Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation in vitro and in vivo. Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.

Objective:To investigate the correlation between the expressions of miR-524-5p and sex determining region Y box protein 9 (SOX9) in advanced gastric cancer and their influences on the efficacy and prognosis of chemotherapy.Methods:A total of 82 patients diagnosed as advanced gastric cancer who received DCF (docetaxel + cisplatin + fluorouracil) chemotherapy in 910th Hospital of Joint Logistics Support Force of Chinese People′s Liberation Army from January 2015 to December 2017 were selected as the research objects. The expression levels of miR-524-5p and SOX9 in gastric cancer tissues were detected by fluorescence quantitative PCR. The correlation between the expressions of miR-524-5p and SOX9 was analyzed, the total effective rates of chemotherapy in patients with different miR-524-5p and SOX9 expression levels were compared, and the predictive value of miR-524-5p combined with SOX9 on the efficacy of chemotherapy was analyzed. Overall survival (OS) and progression-free survival (PFS) were analyzed.Results:The expressions of miR-524-5p and SOX9 were not related to gender or age of patients with advanced gastric cancer (all P>0.05), but were related to the degree of differentiation ( χ2=3.577, P=0.001; χ2=5.654, P<0.001) and distant metastasis ( χ2=2.466, P=0.016; χ2=5.218, P<0.001) of patients with advanced gastric cancer. There was a negative correlation between the expressions of miR-524-5p and SOX9 in advanced gastric cancer ( r=-0.348, P=0.001). According to the median expressions of miR-524-5p and SOX9 in gastric cancer tissues, patients were divided into high expression and low expression groups, miR-524-5p≥0.64 was high expression ( n=41), <0.64 was low expression ( n=41), SOX9≥1.84 was high expression ( n=41), and <1.84 was low expression ( n=41). The total effective rate of advanced gastric cancer patients with high expression of miR-524-5p was 58.54% (24/41), which was higher than that of patients with low expression of miR-524-5p (24.39%, 10/41), and there was a statistically significant difference ( χ2=9.484, P=0.002). The total effective rate of advanced gastric cancer patients with high expression of SOX9 was 21.95% (9/41), which was lower than 60.97% (25/41) of patients with low expression of SOX9, and there was a statistically significant difference ( χ2=12.863, P<0.001). Receiver operating characteristic curve analysis showed that the expressions of miR-524-5p and SOX9 had predictive value for the efficacy of chemotherapy, and the area under the curve was 0.753 (95% CI: 0.644-0.861, P<0.001) and 0.660 (95% CI: 0.540-0.780, P=0.014) respectively. The combination of miR-524-5p and SOX9 had predictive value for the efficacy of chemotherapy, and the area under the curve was 0.768 (95% CI: 0.667-0.868, P<0.001). The median PFS and OS of patients with high expression of miR-524-5p were 8 months and 14 months, which were longer than those of patients with low expression of miR-524-5p (6 months, 9 months), and there were statistically significant differences ( χ2=21.160, P<0.001; χ2=29.730, P<0.001). The median PFS and OS of patients with high expression of SOX9 were 7 months and 10 months, which were shorter than those of patients with low expression of SOX9 (8 months, 12 months), and there were statistically significant differences ( χ2=6.345, P=0.012; χ2=4.107, P=0.043). Conclusion:There is a negative correlation between the expressions of miR-524-5p and SOX9 in advanced gastric cancer tissues. The chemotherapy efficacy and prognosis of patients with high expression of miR-524-5p and low expression of SOX9 are better than those of patients with low expression of miR-524-5p and high expression of SOX9.

