Dynamics of The Γδtcr Repertoires During The Dedifferentiation Process and Pilot Implications for Immunotherapy of Thyroid Cancer.

γδ T cells are evolutionarily conserved T lymphocytes that manifest unique antitumor efficacy independent of tumor mutation burden (TMB) and conventional human leukocyte antigen (HLA) recognition. However, the dynamic changes in their T cell receptor (TCR) repertoire during cancer progression and treatment courses remain unclear. Here, a comprehensive characterization of γδTCR repertoires are performed in thyroid cancers with divergent differentiation states through cross-sectional studies. The findings revealed a significant correlation between the differentiation states and TCR repertoire diversity. Notably, highly expanded clones are prominently enriched in γδ T cell compartment of dedifferentiated patients. Moreover, by longitudinal investigations of the γδ T cell response to various antitumor therapies, it is found that the emergence and expansion of the Vδ2neg subset may be potentially associated with favorable clinical outcomes after post-radiotherapeutic immunotherapy. These findings are further validated at single-cell resolution in both advanced thyroid cancer patients and a murine model, underlining the importance of further investigations into the role of γδTCR in cancer immunity and therapeutic strategies.

Efficacy, safety, and survival of neoadjuvant immunochemotherapy in operable non-small cell lung cancer: a systematic review and meta-analysis.

Background: Neoadjuvant immunochemotherapy may benefit patients with non-small cell lung cancer (NSCLC), but its impact requires further investigation. Methods: A meta-analysis was conducted. PubMed, Embase, Web of Science, and the Cochrane Library were searched. The study was registered in PROSPERO (registration no. CRD42022360893). Results: 60 studies of 3,632 patients were included. Comparing with neoadjuvant chemotherapy, neoadjuvant immunochemotherapy showed higher pCR (RR: 4.71, 95% CI: 3.69, 6.02), MPR (RR, 3.20, 95% CI: 2.75, 3.74), and ORR (RR, 1.46, 95% CI: 1.21, 1.77), fewer surgical complications (RR: 0.67, 95%CI: 0.48, 0.94), higher R0 resection rate (RR: 1.06, 95%CI: 1.03, 1.10, I2 = 52%), and longer 1-year and 2-year OS, without affecting TRAEs. For neoadjuvant immunochemotherapy in NSCLC, the pooled pCR rate was 0.35 (95% CI: 0.31, 0.39), MPR was 0.59 (95% CI: 0.54, 0.63), and ORR was 0.71 (95% CI: 0.66, 0.76). The pooled incidence of all grade TRAEs was 0.70 (95% CI: 0.60, 0.81), and that of >= grade 3 TRAEs was 0.24 (95% CI: 0.16, 0.32). The surgical complications rate was 0.13 (95% CI: 0.07, 0.18) and R0 resection rate was 0.98 (95% CI: 0.96, 0.99). The pooled 1-year OS was 0.97 (95%CI: 0.96, 0.99), and 2-year OS was 0.89 (95%CI: 0.83, 0.94). Patients with squamous cell carcinoma, stage III or higher PD-L1 performed better. Notably, no significant differences were observed in pCR, MPR, and ORR between 2 or more treatment cycles. Pembrolizumab-, or toripalimab-based neoadjuvant immunochemotherapy demonstrated superior efficacy and tolerable toxicity. Conclusion: According to our analysis, reliable efficacy, safety, and survival of neoadjuvant immunochemotherapy for operable NSCLC were demonstrated. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022360893, identifier CRD42022360893.

Leveraging circulating microbiome signatures to predict tumor immune microenvironment and prognosis of patients with non-small cell lung cancer.

