As a hot spot in clinical research today, immune checkpoint inhibitor has been recommended by guidelines in the first- and second-line treatments of advanced cervical cancer as immune monotherapy or combination therapy. It has also achieved good efficacy in clinical practice. In locally advanced cervical cancer, immune checkpoint inhibitors have been included in the guidelines for adjuvant therapy, and good tumor regression effects have been achieved in clinical practice. Based on the results of existing trials, immune checkpoint inhibitors have also shown good clinical potential as neoadjuvant therapy. Furthermore, the issue of immunotherapy rechallenge has increasingly captured clinicians’ attention, offering a potential new therapeutic strategy for cervical cancer patients with prior immunotherapy exposure. In this article, the clinical application and research progress of immune checkpoint inhibitors in the treatment of cervical cancer in recent years are summarized to provide valuable ideas and directions for clinical treatment.

Objective To explore the mechanism of Gualou Xiebai Baijiu Decoction(GXB)in improving atherosclerosis(AS)in mice by regulating the gut microbiota(GM)and its metabolites.Methods Thirty-two male ApoE-/-mice were divided randomly into a Blank group,Model group,atorvastatin(Ato)group,and GXB group(n=8 mice per group).AS was established in all mice,except the Blank group,and the respective treatments were administered by gavage.Aortic plaques were detected by Oil red O staining and pathological changes in aortic tissue were detected by hematoxylin and eosin staining.The GM was analyzed using 16S rRNA gene sequencing technology,and mouse GM metabolites,including trimethylamine oxide(TMAO),short-chain fatty acids(SCFA),and serum levels of triglycerides(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),and nitric oxide(NO)were determined.Results Compared with the Blank group,mice in the Model and Ato groups showed an increase in AS plaque area(P＜0.05).Serum levels of TG,TC,and LDL-C were increased(P＜0.001)while levels of HDL-C and NO were decreased(P＜0.01,P＜0.001)in the Model group compared with the Blank group.The plaque area was decreased(P＜0.05),serum levels of TG,TC,and LDL-C were decreased(P＜0.001),and NO levels were increased(P＜0.01)in the Ato and GXB groups,while HDL-C levels were increased in the GXB group(P＜0.05)compared with the Model group.Plaque area was decreased(P＜0.05)and the NO level was increased(P＜0.01)in the GXB group compared with the Ato group.A total of 6345 characteristic sequences were obtained from 16S rRNA analysis.α-Diversity analysis indicated that GXB reduced the richness of the GM in AS mice(P＜0.001)and improved its uniformity(P＜0.05).β-Diversity analysis suggested that the microbial community structure in the GXB group was similar to that in the Blank group.The abundance of microbial communities differed among the groups at the phylum and genus levels.At the phylum level,the abundance of Proteobacteria was increased(P＜0.01)in AS mice,while GXB intervention reduced the abundance of Proteobacteria(P＜0.01)and increased the abundance of Verrucomimicrobiota(P＜0.05).At the genus level,GXB effectively increased the abundance of Akkermansia(P＜0.05).SCFAs were significantly increased(P＜0.01)and TMAO levels were significantly decreased(P＜0.01)in the GXB group compared with the Model group.Conclusions GXB can regulate the intestinal flora and intestinal flora metabolites SCFA and TMAO to improve AS.Akkermansia may be a key bacterial genus of the gut microbiota through which GXB may improve AS.

Objective This study aims to explore the formation of the dilemma of"giving care"for disabled elderly people in nursing homes from the perspective of active health.Methods Purposive sampling was used to select caregivers and disabled elderly people from a nursing home in Chongqing as research subjects from July 2022 to December 2022.One-on-one in-depth interviews were conducted and Colaizzi's 7-step thematic analysis method was employed to collect and analyze the interview data.Results 4 themes were identified:①the dominance of the"giving"care concept,including the cultural thoughts of filial piety,passive acceptance of care characteristics and consumer psychology regarding paid services;②insufficient"participation"care ability,including lack of knowledge regarding active health and a weakening of skills to promote participation;③the hindrance to"transformation"of care models,including objective limitations in terms of human resources and delays in adapting aging environments;and ④the decline in"utilization"of internal abilities,including excessive avoidance of potential risks,a heavy workload of care and poor quality of individual care.Conclusion The formation of the dilemma of"giving care"for disabled elderly people in nursing homes is affected by multiple factors such as social background,service system,supply resources,and management mode.Transforming disabled elderly individuals from a state of"passive giving care"to"active participation in their health"is an important measure to realize the concept of positive aging and healthy aging.

