Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers.

Despite widespread utilization of immunotherapy, treating immune-cold tumors remains a challenge. Multiomic analyses and experimental validation identified the OTUD4/CD73 proteolytic axis as a promising target in treating immune-suppressive triple negative breast cancer (TNBC). Mechanistically, deubiquitylation of CD73 by OTUD4 counteracted its ubiquitylation by TRIM21, resulting in CD73 stabilization inhibiting tumor immune responses. We further demonstrated the importance of TGF-ß signaling for orchestrating the OTUD4/CD73 proteolytic axis within tumor cells. Spatial transcriptomics profiling discovered spatially resolved features of interacting malignant and immune cells pertaining to expression levels of OTUD4 and CD73. In addition, ST80, a newly developed inhibitor, specifically disrupted proteolytic interaction between CD73 and OTUD4, leading to reinvigoration of cytotoxic CD8+ T cell activities. In preclinical models of TNBC, ST80 treatment sensitized refractory tumors to anti-PD-L1 therapy. Collectively, our findings uncover what we believe to be a novel strategy for targeting the immunosuppressive OTUD4/CD73 proteolytic axis in treating immune-suppressive breast cancers with the inhibitor ST80.

Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity.

Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). We have identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM21high/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.

[Effects of Chlorine Dioxide Disinfection on the Profile of the Super Antibiotic Resistance Genes in a Wastewater Treatment Plant].

In order to study the effects of chlorine dioxide (ClO2) disinfection on the super antibiotic resistance genes (SARGs), the final effluents before and after chlorine dioxide were sampled throughout one year in a wastewater treatment plant (WWTP). The bacteria and extracellular nucleic acid were collected using microporous membrane filtration and nucleic acid adsorption particles, respectively. A total of 9 SARGs was detected through a quantitative real-time polymerase chain reaction (qPCR). The results revealed that both intracellular and extracellular NDM-1, MCR-1, and MEC-A could be positively detected in the samples. Overall, ClO2 disinfection enhanced the relative abundance of the iSARGs (P<0.05), exhibiting a seasonal pattern, and increasing in the spring, summer, and autumn. In spring, it improved the most, up to twice the abundance. No SARGs were detected positive in the winter, either intracellularly or extracellularly. There was no significant variation in the concentrations of eSARGs before and after ClO2 disinfection. Therefore, ClO2 disinfection cannot effectively remove iSARGs and eSARGs in the final effluent from the WWTP.

The vaginal microecology in gynecological outpatients: a report from China / 中华检验医学杂志

Objective To study the vaginal microecology of the patients in the outpatient department of Obstetrics and gynecology in China.Methods A multicenter cross-sectional study was conducted in gynecologic clinic of 9 collaborative hospitals in China.200 consecutive patients were collected in each hospital and their vaginal microecology combined with related factors were analyzed.Results A total of 2 093 specimens were collected in this study.The detection rate of Trichomonas was 5.5%(115/2 093). The detection rate of Candida mycelia was 15.9%(333/2 093), with germinal spores was 4.1%(86/2093).The detection rate of bacterial vaginosis was 18.8%(394/2 093).The distribution results of vaginal flora in patients showed that the normal flora accounted for only 27.3%(571/2 093).The normal flora with the insufficiency of H2O2 accounted for 23%(480/2 093).The bacteria inhibiting flora accounted for 3.8%(79/2 093).The abnormal microflora(non BV type)accounted for 14.9%(312/2 093).The abnormal microflora(BV intermediate type)accounted for 13.4%(280/2 093).The abnormal microflora(BV type)accounted for 17.6%(369/2 093).The average pH of vaginal discharge was 4.58 ±0.495.There was no significant difference of the incidence of trichomonas and bacterial vaginosis between north and south of the Yangtze river, while the detection rate of fungal hyphae and the fungal spores is significantly higher in the south than that in the north.The analysis results of factors affecting the microecology showed that age and contraception methods were two important factors.The patients′age from bacteria inhibition group was 49.64 +16.68 which was significantly higher than that of the other microecology groups.The proportion of abnormal microflora of patients from the oral contraceptive group was 40%(20/50).The proportion of abnormal microflora of patients from IUD group was 36.6%(63/172).Compared with these two contraception methods, the proportion of abnormal microflora of patients from condoms usage group was 27.8%(91/327)which was significantly lower.The incidence of abnormal leucorrhea in the normal group was 37.7%, which was significantly lower than that of other abnormal groups.Conclusion This study showed the vaginal microecology status of the Chinese outpatient ′s clinic and found that the vagina microecology was related to age, region and contraceptive methods.The typical manifestation of microecological abnormality is the increase of leucorrhea.(Chin J Lab Med,2018, 41:287-291)

Clinical Observation of Bispectral Index in Evaluation of the Indications of Extubation in Children′s Total Intravenous Anesthesia / 中国医科大学学报

Objective To evaluate the value of bispectral index(BIS)monitoring as an indicator for extubation sedation level after children's oper?ation by total intravenous anesthesia. Methods One hundred and eighty children(2?13 years old)were randomly divided into six groups with 30 cases in each. Group A kept BIS 56?60,and Group B 61?65,Group C 66?70,Group D 71?75,Group E 76?80,Group F 81?85 till extubation. All children were given fentanyl,propofol and cisatracurium besilate when induced,and maintained with propofol and remifentanil. All cases kept BIS 40?55 during the operation. Then the changes of electrocardiogram,mean arterial pressure,heart rate,SpO2,postoperative complications and recovery time were observed. Results Groups A and B were extubated at deep anesthesia,cycle stability,but with high incidence of adverse reactions and awaked with a long time. Groups E and F were extubated when awaked,but with greater stimulation and easier agitation. Groups C and D were lighter hemodynamic responses,less respiratory effects and less postoperative complications of anesthesia. Conclusion The BIS level of 66?75 is a good se?dation level for extubation,especially in the level of 71?75.