BACKGROUND: Accumulating evidence supports the significant role of human microbiome in development and therapeutic response of tumors. Circulating microbial DNA is non-invasive and could show a general view of the microbiome of host, making it a promising biomarker for cancers. However, whether circulating microbiome is associated with prognosis of non-small cell lung cancer (NSCLC) and its potential mechanisms on tumor immune microenvironment still remains unknown. METHODS: The blood microbiome data and matching tumor RNA-seq data of TCGA NSCLC patients were obtained from Poore's study and UCSC Xena. Univariate and multivariate Cox regression analysis were used to identify circulating microbiome signatures associated with overall survival (OS) and construct the circulating microbial abundance prognostic scoring (MAPS) model. Nomograms integrating clinical characteristics and circulating MAPS scores were established to predict OS rate of NSCLC patients. Joint analysis of blood microbiome data and matching tumor RNA-seq data was used to deciphered the tumor microenvironment landscape of patients in circulating MAPS-high and MAPS-low groups. Finally, the predictive value of circulating MAPS on the efficacy of immunotherapy and chemotherapy were assessed. RESULTS: A circulating MAPS prediction model consisting of 14 circulating microbes was constructed and had an independent prognostic value for NSCLC. The integration of circulating MAPS into nomograms may improve the prognosis predictive power. Joint analysis revealed potential interactions between prognostic circulating microbiome and tumor immune microenvironment. Especially, intratumor plasma cells and humoral immune response were enriched in circulating MAPS-low group, while intratumor CD4 + Th2 cells and proliferative related pathways were enriched in MAPS-high group. Finally, drug sensitivity analysis indicated the potential of circulating MAPS as a predictor of chemotherapy efficacy. CONCLUSION: A circulating MAPS prediction model was constructed successfully and showed great prognostic value for NSCLC. Our study provides new insights of interactions between microbes, tumors and immunity, and may further contribute to precision medicine for NSCLC.

Cranial radiation therapy with hippocampus avoidance in lung cancer treatment: systematic review and meta-analysis.

Background: The role of cranial radiation therapy with hippocampus avoidance (HA-CRT) in neurocognitive function (NCF), brain metastasis (BM), and overall survival (OS) in lung cancer remains unclear. Methods: A meta-analysis was conducted to evaluate the impact of HA-CRT in lung cancer. Data from studies on hippocampal-avoidance prophylactic cranial irradiation (HA-PCI) and whole brain radiotherapy (HA-WBRT) were pooled. Results: A total of 14 studies, including 5 randomized controlled trials, were included. The focus of NCF was mainly via the Hopkins Verbal Learning Test-Revised or the Free and Cued Selective Reminding Test. At 6 months post-radiotherapy, the pooled proportion of participants with decline in the performance of total recall, delayed recall, and discrimination in neurocognitive tests were 0.22 (95% CI 0.15, 0.29), 0.20 (95% CI 0.13, 0.27), and 0.14 (95% CI 0.05, 0.24) respectively. After 12 months, the proportion were 0.16 (95% CI 0.08, 0.23), 0.10 (95% CI 0.04, 0.16), and 0.04 (95% CI 0, 0.09) respectively. For HA zone relapse, the RR of HA-CRT versus CRT was 2.72 (95% CI 0.53, 13.87), and for 2-year BM, it was 1.20 (95% CI 0.82, 1.75). Regarding HA-PCI in SCLC, the 1-year BM rate was 0.12 (95% CI 0.07, 0.17), and the 2-year BM rate was 0.20 (95% CI 0.16, 0.25). For HA-WBRT in NSCLC with BM, the 2-year intracranial progression rate was 0.38 (95% CI 0.13, 0.62). There was no significant difference in OS between HA-CRT and CRT. Conclusions: HA-CRT appears to be safe in lung cancer, but it may not outperform conventional CRT. Larger RCTs comparing HA-CRT and CRT are warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022360890, identifier CRD42022360890.

Diverse regulated cell death modes predict the immune microenvironment and drug sensitivity in lung adenocarcinoma.

Integrated action modes of regulated cell death (RCD) in lung adenocarcinoma (LUAD) have not been comprehensively dissected. Here, we adopted 15 RCD modes, including 1350 related genes, and established RCD signature scores. We found that LUAD patients with high RCD scores had a significantly worse prognosis in all four different cohorts (TCGA, KM-plotter, GSE31210, and GSE30219). Our nomogram established based on the RCD score and clinical characteristics performed well in both the discovery and validation sets. There was a close correlation between the RCD scores and LUAD molecular subtypes identified by unsupervised consensus clustering. Furthermore, we profiled the tumor microenvironment via deconvolution and found significant differences in immune activity, transcription factor activity and molecular pathway enrichment between the RCD-high and RCD-low groups. More importantly, we revealed that the regulation of antigen presentation is the crucial mechanism underlying RCD. In addition, higher RCD scores predict poorer sensitivity to multiple therapeutic drugs, which indicates that RCD scores may serve as a promising predictor of chemotherapy and immunotherapy outcomes. In summary, this work is the first to reveal the internal links between RCD modes, LUAD, and cancer immunity and highlights the necessity of RCD scores in personalizing treatment plans.

