Determination of Ascorbic Acid in Pharmaceutical Formulations Using Modified Iodine-Coated Platinum Electrode / Determinación voltamétrica del ácido ascórbico en formulaciones farmacéuticas utilizando un electrodo de platino modificado recubierto de yodo

Background: Despite the high reactivity of the platinum electrode, the iodine-coated platinum electrode shows obvious inertness toward adsorption and surface processes. For that, iodine-coated platinum electrodes accommodate themselves to interesting voltammetric applications. Objectives: This study reports using the modified iodine-coated polycrystalline platinum electrode as a voltammetric sensor for ascorbic acid determination in pharmaceutical formulations. Methods: The developed voltammetric method based on recording cyclic voltammograms of ascorbic acid at iodine-coated electrode The optimized experimental parameters for the determination of ascorbic acid were using 0.1 M KCl as a supporting electrolyte with a scan rate of 50mV/s. Results: The anodic peak related to ascorbic acid oxidation was centered at nearly 0.28V. An excellent and extended linear dependence of the oxidative peak current on the concentration of ascorbic acid was observed in the range 2.84x10-3 - 5.68 mM. The limit of detection (LOD) and limit of quantitation (LOQ) were 1.0 µM and 3.01 µM, respectively, attesting to the method's sensitivity. The investigation for the effect of potential interference from multivitamin tablet ingredients (vitamins B1, B6, B12, folic acid, citric acid, sucrose, glucose, and zinc) indicated specific selectivity toward ascorbic acid and the absence of any electrochemical response toward these components. Recovery results in the range 98.93±2.78 - 99.98±5.20 for spiked standard ascorbic acid in pharmaceutical formulations further confirmed the potential applicability of the developed method for the determination of ascorbic acid in real samples. Conclusions: The developed method was successfully applied to the analysis of ascorbic acid (vitamin C), and the obtained results were in good agreement with the labeled values; besides, the statistical tests indicated no significant difference at p=0.05 with a 95% confidence level

Antecedentes: A pesar de su alta reactividad, el electrodo de platino recubierto de yodo muestra una inercia evidente hacia la adsorción y los procesos superficiales. Por ello, los electrodos de platino recubiertos de yodo se adaptan a interesantes aplicaciones voltamétricas. Objetivos: Este estudio informa sobre el uso del electrodo de platino policristalino recubierto de yodo modificado como sensor voltamétrico para la determinación del ácido ascórbico en formulaciones farmacéuticas. Métodos: El método voltamétrico desarrollado se basa en el registro de voltamperogramas cíclicos del ácido ascórbico en el electrodo recubierto de yodo Los parámetros experimentales optimizados para la determinación del ácido ascórbico fueron utilizando KCl 0,1 M como electrolito de soporte con una velocidad de barrido de 50mV/s. Resultados: El pico anódico relacionado con la oxidación del ácido ascórbico se centró en casi 0,28V. Se observó una excelente y extendida dependencia lineal de la corriente del pico oxidativo con respecto a la concentración de ácido ascórbico en el rango 2,84x10-3 - 5,68 mM. El límite de detección (LOD) y el límite de cuantificación (LOQ) fueron 1,0 µM y 3,01 µM, respectivamente, lo que demuestra la sensibilidad del método. La investigación del efecto de la interferencia potencial de los ingredientes de las tabletas multivitamínicas (vitaminas B1, B6, B12, ácido fólico, ácido cítrico, sacarosa, glucosa y zinc) indicó una selectividad específica hacia el ácido ascórbico y la ausencia de cualquier respuesta electroquímica hacia estos componentes. Los resultados de recuperación en el rango de 98,93±2,78 - 99,98±5,20 para el ácido ascórbico estándar adicionado en formulaciones farmacéuticas confirmaron además la potencial aplicabilidad del método desarrollado para la determinación del ácido ascórbico en muestras reales. Conclusiones: El método desarrollado se aplicó con éxito al análisis de ácido ascórbico (vitamina C), y los resultados obtenidos coincidieron con los valores etiquetados; además, las pruebas estadísticas no indicaron diferencias significativas a p=0,05 con un nivel de confianza del 95%

Mesotelioma en paciente colombiano con sobrevida mayor a tres años: presentación de caso / Mesothelioma in a Colombian Patient over three years: Case Presentation / Mesotelioma em paciente colombiano com sobrevivência superior a três anos: apresentação de caso