Shengmai Yin (SMY) is a Chinese herbal decoction that effectively alleviates the side effects of radio-therapy in various cancers and helps achieve radiotherapy's clinical efficacy.In this study,we explored the interaction mechanism among SMY,DNA methylation,and nasopharyngeal carcinoma (NPC).We identified differences in DNA methylation levels in NPC CNE-2 cells and its radioresistant cells (CNE-2R)using the methylated DNA immunoprecipitation array and found that CNE-2R cells showed genome-wide changes in methylation status towards a state of hypomethylation.SMY may restore its original DNA methylation status,and thus,enhance radiosensitivity.Furthermore,we confirmed that the dif-ferential gene Tenascin-C (TNC) was overexpressed in CNE-2R cells and that SMY downregulated TNC expression.This downregulation of TNC inhibited NPC cell radiation resistance,migration,and invasion.Furthermore,we found that TNC was hypomethylated in CNE-2R cells and partially restored to a hypermethylated state after SMY intervention.DNA methyltransferases 3a may be the key protein in DNA methylation of TNC.

Objective To investigate the effects of Dingkoulizhong decoction on cellular immune factors and adverse reactions in patients with advanced gastric cancer treated with chemotherapy.Methods One hundred and thirty-eight patients with advanced gastric cancer were enrolled in our hospital from October 2014to December 2016,and were randomly divided into control group (n =69) and observation group (n =69) by using the random number table.The patients of the control group were treated with FOLFOX4 chemotherapy (oxaliplatin + calcium folinate + fluorouracil),while the patients of the observation group were given by the treatment of Dingkoulizhong decoction on the basis of the control group.The peripheral blood samples of the patients were collected before and after the treatment.The levels of cellular immune factors CD3 +,CD4 +,CD8 + and CD4 +/CD8 + were detected,and the clinical efficacy and adverse reactions of the patients of the two groups were observed.Results After the treatment,the number of complete remission (CR),partial remission (PR),stable disease (SD) and progressive disease (PD) in the observation group were 16,25,16 and 12 cases respectively,while the control group were 9,20,19 and 21 cases respectively,and there was a statistically significant difference in the distribution of clinical efficacy between the two groups (Z =4.381,P =0.036).Compared with the control group,the clinical benefit rate (CBR) of the observation group was significantly improved (59.42％ vs.42.03％),with a statistically significant difference (x2 =4.175,P =0.041).The cellular immune factors CD3 + [(52.67 ±6.21)％ vs.(53.45 ±6.54)％],CD4 + [(23.56 ±3.85)％ vs.(24.09±2.91)％],CD8 +[(28.16±3.49)％ vs.(27.87±3.26)％] and CD4 +/CD8+(1.13 ± 0.27 vs.1.19 ±± 0.31) of the patients of the observation group showed no statistically significant difference (t=0.718,P=0.474;t=0.912,P=0.363;t=0.504,P=0.615;t=1.212,P=0.227) beforeand after the treatment,but the cellular immune factor CD3 + [(50.36 ± 3.74)％ vs.(53.13 ± 6.12)％],CD4 +[(21.26±2.37)％ vs.(23.44 ±3.96)％] andCD4+/CD8*(0.96±0.26vs.1.15±0.25) of the patients of the control group after the treatment were significantly lower than those before the treatment,and CD8 +[(31.64 ± 4.05) ％ vs.(27.98 ± 3.52) ％] after the treatment was significantly higher than that before the treatment,all with statistically significant differences (t =3.208,P ＜ 0.001;t =3.924,P ＜ 0.001;t =4.289P ＜ 0.001,t =5.666,P ＜ 0.001).Compared with the control group,the level of CD3 + [(53.45 ± 6.54) ％ vs.(50.36±±3.74)％],CD4+[(24.09±±2.91)％ vs.(21.26±2.37)％] andCD4+/CD8+(1.19±0.31vs.0.96 ± 0.26) of the patients of the observation group after the treatment were significantly improved,and CD8 +[(27.87 ± 3.26) ％ vs.(31.64 ± 4.05) ％] was significantly decreased,all with statistically significant differences (t=3.407,P=0.001;t =6.264,P＜0.001;t =4.722,P＜0.001;t =6.023,P＜0.001).Compared with the control group,the total adverse reaction rate of the observation group was significantly decreased (36.23％ vs.55.07％),with a statistically significant difference (x2 =4.936,P =0.026).Conclusion Dingkoulizhong decoction can significantly improve the clinical efficacy in patients with advanced gastric cancer treated with chemotherapy,alleviate the immune function damage caused by chemotherapy,and it can reduce the occurrence of adverse reactions.