Mechanisms underlying the effects, and clinical applications, of oral microbiota in lung cancer: current challenges and prospects.

The oral cavity contains a site-specific microbiota that interacts with host cells to regulate many physiological processes in the human body. Emerging evidence has suggested that changes in the oral microbiota can increase the risk of lung cancer (LC), and the oral microbiota is also altered in patients with LC. Human and animal studies have shown that oral microecological disorders and/or specific oral bacteria may play an active role in the occurrence and development of LC through direct and/or indirect mechanisms. These studies support the potential of oral microbiota in the clinical treatment of LC. Oral microbiota may therefore be used in the prevention and treatment of LC and to improve the side effects of anticancer therapy by regulating the balance of the oral microbiome. Specific oral microbiota in LC may also be used as screening or predictive biomarkers. This review summarizes the main findings in research on oral microbiome-related LC and discusses current challenges and future research directions.

Patient-derived organoids of lung cancer based on organoids-on-a-chip: enhancing clinical and translational applications.

Lung cancer is one of the most common malignant tumors worldwide, with high morbidity and mortality due to significant individual characteristics and genetic heterogeneity. Personalized treatment is necessary to improve the overall survival rate of the patients. In recent years, the development of patient-derived organoids (PDOs) enables lung cancer diseases to be simulated in the real world, and closely reflects the pathophysiological characteristics of natural tumor occurrence and metastasis, highlighting their great potential in biomedical applications, translational medicine, and personalized treatment. However, the inherent defects of traditional organoids, such as poor stability, the tumor microenvironment with simple components and low throughput, limit their further clinical transformation and applications. In this review, we summarized the developments and applications of lung cancer PDOs and discussed the limitations of traditional PDOs in clinical transformation. Herein, we looked into the future and proposed that organoids-on-a-chip based on microfluidic technology are advantageous for personalized drug screening. In addition, combined with recent advances in lung cancer research, we explored the translational value and future development direction of organoids-on-a-chip in the precision treatment of lung cancer.

Immunogenetic polymorphisms predict therapeutic efficacy and survival outcomes in tumor patients receiving PD-1/PD-L1 blockade.

BACKGROUND: While immune checkpoint inhibitors (ICIs) demonstrate remarkable clinical responses, only a small subset of patients obtains benefits. Genes linked to the tumor immune system are confirmed to be critical for the treatment of ICIs, and their polymorphisms can contribute to ICI efficacy. Here, we examined the potential of immunogenetic variations to predict the efficacy and survival of the PD-1/PD-L1 blockade. METHODS: Cancerous patients receiving PD-1/PD-L1 blockade were recruited and followed up. Pivotal genes related to tumor-immunity were filtered through a protein-protein interaction network and the degree algorithm in Cytoscape. Finally, 39 genetic variants were genotyped through multiplex genotyping assays. Association analyses between variants and ICI efficacy and progression-free survival (PFS) were performed. RESULTS: Overall, 318 patients were ultimately enrolled. Hence, three immunogenetic variants were identified as predictors of PD-1/PD-L1 blockade response. Mutant alleles from ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911 were all at increased risk of tumor progression following ICI therapy (OR: 1.475, 1.641, 1.462, respectively; P value: 0.028, 0.017, 0.027, respectively). Significant immunogenetic variants also attained similar trends in the PD-1 blockade, lung cancer, or lung cancer using PD-1 blockade subgroups. Furthermore, the mutant genotypes of CD274 rs2297136 (GG as the reference: HR: 0.50 (95%CI: 0.29-0.88), P value: 0.015) and TLR4 rs1927911 (AA as the reference: HR: 0.65 (95%CI: 0.47-0.91), P value: 0.012) indicated poorer PFS and were both independent prognostic factors. CONCLUSION: Immunogenetic polymorphisms, including ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911, were first identified as potential predictors of response to PD-1/PD-L1 blockade in tumor patients.

Immunogenetic variations predict immune-related adverse events for PD-1/PD-L1 inhibitors.