Objective:To explore the repeatability of ultrasound shear wave elastography (SWE) in evaluating the Young′s modulus (E) of the lumbar multifidus (LM) and the difference in E of the bilateral LM, and to analyze the E′s change ratio of LM and its impact factors at upright and 90° forward bend positions.Methods:A total of 60 healthy volunteers, selected from interns, standardized training residents and refresher doctors in department of diagnostic ultrasound of Sir Run Run Shaw Hospital of Zhejiang University School of Medicine from July to December in 2020, were examined twice by SWE to estimate the E value of LM at prone, upright and 90° flexion positions, respectively. Firstly, the intraclass correlation coefficient (ICC) was applied to test the reliability between the two repeated measurements.Secondly, the differences in E of the bilateral LM were discussed. The discrepancies in the E value of male and female volunteers at prone, upright and 90° flexion positions and the change ratio of the E value at upright and 90° forward bend positions were also discussed, respectively. Finally, Spearman correlation coefficient was utilized to evaluate the correlations of E and its change ratio with gender, age, BMI and activity level at upright and 90° forward bend positions, respectively.Results:The ICC value in LM measured by SWE was in the range of 0.691 to 0.951. No obvious change in bilateral E values of the same posture was observed for an individual(all P>0.05). The change ratios of E at upright and 90° flexion positions were approximate to 2 and 7, respectively. Moreover, at prone position, the E value exhibited negative correlation with age and activity level of self-assessment ( rs=-0.300, P=0.020; rs=-0.383, P=0.002). The E in female was higher compared with that in male. At active states the change ratio in E was positively correlated with age and activity level ( rs=0.278, P=0.031; rs=0.495, P<0.001), and the E′s change ratio in male was higher than that in female. Conclusions:SWE possesses excellent repeatability in evaluating the E value of LM with no significant difference in E of bilateral LM. The E′s change ratio in LM varies with different contraction strategies and changes with age, sex and self-reported activity level.

Bacitracin is a broad-spectrum cyclic peptide antibiotic, and mainly produced by Bacillus. Energy metabolism plays as a critical role in high-level production of target metabolites. In this study, Bacillus licheniformis DW2, an industrial strain for bacitracin production, was served as the original strain. First, our results confirmed that elimination of cytochrome bd oxidase branch via deleting gene cydB benefited bacitracin synthesis. Bacitracin titer and ATP content were increased by 10.97% and 22.96%, compared with those of original strain, respectively. Then, strengthening cytochrome aa3 oxidase branch via overexpressing gene qoxA was conducive to bacitracin production. Bacitracin titer and ATP content were increased by 18.97% and 34.00%, respectively. In addition, strengthening ADP synthesis supply is also proven as an effective strategy to promote intracellular ATP accumulation, overexpression of adenosine kinase DcK and adenylate kinase AdK could all improve bacitracin titers, among which, dck overexpression strain showed the better performance, and bacitracin titer was increased by 16.78%. Based on the above individual methods, a method of combining the deletion of gene cydB and overexpression of genes qoxA, dck were used to enhance ATP content of cells to 39.54 nmol/L, increased by 49.32% compared to original strain, and bacitracin titer produced by the final strain DW2-CQD (DW2ΔcydB::qoxA::dck) was 954.25 U/mL, increased by 21.66%. The bacitracin titer produced per cell was 2.11 U/CFU, increased by 11.05%. Collectively, this study demonstrates that improving ATP content was an efficient strategy to improve bacitracin production, and a promising strain B. licheniformis DW2-CQD was attained for industrial production of bacitracin.
Bacillus licheniformis ; metabolism ; Bacitracin ; biosynthesis ; Energy Metabolism ; genetics ; Industrial Microbiology ; methods

