DNA Damage-driven Inflammatory Cytokines:Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy

DNA damage occurs across tumorigenesis and tumor development.Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment(TIME)and dominate tumor progression.Accumulating evidence documents that multiple signaling pathways,including cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein(ATM/ATR),are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines.These cytokines possess multifaced functions in the anti-tumor immune response.Thus,it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines,critical for the development of effective tumor therapies.This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines.We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.

Inhibition of Cyclin F Promotes Cellular Senescence through Cyclin-dependent Kinase 1-mediated Cell Cycle Regulation

Objective Kidney renal clear cell carcinoma(KIRC)is a common renal malignancy that has a poor prognosis.As a member of the F box family,cyclin F(CCNF)plays an important regulatory role in normal tissues and tumors.However,the underlying mechanism by which CCNF promotes KIRC proliferation still remains unclear.Methods Bioinformatics methods were used to analyze The Cancer Genome Atlas(TCGA)database to obtain gene expression and clinical prognosis data.The CCK8 assay,EdU assay,and xenograft assay were used to detect cell proliferation.The cell senescence and potential mechanism were assessed by SA-β-gal staining,Western blotting,as well as ELISA.Results Our data showed that CCNF was highly expressed in KIRC patients.Meanwhile,downregulation of CCNF inhibited cell proliferation in vivo and in vitro.Further studies showed that the reduction of CCNF promoted cell senescence by decreasing cyclin-dependent kinase 1(CDK1),increasing the proinflammatory factors interleukin(IL)-6 and IL-8,and then enhancing the expression of p21 and p53.Conclusion We propose that the high expression of CCNF in KIRC may play a key role in tumorigenesis by regulating cell senescence.Therefore,CCNF shows promise as a new biomarker to predict the clinical prognosis of KIRC patients and as an effective therapeutic target.

A clinical protocol: A double-blinded, randomized controlled trial on the effect of traditional Chinese medicine formula Shoutai Pill in the treatment of threatened abortion

for about 20%of all clinically confirmed pregnancy.It is the main cause of early abortion.Vaginal bleeding is the main clinical manifestation,which seriously affects the mental health and quality of life of pregnant women.Currently,there is effective treatment for this condition.A recent meta-analysis showed that Shoutai Pill(ST Pill),a traditional Chinese medicine(TCM)formula,can effectively decrease the rate of threatened abortion.However,high heterogeneity was found among the studies included in the meta-analysis,this conclusion on the efficacy of TCM is not definitive.Although several have been conducted,some of them do not describe randomization and blinding methods.To address these problems,this article proposes an improved clinical treatment scheme based on ST Pill,which is to be tested through a well-designed randomized controlled trial,for the treatment of threatened abortion.Methods:This is a double-blinded,randomized,placebo-controlled trial to be conducted in a public Three-A hospital in China's Mainland.A total of 200 people will be enrolled.Using computer-generated random numbers,the participants will be randomly divided into two groups at a ratio of 1:1(treatment group(treated with ST Pill group)and placebo group).Both groups will receive medication to the end of the 20th gestational week or 1 week after vaginal bleeding stops,depending on which is longer.Participants in the treatment group will be treated with ST Pill(20 pills/time,once a day),and those in the placebo group will receive a placebo drug which is similar in appearance and smell with ST Pill.The main observation index is the live birth rate.Discussion:Although the efficacy of ST Pill in threatened abortion is well-known,no study has tested its efficacy through a double-blinded,randomized trials.Therefore,there is an urgent need for a standardized randomized double-blinded controlled trial to evaluate the clinical efficacy of ST Pill.ST Pill is likely to be a convenient and effective TCM pill for the prevention of threatened abortion.

Analysis of uterine artery and sex hormones in treating diminished ovarian reserve with tiaojing decoction

Objective: To observe the effect of tiaojing decoction and climen on diminished ovarian reserve patients with de ficiency of Kidney-Yin by sex hormone and uterine artery blood flow parameters. To verify the e ffectiveness of tiaojing decoction on diminished ovarian reserve and uterine artery blood flow parameters, explore the correlation between uterine artery blood flow parameters and sex hormones. Methods: Total 60 diminished ovarian reserve patients with deficiency of Kidney-Yin were randomly divided into the experimental group (n=30, taking tiaojing decoction and climen) and the control group (n=30, taking climen) and they were treated in 3 months. Observe bFSH, bE2, uterine artery PSV, EDV, S/D, RI before and after the treatment in the 2-4 day of menstruation. Results: After treatment, serum sex hormone levels and uterine artery blood flow parameters of the two groups were significantly different (P < 0.05), and the experimental group was significantly better than the control group. There was a linear correlation between PSV and FSH, PSV and E2, FSH and E2. Conclusion: Tiaojing decoction combined with climen has significant effect on diminished ovarian reserve patients with deficiency of Kidney-Yin. Uterine artery blood flow parameters can reflect the sex hormone levels.