BACKGROUND: PD-1/PD-L1 inhibitors have brought remarkable benefits but can cause profound immune-related adverse events (irAEs). The host immunogenetic background is likely to play a role in irAE susceptibility. In this study, we aimed to identify potential immunogenetic biomarkers to predict irAEs. METHODS: Patients with solid tumours receiving PD-1/PD-L1 blockade were recruited and followed up. Genes considered pivotal contributors to tumour-immunity and autoimmune diseases were screened out via protein-protein interaction network and Cytoscape. Consequently, thirty-nine variants in eighteen genes were genotyped using the multiplex genotyping assay. Association analysis between genetic variants and irAEs as well as irAEs-free survival was performed. RESULTS: Four immunogenetic variants as predictive biomarkers of irAEs were identified. The C allele of Mitogen-Activated Protein Kinase 1 (MAPK1) rs3810610 (odds ratio [OR] = 1.495, 95% confidence interval [CI] = 1.093-2.044, P = 0.012) was a risk predictor while the A allele of PTPRC rs6428474 (OR = 0.717, 95% CI = 0.521-0.987, P = 0.041) was a protective factor for all-grade irAEs. The A allele of ADAD1 rs17388568 (OR = 2.599, 95% CI = 1.355-4.983, P = 0.003) increased the risk while the G allele of IL6 rs1800796 (OR = 0.425, 95% CI = 0.205-0.881, P = 0.018) protected patients from high-grade irAEs. Significant immunogenetic variants reached a similar tendency in PD-1 blockade or lung cancer subgroups. In multivariate Cox regression analysis, the MAPK1 rs3810610 was an independent factor regarding all-grade irAEs-free survival (CC versus CT or TT: hazard ratio [HR] = 0.71, 95% CI = 0.52-0.99, P = 0.042). ADAD1 rs17388568 (AA versus AG or GG: HR = 0.11, 95% CI = 0.025-0.49, P = 0.004) and IL6 rs1800796 (GG or GC versus CC: HR = 3.10, 95% CI = 1.315-7.29, P = 0.01) were independent variables for high-grade irAEs-free survival. CONCLUSION: We first identified several immunogenetic polymorphisms associated with irAEs and irAEs-free survival in PD-1/PD-L1 blockade-treated tumour patients, and they may serve as potential predictive biomarkers.

Allele frequency and proportion defined by circulating tumor DNA profiling predict tyrosine kinase inhibitors' therapeutic outcomes for non-small cell lung cancer.

PURPOSE: Circulating tumor DNA is more and more accessible for patients who cannot undergo biopsy. No consistent conclusion has been reached on whether frequency and proportion of mutations defined by ctDNA profiling can predict therapeutic outcomes. METHODS: One hundred patients with non-small cell lung cancer harboring activating EGFR mutations (exon 19 deletion, L858R and T790M mutation) were collected in West China hospital from December 18, 2017 to December 31, 2019. We retrospectively analyzed the frequency and proportion distribution of ctDNA mutations and its relationship with tyrosine kinase inhibitors therapeutic outcomes. RESULTS: Patients with lower frequency of sensitizing EGFR mutations (< 3%) had a longer progression-free survival (PFS) time than those with higher frequency (15 months vs. 10 months, p = 0.028). Moreover, patients with the lower ratio of T790M mutation frequency and the maximum-somatic-allele-frequency (T790M/MSAF < 30%) had a less prolonged PFS than those with higher T790M/MSAF (7 months vs. 15 months, p = 0.013). CONCLUSION: The frequency and proportion of ctDNA mutations are worth clinical attention in the prediction of therapeutic outcomes.

Novel directions of precision oncology: circulating microbial DNA emerging in cancer-microbiome areas.

Microbiome research has extended into the cancer area in the past decades. Microbes can affect oncogenesis, progression, and treatment response through various mechanisms, including direct regulation and indirect impacts. Microbiota-associated detection methods and agents have been developed to facilitate cancer diagnosis and therapy. Additionally, the cancer microbiome has recently been redefined. The identification of intra-tumoral microbes and cancer-related circulating microbial DNA (cmDNA) has promoted novel research in the cancer-microbiome area. In this review, we define the human system of commensal microbes and the cancer microbiome from a brand-new perspective and emphasize the potential value of cmDNA as a promising biomarker in cancer liquid biopsy. We outline all existing studies on the relationship between cmDNA and cancer and the outlook for potential preclinical and clinical applications of cmDNA in cancer precision medicine, as well as critical problems to be overcome in this burgeoning field.

KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming.

Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5'-adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.

A Promising Preoperative Prediction Model for Microvascular Invasion in Hepatocellular Carcinoma Based on an Extreme Gradient Boosting Algorithm.