Objective:To compare long-term efficacy between watch and wait (W&W) strategy and total mesorectal excision (TME) in patients who were diagnosed with locally advanced rectal cancer (LARC) and attained clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT).Methods:A retrospective cohort study was carried out. A total of 238 patients with stage II-III LARC exhibiting cCR after nCRT in Sun Yat-sen University Cancer Center from September 16, 2010 to January 9, 2018 were enrolled. Patients who were diagnosed with other malignant tumor within 5 years, did not receive regular follow-up in our center for more than 1 year and had no complete examination items after nCRT were excluded. Of 238 patients, 151 were male and 87 were female with a median age of 57 (27-83) years old. According to TNM stage, 61 cases were cII, 177 cases were cIII. Concurrent chemoradiotherapy (CCRT) was performed in 20 patients. CCRT plus induction/consolidated chemotherapy was performed in 218 patients. Intensity-modulated radiotherapy (IMRT) was applied to radiotherapy. The median radiation dose was 50 Gy/25 Fr for both the primary tumor and clinical target volumes, and the total dose was 45.0 to 50.6 Gy for 227 patients. In 27 patients, single-agent fluorouracil or capecitabine was used as concurrent chemotherapy. But in the other 211 patients, a combined regimen of oxaliplatin and fluorouracil or capecitabine was used. After nCRT, 59 and 179 patients received W&W (W&W group) and TME 6-12 weeks later (TME group), respectively. After the ending of treatment, patient was interviewed one time every 3 months and after 3 years, one time every six months. Overall survival (OS) rate, distant-metastasis-free survival (DMFS) rate, and local-recurrence-free survival (LRFS) rate were compared between two groups. The salvage treatment and sphincter preservation rate were analyzed. The survival curve was drawn with Kaplan-Meier method and evaluated by log-rank method.Results:In the cases treated with TME, the median interval from nCRT to surgery was 59 days. The postoperative pCR rate was 63.1%(113/179). The median follow-up time of the whole cohort was 41.8 (12.0-99.0) months. The 3-year and 5-year OS rates were 98.4% and 96.5%; the 3-year and 5-year LRFS rates were 96.5% and 96.5%; the 3- and 5-year DMFS rates were 91.0% and 87.9%, respectively. The 3-year OS rates in the W&W group and the TME group were 100% and 97.9%; the 5-year OS rates in W&W group and the TME group were 90.6% and 97.9% ( P=0.339); The 3-year local recurrence rate (LRR) in the W&W group was 12.9% (7 cases recurred within 2 years), which was significanthy higher then that in the TME group (0.6%, P=0.003). Salvage surgery was successful in 5/6 cases. After salvage surgery, LRFS rate was not significantly different between the two groups ( P=0.137). The 3-year DMFS rate in the W&W group and the TME group were 88.4% and 81.1%, whose difference was not significant ( P=0.593). Recurrence with simultaneous metastasis was seen in 3/7 cases of the W&W group. The sphincter was preserved in 89.8% (53/59) of patients in the W&W group, which was significantly higher than 73.7% (132/179) in the TME group ( P<0.001). When distance of tumor from the anal verge was ≤ 5 cm, the sphincter preservation rate (SPR) in the W&W group was 88.0% (44/50), which was significantly higher than the 54.4% (56/103) in the TME group ( P<0.001). Conclusions:W&W is safe and feasible for patients with LARC and cCR after nCRT. The results should be verified by further clinical trials.