Objective:To explore the expression and clinical significance of ubiquitin-like with PHID and ring finger domains 2 (UHRF2) in intrahepatic cholangiocarcinoma (ICC).Methods:The expression of UHRF2 in 138 ICC was determined by immunohistochemistry,and the relationships between UHRF2 expression with prognosis and clinicopathological features of ICC were analyzed:Results:UHRF2 was highly expressed in ICC compared with paratumorous tissues.Level of UHRF2 was associated with high AFP level (P=0.010),poor tunor differentiation (P=0.026),lymph node metastasis (P=0.001),and advanced TNM stage (P=0.019).Hevated UHRF2 expression was suggested to be associated with poor prognosis and high recurrence rate in ICC patients (P＜ 0.001),and multivariable analysis indicated that UHRF2 was of theprognostic indicators of ICC (P＜0.05).Conclusions:High level of UHRF2 is related to the malignant phenotype of ICC,and can be a prognostic and recurrent indicator of postoperative patients.

Objective To study the effects of ginkgo biloba extract(GBE)on c-reactive protein(CRP) and tumor necrosis factor-α(TNF-α)in serum and alveolar lavage fluid(BALF)from rats with chronic obstructive pulmonary disease(COPD). Methods 90 rats were randomly divided into groups A,B,C,D,E and F. There were 15 rats in each group. The rat model of COPD were established in groups B,C,D,E and F. Groups C and D were given intraperitoneal injections with GBE from day l to day l4 and day 29 to day 42. Groups E and F weregiven intraperitoneal injections with erythromycin from day l to day l4 and day 29 to day 42. After the end of experi-ment ,the contents of CRP and TNF-α in serum and BALF were detected in all groups. Results The contents of CRP and TNF-α in the serum and the BALF were markedly lower in groups C,D,E and F than in group B (P<0.05);and the contents of CRP in the serum and the BALF and TNF-αin the BALF were lower in groups C, E and F than in group D(P<0.05). Conclusions GBE can inhibit the airway and systemic inflammatory response in COPD rats. Early intervention is more effective.

Objective To observe the effect of Fufei Gushen Decoction on the BODE index, an index for body mass index(BMI), airflow obstruction, dyspnea, and exercise capacity, in severe and extremely severe chronic obstructive pulmonary disease (COPD) patients with lung-kidney deficiency interweaved with phlegm and blood stasis at stable stage. Methods Eighty qualified COPD patients were randomly divided into treatment group and control group, 40 cases in each group. Both groups were given inhalation of Seretide (Salmeterol Xinafoate and Fluticasone Propionate Powder for inhalation) , and the treatment group was given oral use of Fufei Gushen Decoction additionally. The treatment for the two groups lasted for 3 months. Before and after treatment, BMI, the percentage of forced expiratory volume in one second of the predicted value (FEV1%) , dyspnea index of modified British Medical Research Council (MMRC), and exercise performance index of 6-min walking test (6MWT) in the two groups were observed. Results (1) After treatment, FEV1%, MMRC dyspnea index, 6MWT scores and BODE index overall scores of severe and extremely severe patients in the treatment group were much improved(P < 0.05 compared with those before treatment ), but BMI was not much improved(P > 0.05). MMRC dyspnea index, 6MWT scores and BODE index overall scores of severe and extremely severe patients inthe control group were much improved (P<0.05 compared with those before treatment) , b ut the improvement of FEV1% and BMI was not obvious(P > 0.05).(2) Except for BMI, the parameters of FEV1%, MMRC dyspnea index, 6MWT scores and BODE index overall scores of the treatment group were much improved as compared with those of the control group after treatment(P < 0.05). Conclusion Fufei Gushen Decoction combined with inhalation of Seretide exerts certain effects on decreasing the BODE index scores, relieving symptoms, and improving pulmonary function, exercise performance and the quality of life of COPD patients with lung-kidney deficiency interweaved with phlegm and blood stasis at stable stage.

