In the present study we describe the complete cytochrome P450 complement, the "CYPome," of Streptomyces coelicolor A3(2). Eighteen cytochromes P450 (CYP) are described, in contrast to the absence of CYPs in Escherichia coli, and the twenty observed in Mycobacterium tuberculosis. Here we confirm protein identity as cytochromes P450 by heterologous expression in E. coli and measurement of reduced carbon monoxide difference spectra. We also report on their arrangement in the linear chromosome and relatedness to other CYPs in the superfamily. The future development of manipulation of antibiotic pathways and the use of streptomycetes in bioremediation and biotransformations will involve many of the new CYP forms identified here.

Purpose: This study (ClinicalTrials.gov identifier, NCT03676959) is an open, phase I dose-escalation and expansion study investigating the safety and efficacy of the recombinant, fully human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody Socazolimab in patients diagnosed with recurrent or metastatic cervical cancer. Experimental Design: Patients received Socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. The primary endpoints of the dose-expansion phase were safety and the objective response rate (ORR) of the 5mg/kg dose. Efficacy was assessed by the third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: One hundred four patients were successfully enrolled into the study. Twelve patients were included in the dose-escalation phase, with one complete response and two partial responses in the 5mg/kg treatment group. Ninety-two patients (5mg/kg) were enrolled in the dose-expansion phase. Fifty-four patients (59.3%) had baseline PD-L1-positive tumor expression (combined positive score, CPS≥1). ORR was 15.4% (95% CI, 8.7 to 24.5%). Median PFS was 4.44 months (95% CI, 2.37 to 5.75 months), and the median OS was 14.72 months (95% CI, 9.59 to NE months). ORR of PD-L1-positive patients was 16.7%, and the ORR of PD-L1-negative patients was 17.9%. No treatment-related deaths occurred. Conclusions: Our study demonstrates that Socazolimab has durable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti-PD-1/PD-L1 monoclonal antibodies.

Endometrial carcinogenesis may be related to the long-term effects of estradiol with no antagonism. However, how estradiol regulates cell proliferation is unknown. In the present study, through investigating the molecular events involved in estradiol induced angiogenics factors VEGF and bFGF, we found that estradiol induced endometrial cancer cell division, proliferation, migratory and invasive capacity in vitro and upregulated mRNA expression and protein synthesis of VEGF and bFGF. The estradiol-dependent induction of the expression of VEGF and bFGF was blocked by ER inhibitor, AKT inhibitor and NF-κB inhibitor (PDTC) in estrogen receptor positive Ishikawa cells and blocked by AKT inhibitor, NF-κB inhibitor (PDTC) in estrogen receptor negative HEC-1A cells. Moreover, estradiol activation of AKT was also blocked by AKT antagonist. NF-κB activation was restricted by estradiol concentration and time. Estradiol leading to VEGF and bFGF induction was also confirmed by the development of xenograft tumors in vivo. Taken together, our data suggest that estradiol induces the production of angiogenic factors via a mechanism involving AKT-mediated NF-κB activation partly in non-genomic manner without the estrogen receptor.

Cervical cancer (CC) holds the second highest incidence and is the fourth dominating cause of cancer-induced death in women. It has been widely accepted that long noncoding RNAs (lncRNAs) are implicated in pathological and physiological activities of CC. However, the research of lncRNAs is still in the initial stage. The biological function of lncRNA deoxyguanosine kinase antisense RNA 1 (DGUOK-AS1) in human cancers has not been reported yet. We found that DGUOK-AS1 was aberrantly upregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tissues through TCGA database. Real-time quantitative polymerase chain reaction (RT-qPCR) also verified the high expression of DGUOK-AS1 in CC cell lines. Loss-of-function assays indicated that DGUOK-AS1 silence repressed CC cell growth. In addition, dual-luciferase reporter and RNA immunoprecipitation (RIP) experiments validated the binding relation between miR-653-5p and DGUOK-AS1 or EMSY. Results of the rescue assays elucidated that EMSY overexpression or miR-653-5p downregulation reversed the suppressive function of DGUOK-AS1 knockdown on cell growth and DNA repair in CC. To sum up, this research highlighted that DGUOK-AS1 could promote CC cell proliferation via serving as a ceRNA of miR-653-5p to release EMSY, which might inspire us to discover novel strategies for CC treatment. Significance of the study: DGUOK-AS1 knockdown hinders proliferation of CC cells. DGUOK-AS1 sequesters miR-653-5p to elevate EMSY in CC. EMSY is required for DGUOK-AS1 to induce cell proliferation and repress DNA damage in CC.

Objective: To evaluated the oncologic outcomes associated with platinum-based adjuvant chemotherapy following concurrent chemoradiotherapy (CCRT) in the management of patients with locally advanced cervical cancer (LACC). Methods: A total of 695 patients with FIGO stage IB2, IIA2, IIB-IVA LACC treated at 6 medical facilities were enrolled and divided into 2 groups: 478 were assigned to CCRT alone (CCRT group) and 217 to adjuvant chemotherapy after CCRT (CCRT-ACT group). The treatment outcomes were retrospectively compared and reported after the propensity score matching (PSM) analysis. Results: With a median follow-up of 56.4 months, no statistically significant differences were found in overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and distance metastasis-free survival (DMFS) between 2 groups. In CCRT-ACT group, patients with lymph nodes involvement or squamous cell carcinoma (SCC) had significantly longer DMFS, but no significant benefit in survival outcomes were observed with more than 2 cycles of adjuvant chemotherapy. Moreover, patients with a high level of CA125 (>20.5U/mL) or SCC-Ag (>22.8μg/L) had a relatively better DFS or PFS, and grade 3-4 acute hematological toxicity, late urinary and lower gastrointestinal complications and diarrhea symptom were more frequent in CCRT-ACT group. Conclusions: Adjuvant chemotherapy after CCRT has a potential role in further improving disease control for LACC patients with lymph nodal-metastasis or SCC with a high level of CA125 or SCC-Ag. Due to increased treatment-related complications and diarrhea symptom affecting the quality of life, post-CCRT adjuvant chemotherapy with excessive cycles was not be considered as the most appropriate choice in general.