Resumen Introducción: el mesotelioma epitelioide es un tumor que se desarrolla en las capas embrionarias mesoteliales; es de etiología desconocida, pero se relaciona con la exposición al asbesto, con una presentación clínica inespecífica y con un pronóstico de sobrevida corto después del diagnóstico. Presentación del caso: hombre de profesión mecánico automotor, con tos sin expectoración, disnea, hipertermia y emaciación posterior a la extracción quirúrgica de lipomas que afectaban el tórax, quien posteriormente fue diagnosticado con mesotelioma epitelioide maligno con ubicación en la pleura del hemitórax derecho y fue tratado con toracotomía, quimioterapia con los medicamentos pemetrexed y cisplatino y sesiones de radioterapia, que mostraron un aumento en la sobrevida 3 tres años. Conclusión: este caso permitió identificar que el uso de la pleurodesis química con quimioterapia como tratamiento podría ser responsable del aumento de la esperanza de vida y la calidad de esta en los pacientes que padecen este tipo de tumor.

Abstract Introduction: Epithelioid mesothelioma is a tumor that develops in the mesothelial embryonic layers; it is of an unknown etiology, but it is related to asbestos exposure with a nonspecific clinical presentation and a short survival prognosis after diagnosis. Case presentation: An automotive mechanic patient presents with cough without expectoration, dyspnea, hyperthermia, and emaciation following surgical removal of lipomas. This affected the chest and the patient was subsequently diagnosed with malignant epithelioid mesothelioma located in the pleura of the right hemithorax. The patient was treated with thoracotomy, chemotherapy with the drugs pemetrexed and cisplatin, and radiation therapy sessions which resulted in an increased survival rate at 4 years. Conclusion: This case report identifies the use of chemical pleurodesis in combination with chemotherapy as an effective treatment for increasing the life expectancy and quality of life in patients suffering from this type of tumor.

Resumo Introdução: o mesotelioma epitelióide é um tumor que se desenvolve nas camadas embrionárias mesote-liais; é de causa desconhecida, mas está relacionado com a exposição ao amianto e possui uma manifestação clínica inespecífica e com prognóstico de sobrevivência curto após o diagnóstico. Apresentação do caso: o paciente é um mecânico automotivo, que apresentou tosse seca, dispneia, hipertermia e emagrecimento posterior a extração cirúrgica de lipomas que afetavam o tórax sendo posteriormente diagnosticado com mesotelioma epitelióide maligno localizado na pleura do hemitórax direito e foi tratado com toracotomia, quimioterapia com os medicamentos pemetrexed e cisplatino além de sessões de radioterapia, mostrando um aumento de expectativa de vida para 4 anos. Conclusão: este estudo de caso permite identificar que o uso da pleurodese química com quimioterapia como tratamento poderia ser a responsável pelo aumento da expectativa e qualidade de vida em pacientes acometidos por este tipo de tumor.

Effects of radical radiotherapy combined with different regimens of chemotherapy on radiation intestinal injury in patients with non-metastatic anal squamous cell carcinoma / 中华胃肠外科杂志

Objective: To investigate the effects of radical radiotherapy combined with different chemotherapy regimens (fluorouracil-based versus docetaxel plus cisplatin) on the incidence of radiation intestinal injury and the prognosis in patients with non-metastatic anal squamous cell carcinoma. Methods: A retrospective cohort study was conducted to recruit non-metastatic anal squamous cell carcinoma patients who underwent chemoradiotherapy in the Sixth Affiliated Hospital of Sun Yat-sen University and Nanfang Hospital from July 2013 to January 2021. Inclusion criteria: (1) newly diagnosed anal and perianal squamous cell carcinoma; (2) completed radical radiotherapy combined with concurrent chemotherapy; (3) tumor could be evaluated before radiotherapy. Exclusion criteria: (1) no imaging evaluation before treatment, or the tumor stage could not be determined; (2) patients undergoing local or radical resection before radiotherapy; (3) distant metastasis occurred before or during treatment; (4) recurrent anal squamous cell carcinoma. A total of 55 patients (48 from the Sixth Affiliated Hospital of Sun Yat-sen University and 7 from Nanfang Hospital) were given fluorouracil (the 5-FU group, n=34) or docetaxel combined with the cisplatin (the TP group, n=21). The evaluation of radiation intestinal injury, hematological toxicity and 3-year disease-free survival (DFS) rate were compared between the two groups. The effects of chemotherapy regimen and other clinicopathological factors on the incidence and severity of acute and chronic radiation intestinal injury were analyzed. The assessment of radiation intestinal injury was based on the American Cancer Radiotherapy Cooperation Group (RTOG) criteria. Results: During radiotherapy and within 3 months after radiotherapy, a total of 45 patients developed acute radiation intestinal injury, including 18 cases of grade 1 (32.7%), 22 cases of grade 2 (40.0%) and 5 cases of grade 3 (9.1%). No patient developed chronic radiation intestinal injury. Among the 34 patients in the 5-FU group, 21 had grade 2-3 radiation intestinal injury (21/34, 61.8%), which was significantly higher than that in the TP group (6/21, 28.6%) (χ(2)=5.723, P=0.017). Multivariate analysis showed that 5-FU chemotherapy regimen was an independent risk factor for radiation intestinal injury (HR=4.038, 95% CI: 1.250-13.045, P=0.020). With a median follow-up period of 26 (5-94) months, the 3-year DFS rate of patients in TP group and 5-FU group was 66.8% and 77.9%, respectively, whose difference was not significant (P=0.478). Univariate analysis showed that the DFS rate was associated with sex, age, tumor location, T stage, N stage, and induction chemotherapy (all P<0.05), while the DFS rate was not associated with chemotherapy regimen or radiation intestinal injury (both P>0.05). Multivariate analysis revealed that age ≥ 50 years old was an independent risk factor affecting the prognosis of patients (HR=8.301, 95% CI: 1.130-60.996, P=0.038). Conclusions: For patients with non-metastatic anal squamous cell carcinoma, radical radiotherapy combined with TP chemotherapy regimen can significantly reduce the incidence of radiation intestinal injury as compared to 5-FU regimen. However, due to the short follow-up time, the effect of different chemotherapy regimens on the prognosis is not yet clear.