Aim To investigate the effect of curcumin on radiosensitivity of radioresistant nasopharyngeal carcinoma cell line CNE-2R and its mechanism.Methods The concentration of curcumin was screened by MTT assay.Dose-survival curves were obtained according to the colony forming test for L-Q matching and multitarget-single hitting matching,while SF2 and the correlation parameters of radiation biology were calculated.The changes of cell cycle in CNE-2R cells caused by curcumin were also tested by flow cytometry(FCM).The differential expression of genes related to cell cycle and DNA damage repair were detected by RT-qPCR.Results CNE-2R cells could not be inhibited by 10 μmol·L-1 curcumin.Dealt with 10 μmol·L-1 curcumin for 24 h,the value of α/β increased to 1 596 from 6.56;the value of SF2 decreased to 0.361 Gy from 1.93 Gy;the value of N decreased to 1.06 from 1.60;the value of D0 decreased to 2.12 from 3.27;the value of Dq decreased to 0.12 from 1.53.FCM showed that the cells in G2 phase had a significant increase and the cells in S phase had a significant decrease after dealt with 10 μmol·L-1 curcumin for 24 h.The expression of CDK4 was significantly up-regulated and GADD45g,BRCA1 were significantly down-regulated.Conclusion Curcumin radiosensitizes nasopharyngeal carcinoma cell line CNE-2R by changing cell cycle and affecting DNA damage repair through regulating the expression of CDK4,GADD45 g and BRCA1.

Objective To optimize the matrix formula of propranolol hydrochloride gels. Methods On the basis of single factor experiment, central composite design-response surface method was used to optimize the formula. Addition levels of glycerol (A), PEG-400 (B) and HPMC (C) were evaluated as the independent variables.Eight-hour accumulative penetration amount per unit area measured by HPLC was used as the index. Quadratic polynomial was used to estimate the relationship between the index and the independent variables, and to delineate response surface and overlay contour plots in order to select the optimal formulations.Finally, predicted responses were verified. Results The optimized formula consisted of 18.53% glycerol, 8.54% PEG-400 and 2.35% HPMC.The quadratic polynomial regression model of 8-h accumulative penetration amount per unit area:R1=-7 415. 69+306. 10A+167. 47B+4 820. 59C-8. 26A2-9. 81B2-1 025. 75C2 , and the cumulative transmittance was 49.6%. Conclusion A credible model is established by using central composite design-response surface method and the formula of propranolol hydrochloride gels is optimized and the gel is stable and controllable.

Objective To observe the long dwell ultrafiltration volume after using 7.5% icodextrin in different peritoneal transport characteristics of peritoneal dialysis patients. Methods Subgroup analysis of a perspective multicenter randomized double blind and parallel control study was performed. Continuous ambulatory peritoneal dialysis (CAPD) patients were divided into high transport (H) group, high-average transport (HA) group, low-average transport (LA) group and low transport (L) group according to D/Pcr and Twardoski standard. Ultrafiltration volume of night long dwell dialysate was calculated before and after clinic trial for 2 weeks and 4 weeks to evaluate the different effect of transporters on ultrafiltration volume. Results A total of 201 CAPD patients were enrolled in the study, including 98 patients in icodextrin group (ICO group) and 103 patients in glucose group (GLU group). Male and female cases were 96 and 105 respectively. Age was (56.1±13.7) years old (range from 18 to 81). One hundred and ninety-eight patients finished peritoneal equilibrium test (PET), including 24 (12.1%) of H, 72(36.2%)of HA, 81(40.7%)of LA,and 21 (11.0%)of L. After follow-up for four weeks, the ultrafiltration volume was much higher than baseline in H, HA and LA groups. Also ultrafiltration volume in icodextrin group was much higher than that in glucose-based dialysate. Howerve, the increased volume was not significantly difference in L group. Ultrafiltration volume of icodextrin was positively correlated to D/Pcr (R2=0.1681,P＜0.01), while ultratration volume of dextrose was negatively correlated to D/Pcr (R2=0.0949,P＜0.01). Conclusion Compare to glucose-based dialysate (Dineal), 7.5% icodextrin dialysate (Extraneal) improves the ultrafiltration and peritoneal creatinine clearance of long dwell notabily in H, HA and LA group.