Objective:To compare long-term efficacy between watch and wait (W&W) strategy and total mesorectal excision (TME) in patients who were diagnosed with locally advanced rectal cancer (LARC) and attained clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT).Methods:A retrospective cohort study was carried out. A total of 238 patients with stage II-III LARC exhibiting cCR after nCRT in Sun Yat-sen University Cancer Center from September 16, 2010 to January 9, 2018 were enrolled. Patients who were diagnosed with other malignant tumor within 5 years, did not receive regular follow-up in our center for more than 1 year and had no complete examination items after nCRT were excluded. Of 238 patients, 151 were male and 87 were female with a median age of 57 (27-83) years old. According to TNM stage, 61 cases were cII, 177 cases were cIII. Concurrent chemoradiotherapy (CCRT) was performed in 20 patients. CCRT plus induction/consolidated chemotherapy was performed in 218 patients. Intensity-modulated radiotherapy (IMRT) was applied to radiotherapy. The median radiation dose was 50 Gy/25 Fr for both the primary tumor and clinical target volumes, and the total dose was 45.0 to 50.6 Gy for 227 patients. In 27 patients, single-agent fluorouracil or capecitabine was used as concurrent chemotherapy. But in the other 211 patients, a combined regimen of oxaliplatin and fluorouracil or capecitabine was used. After nCRT, 59 and 179 patients received W&W (W&W group) and TME 6-12 weeks later (TME group), respectively. After the ending of treatment, patient was interviewed one time every 3 months and after 3 years, one time every six months. Overall survival (OS) rate, distant-metastasis-free survival (DMFS) rate, and local-recurrence-free survival (LRFS) rate were compared between two groups. The salvage treatment and sphincter preservation rate were analyzed. The survival curve was drawn with Kaplan-Meier method and evaluated by log-rank method.Results:In the cases treated with TME, the median interval from nCRT to surgery was 59 days. The postoperative pCR rate was 63.1%(113/179). The median follow-up time of the whole cohort was 41.8 (12.0-99.0) months. The 3-year and 5-year OS rates were 98.4% and 96.5%; the 3-year and 5-year LRFS rates were 96.5% and 96.5%; the 3- and 5-year DMFS rates were 91.0% and 87.9%, respectively. The 3-year OS rates in the W&W group and the TME group were 100% and 97.9%; the 5-year OS rates in W&W group and the TME group were 90.6% and 97.9% ( P=0.339); The 3-year local recurrence rate (LRR) in the W&W group was 12.9% (7 cases recurred within 2 years), which was significanthy higher then that in the TME group (0.6%, P=0.003). Salvage surgery was successful in 5/6 cases. After salvage surgery, LRFS rate was not significantly different between the two groups ( P=0.137). The 3-year DMFS rate in the W&W group and the TME group were 88.4% and 81.1%, whose difference was not significant ( P=0.593). Recurrence with simultaneous metastasis was seen in 3/7 cases of the W&W group. The sphincter was preserved in 89.8% (53/59) of patients in the W&W group, which was significantly higher than 73.7% (132/179) in the TME group ( P<0.001). When distance of tumor from the anal verge was ≤ 5 cm, the sphincter preservation rate (SPR) in the W&W group was 88.0% (44/50), which was significantly higher than the 54.4% (56/103) in the TME group ( P<0.001). Conclusions:W&W is safe and feasible for patients with LARC and cCR after nCRT. The results should be verified by further clinical trials.

Objective To investigate the feasibility of non-operative management (NOM) by comparing the therapeutic effects between NOM and total mesorectal excision (TME) for rectal cancer patients with clinical complete response (cCR) after neo-adjuvant chemoradiotherapy.Methods A total of 135 patients with stage Ⅱ/Ⅲ rectal cancer who obtained cCR after neo-adjuvant chemoradiotherapy in Sun Yat-sen University Cancer Center from 2006 to 2016 were recruited and assigned into the NOM (n =43) and standard operative management (SOM) groups (n=92).The local recurrence rate,accumulative local control (LC) rate after salvage therapy,disease-free survival (DFS),overall survival (OS) and sphincter preservation rate were statistically compared between two groups.Kaplan-Meier analysis and log-rank test were utilized to calculate the LC,OS and DFS.Chi-square test was performed to calculate the sphincter preservation rate.Results The mean follow-up duration was 39 months (range:10-127 months).Of 135 patients,the local recurrence rate and distant metastasis rate were 3.7％ and 11.1％,and the 3-year DFS and OS were 90.5％ and 97.0％.In the NOM and SOM groups,the 3-year DFS were 87％ and 93％,and the 5-year DFS were 73％ and 87％(P=0.089).The 3-year OS were 98％ and 99％,and the 5-year OS were 98％ and 97％ (P=0.578).In the NOM group,the local recurrence rate was 12％ (n =5),80％ of patients received salvage treatment and the accumulative LC rate was calculated as 98％.In the SOM group,the local recurrence rate was 0,which was significantly lower than that in the NOM group (P=0.O10).In the NOM group,the sphincter preservation rate was 93％,significantly higher compared with 70％ in the SOM group (P=0.030).Conclusions It is feasible for rectal cancer patients with cCR to receive NOM following neo-adjuvant chemoradiotherapy.Partial locally recurrent patients can be healed by timely salvage therapy,thereby averting TME and relevant complications and enhancing the quality of life of rectal cancer patients.

