RESUMEN
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.
Asunto(s)
5'-Nucleotidasa , Proteolisis , Neoplasias de la Mama Triple Negativas , Animales , Femenino , Humanos , Ratones , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/inmunología , 5'-Nucleotidasa/antagonistas & inhibidores , Línea Celular Tumoral , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas de Neoplasias/inmunología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Ubiquitinación , Proteasas Ubiquitina-EspecíficasRESUMEN
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)
RESUMEN
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.