The in-vivo assessment of Turkish propolis and its nano form on testicular damage induced by cisplatin / 中西医结合学报

OBJECTIVE@#Chemotherapeutic drugs, such as cisplatin (CP), which are associated with oxidative stress and apoptosis, may adversely affect the reproductive system. This study tests whether administration of propolis and nano-propolis (NP) can alleviate oxidative stress and apoptosis in rats with testicular damage induced by CP.@*METHODS@#In this study, polymeric nanoparticles including propolis were synthesized with a green sonication method and characterized using Fourier transform-infrared spectroscopy, Brunauer-Emmett-Teller, and wet scanning transmission electron microscopy techniques. In total, 56 rats were divided into the following seven groups: control, CP, propolis, NP-10, CP + propolis, CP + NP-10, and CP + NP-30. Propolis (100 mg/kg), NP-10 (10 mg/kg), and NP-30 (30 mg/kg) treatments were administered by gavage daily for 21 d, and CP (3 mg/kg) was administered intraperitoneally in a single dose. After the experiment, oxidative stress parameters, namely, malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT), and apoptotic pathways including B cell leukemia/lymphoma-2 protein (Bcl-2) and Bcl-2-associated X protein (Bax) were measured in testicular tissues. Furthermore, sperm quality and weights of the testis, epididymis, right cauda epididymis, seminal vesicles and prostate were evaluated.@*RESULTS@#Propolis and NP (especially NP-30) were able to preserve oxidative balance (decreased MDA levels and increased GSH, CAT, and GPx activities) and activate apoptotic pathways (decreased Bax and increased Bcl-2) in the testes of CP-treated rats. Sperm motility in the control, CP, and CP + NP-30 groups were 60%, 48.75%, and 78%, respectively (P < 0.001). Especially, NP-30 application completely corrected the deterioration in sperm features induced by CP.@*CONCLUSION@#The results show that propolis and NP treatments mitigated the side effects of CP on spermatogenic activity, antioxidant situation, and apoptosis in rats.

Human esophageal fibroblast-derived exosomal miR-21 reduced the cisplatin sensitivity to esophageal carcinoma EC9706 cells

The objective of this study was to investigate the effect of human esophageal fibroblast-derived exosomal miR-21 on cisplatin sensitivity against esophageal squamous EC9706 cells. EC9706 cells were co-cultured indirectly with human esophageal fibroblasts (HEF) or miR-21 mimics transfected-HEF in the transwell system. The exosomes in HEF-culture conditioned medium were extracted by differential ultracentrifugation. EC9706 cells were co-cultured with HEF-derived exosomes directly. The cisplatin sensitivity against EC9706 cells was revealed via half maximal inhibitory concentration (IC50) values using MTT assay. The expressions of miR-21, programmed cell death 4 (PDCD4) mRNA, and gene of phosphate and tension homology deleted on chromosome ten (PTEN) mRNA were determined by qRT-PCR. The changes of the protein level were detected using western blot assay. IC50 values of cisplatin against EC9706 cells were increased after EC9706 cells were co-cultured with either HEF or exosomes derived from miR-21 mimics-transfected HEF. Following the increased level of miR-21, the mRNA expression and protein levels of PTEN and PDCD4 were decreased in EC9706 cells. The cisplatin sensitivity to EC9706 cells was reduced by HEF-derived exosomal miR-21 through targeting PTEN and PDCD4. This study suggested that non-tumor cells in the tumor micro-environment increased the tumor anti-chemotherapy effects through their exosomes.