Objective To investigate the function of sorafenib on the growth of hepatocellular carcinoma by establishing subcutaneous transplantation tumor model with nude mice.To explore the effect of sorafenib on circadian clock gene expression in hepatoma cells.Methods Mouse tumor model was established by implanting hepatocarcinoma cell (HepG2) subcutaneously in Balb/C nude mice.Sixteen experimental mice were randomly divided into two groups:sorafenib treatment group (n =8) and solvent control group (n =8).The nude mice were treated with sorafenib (100 mg/kg) and DMSO daily by intragastric administration,respectively.The volume of tumors was recorded every 3 days.The expressions level of circadian clock genes (Per1,Per2,Per3,CLOCK,Cry1,Cry2,BMAL1 and CKIε) were detected by real-time polymerase chain reaction (Real-time PCR).The correlations between the size of the xenografts and the expressions of the circadian clock genes were further analyzed.Results Compared with the control group,the tumor size in the sorafenib treatment group were significantly smaller comparing with the control group.Results of Real-time PCR showed that the expression level of Per1,Cry1 and BMAL1 mRNA was remarkably decreased in the treatment group (Per1,P =0.02;Cry1,P =0.002;BMAL1,P =0.035),the differences were statistically significant.Correlation analysis showed that the size of subcutaneous transplantation tumorsin nude mice was negatively correlated with the expressions of Per1,Per2,Cry1 and Cry2 mRNA in control group.While,the size of subcutaneous transplantation tumors was negatively correlated with the expressions of Per2,Per3 and BMAL1 levels in the sorafenib treatment group.Conclusions There is a negative correlation between the expression levels of some biological clock genes and the size of transplantation tumor in nude mice.Sorafenib treatment significantly inhibited the growth of hepatocellular carcinoma in nude mice and down-regulation the expressions of Per1,Cry1 and BMAL1 mRNA in hepatoma cells.

Objective To evaluate the mid-to long-term survival benefits of preoperative sandwich-like neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (LARC).Methods A total of 45 LARC patients who underwent neoadjuvant sandwich CRT in the form of XELOX regimen prior to,concurrently with,and following volumetric modulated arc radiotherapy (VMAT) in 2012 were enrolled in this study.VMAT was given at a gross tumor volume dose of 50 Gy in 25 fractions,and a clinical target volume dose of 45-46 Gy in 25 fractions.Total mesorectal excision was performed 6 to 8 weeks after completion of VMAT.The overall survival (OS) and disease-free survival (DFS) were determined by the Kaplan-Meier method,and survival comparison and univariate prognostic analysis were performed using the log-rank test.Results The median follow-up time was 46.7 months.There was no local recurrence detected among the patients.The 3-year distant metastasis (DM) rate was 18%,and the 3-year OS and DFS were 96% and 84%,respectively.Univariate analysis indicated that perineural invasion,N1-N2 pathology (pathological stage Ⅲ),and Ca-199>35 U/ml before treatment were risk factors for DM (P=0.000,0.000,and 0.013,respectively).Conclusions The significant short-term efficacy of preoperative sandwich-like neoadjuvant CRT can be extended to a positive mid-term survival in LARC patients.However,further phase Ⅲ clinical studies will be needed to confirm this finding.