To study the mechanisms whereby cisplatin suppresses survival of human esophageal squamous cell carcinoma cells.The cytotoxicity of cisplatin in cisplatin-resistant cell line EC109 /CDDP and its parental cell line EC109 was measured by cell viability assay.Western blotting was used to investigate the protein expression of to-tal p53 and phosphorylated p53 at Ser15.Colony formation assay was employed to evaluate the ability of cells to recover from treatments and form colonies.The results indicated that EC109 /CDDP cells were more resistant to cisplatin-induced cytotoxicity than EC109 cells,with the IC50 values of (20.4 ±4.4)μmol /L and (5.7 ±0.1 )μmol /L,respectively.Although cisplatin did not alter the total protein level of p53,it obviously increased the phosphorylation of p53 at Ser15.Cisplatin inhibited survival of both EC109 /CDDP and EC109.Notably,inhibition of p53 by Pifithrin-αsignificantly promoted recovery of cisplatin-treated EC109 and EC109 /CDDP cells to differ-ent degrees.In this respect,p53 protein was found to be activated in response to cisplatin treatment in both EC109 /CDDP and EC109,which may contribute to the cytotoxic effect of cisplatin.

OBJECTIVE To provide reference for improving rational use of antibiotics in medical institutions. METHODS With the help of information construction， strengthening personnel training and assessment， carrying out science popularization and education， optimizing drug catalogs， equipping full-time clinical pharmacists， optimizing assessment indicators and releasing pharmaceutical information in time， new fine management mode of antibiotics was constructed in our hospital. Through the hospital information system， the relevant data of our hospital in Jan.-Dec. 2020 （before the implementation） and Jan.-Dec. 2021 （after the implementation） were collected and compared， such as utilization rate of antibiotics， intensity of antimicrobial use， the incidence of hospital infection in the inpatients， the incidence of surgical site infection， the qualified rate of antibiotic medical order， and the proportion of antibiotics in the total outbound amount of Western medicine. RESULTS Compared with 2020， the utilization rate of antibiotics in hospitalized patients in 2021 decreased from 34.94% to 32.44%， intensity of antimicrobial use decreased from 39.07 DDDs （defined daily doses） to 30.77 DDDs， and the incidence of nosocomial infections among inpatients decreased from 2.64% to 1.91%； the incidence of surgical site infections decreased from 0.26% to 0.03%； the qualified rate of antibiotic medical orders increased from 93.82% to 97.75%； the proportion of antibiotics in the total outbound amount of Western medicine decreased from 14.86% to 12.51%.CONCLUSIONS Through a series of fine management measures， our hospital has built a new fine management mode of antibiotics， which has improved the rationality of antibiotics use while ensuring the treatment effect.

OBJECTIVE: To explore whether bortezomib and a Bcl-2 inhibitor exhibit synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells. METHODS: MTT assay was used to determine the cytotoxicity of bortezomib in the absence or presence of Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) in Jurkat cells. The effects of drug treatment on the expression of Bcl-2 family proteins, LC3B, p62, ubiquitin, BiP/Grp78, p-JNK, p-p38 and CHOP proteins were examined by Western blotting. Flow cytometry was used to determine the effects of bortezomib and Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) on cell apoptosis. Quantitative real-time PCR was used to measure the mRNA expression levels of the key regulatory factors of unfolded protein reaction (UPR). A zebrafish xenograft model was used to study the anti-tumor effect of bortezomib, obatoclax and their combination in vivo. RESULTS: Bortezomib or Bcl-2 inhibitors alone inhibited the cell viability of Jurkat cells, but only obatoclax and bortezomib showed synergistic cytotoxicity and pro-apoptotic effect. Obatoclax, rather than AT-101 and ABT- 199, blocked autophagic flux in the cells evidenced by concomitant accumulation of LC3B-Ⅱ and p62. Both bortezomib and obatoclax alone caused accumulation of polyubiquinated proteins, and their combination showed a synergistic effect, which was consistent with their synergistic cytotoxicity. The dual blockade of proteasome and autophagy by the combination of bortezomib and obatoclax triggered unfolded protein response followed by cell apoptosis. Preventing UPS dysfunction by tauroursodeoxycholic acid (TUDCA) significantly attenuated the cytotoxicity and pro-apoptotic effect of bortezomib in combination with obatoclax. In zebrafish xenograft models, bortezomib combined with obatoclax significantly decreased tumor foci formation. CONCLUSIONS Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.
Antineoplastic Agents ; Apoptosis ; Bortezomib ; Cell Line, Tumor ; Drug Synergism ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Proteolysis ; Proto-Oncogene Proteins c-bcl-2 ; Pyrroles