Radioterapia y 5-fluorouracilo-cisplatino en el tratamiento del cáncer de cuello uterino de alto riesgo / Radiotherapy and 5-fluorouracil-cisplatin treatment for high-risk uterine cervical cancer

Objetivo: evaluar la eficacia de la combinación de radioterapia y 5-fluorouracilo-cisplatino en el tratamiento del cáncer de cuello uterino de alto riesgo. Materiales y métodos: estudio retrospectivo en el que se revisaron los datos de pacientes tratadas en el periodo enero 2009 a diciembre 2019 en el Hospital Central "Dr. Urquinaona", Maracaibo, Venezuela. Se revisaron los registros clínicos de todas las pacientes sometidas a histerectomía radical y linfadenectomía pélvica bilateral que recibieron quimio-radioterapia concurrente adyuvante con 5-fluorouracilo-cisplatino (grupo de tratamiento) y se compararon con quienes no fueron manejadas con este régimen, las que no recibieron ningún tratamiento adyuvante o solo fueron tratadas con radioterapia (grupo control). Se evaluaron las características generales, efectos adversos del tratamiento, recurrencias de la enfermedad y supervivencia. Resultados: para el análisis final quedaron 164 pacientes, de las cuales 115 (70,1%) fueron del grupo de tratamiento y 49 (29,9%) del control. No se encontraron diferencias estadísticamente significativas en las características clínicas entre ambos grupos (p = ns); sí las hubo en la frecuencia de recurrencias a distancia (p = 0,0056). La supervivencia libre de progresión y la global de ambos grupos no mostraron diferencias significativas (p = 0,2678 y p = 0,3452). Conclusión: no existen beneficios evidentes del uso de 5-fluorouracilo-cisplatino desde el punto de vista de progresión o supervivencia general, en pacientes con carcinoma cuello uterino de alto riesgo.

Objective: to evaluate the efficacy of radiotherapy combined with 5-fluorouracil-cisplatin in the treatment of high-risk uterine cervical cancer. Materials and methods: Retrospective study, in which the data of patients treated between January 2009 and December 2019 at Hospital Central "Dr. Urquinaona", Maracaibo, Venezuela, was analyzed. The clinical records of all patients who underwent radical hysterectomy and bilateral pelvic lymphadenectomy and received adjuvant concurrent chemoradiotherapy with 5-fluorouracil-cisplatin (treatment group) compared with those patients not managed with this regimen, those who did not receive any adjuvant treatment or received only radiotherapy (control group), were reviewed. The general characteristics, treatment adverse effects, disease recurrences and survival rate were evaluated. Results: 164 patients remained for the final analysis, of which 115 (70.1%) were in the treatment group and 49 (29.9%) in the control group. No statistically significant differences were found in the clinical characteristics of patients between the two groups (p = ns); while differences in the distant recurrence rate (p = 0.0056) were found. Progression-free survival and overall survival in both groups did not show significant differences (p = 0.2678 and p = 0.3452). Conclusion: there is no evident benefit of the use of 5-fluorouracil-cisplatin in terms of progression or overall survival in patients with high-risk cervical carcinoma.

Which Tyrosine Kinase Inhibitor Must We Apply Before? A Case Report of Crizotinib-resistant Patient with Concomitant EGFR and EML4-ALK Gene Mutations

ABSTRACT The concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocations in lung adenocancers are very rare scenarios. Until now, 42 cases described in the literature have all been treated by different drugs. There is no overall consensus regarding the treatment for this adenocarcinoma subgroup. We report here a case of lung adenocarcinoma with concomitant EGFR mutation in exon 21 (L858R) and ALK rearrangement in primary tumour, EGFR mutation in exon 21 (L858R) and no ALK rearrangement in its synchronous metastasis. We treated this patient with crizotinib as the second-line therapy (after the first line docetaxel-cisplatin chemotherapy), but no response was obtained. The therapeutic choice for the lung adenocancer patients with concomitant EGFR mutation and ALK rearrangement is unclear. Examination of c-ros oncogene 1 mutation can be used as an indicator in the prediction of the crizotinib treatment success. The ALK mutation may not responsible for the resistance to EGFR-tyrosine kinase inhibitors (TKI), and EGFR-TKI can be initiated to EGFR and ALK dual mutant patients as the first treatment.