Background: The non-invasive preoperative diagnosis of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is vital for precise surgical decision-making and patient prognosis. Herein, we aimed to develop an MVI prediction model with valid performance and clinical interpretability. Methods: A total of 2160 patients with HCC without macroscopic invasion who underwent hepatectomy for the first time in West China Hospital from January 2015 to June 2019 were retrospectively included, and randomly divided into training and a validation cohort at a ratio of 8:2. Preoperative demographic features, imaging characteristics, and laboratory indexes of the patients were collected. Five machine learning algorithms were used: logistic regression, random forest, support vector machine, extreme gradient boosting (XGBoost), and multilayer perception. Performance was evaluated using the area under the receiver operating characteristic curve (AUC). We also determined the Shapley Additive exPlanation value to explain the influence of each feature on the MVI prediction model. Results: The top six important preoperative factors associated with MVI were the maximum image diameter, protein induced by vitamin K absence or antagonist-II, α-fetoprotein level, satellite nodules, alanine aminotransferase (AST)/aspartate aminotransferase (ALT) ratio, and AST level, according to the XGBoost model. The XGBoost model for preoperative prediction of MVI exhibited a better AUC (0.8, 95% confidence interval: 0.74-0.83) than the other prediction models. Furthermore, to facilitate use of the model in clinical settings, we developed a user-friendly online calculator for MVI risk prediction based on the XGBoost model. Conclusions: The XGBoost model achieved outstanding performance for non-invasive preoperative prediction of MVI based on big data. Moreover, the MVI risk calculator would assist clinicians in conveniently determining the optimal therapeutic remedy and ameliorating the prognosis of patients with HCC.

Application of Metanephrine and Normetanephrine in Evaluating the Selectivity of Adrenal Vein Sampling.

The aim of the study was to investigate the usefulness of metanephrine (MN) and normetanephrine (NMN) in bilateral simultaneous adrenal vein sampling (AVS) with and without ACTH stimulation. The study was conducted in a single referral center. Prospective recruited patients with PA were treated with AVS. The effects of cortisol, MN and NMN on selectivity catheterization were assessed and determined by lateralization. We enrolled 54 patients with PA who were treated with simultaneous bilateral AVS with ACTH. The Selectivity Index (SI) calculated by MN was higher than that calculated by other indicators (p<0.001), the catheterization success rate of MN at baseline was the same as that of cortisol after ACTH stimulation, and in lateralization diagnosis, MN was not inferior to cortisol. In conclusion, among the studied indicators, MN is the best index for determining the catheterization selectivity in AVS, especially in the absence of ACTH stimulation.

The long non-coding RNA HOXA11-AS activates ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p.

BACKGROUND: miR-124-3p can inhibit integrin ß3 (ITGB3) expression to suppress the migration and invasion of gastric cancer (GC), and in the process lncRNA HOXA11-AS may act as a molecular sponge. METHODS: Luciferase reporter assay was conducted to verify the binding of miR-124-3p and HOXA11-AS. RT-PCR and western blot were performed to detect the expression of HOXA11-AS, miR-124-3p and ITGB3 in GC tissues and cells. Gene silence and overexpression experiments as well as cell migration and invasion assays on GC cell lines were performed to determine the regulation of molecular pathways, HOXA11-AS/miR-124-3p/ITGB3. Furthermore, the role of HOXA11-AS in GC was confirmed in mice models. RESULTS: We found HOXA11-AS is up-regulated in GC tissues and can bind with miR-124-3p. Through overexpression/knockdown experiments and function tests in vitro, we demonstrated HOXA11-AS can promote ITGB3 expression by sponging miR-124-3p, consequently enhance the proliferation, migration, and invasion of GC cells. Meanwhile, we validated that HOXA11-AS promotes migration and invasion of GC cells via down-regulating miR-124-3p and up-regulating ITGB3 in vivo. CONCLUSIONS: We demonstrated that lncRNA HOXA11-AS can increase ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p. Our results suggested that HOXA11-AS may reasonably serve as a promising diagnostic biomarker and a potential therapeutic target of GC.

Effect of Adrenocorticotropic Hormone Stimulation During Simultaneous Bilateral Adrenal Vein Sampling in Primary Aldosteronism.

The aim of the study was to investigate the significance and influence of adrenocorticotropic hormone (ACTH) stimulation in primary aldosteronism (PA) patients with simultaneous bilateral adrenal vein sampling (AVS). All patients diagnosed with PA underwent simultaneous bilateral AVS with ACTH. In 95 patients, the post-ACTH SI significantly increased (p<0.001), and it gradually decreased from t10-t30 after ACTH stimulation (p<0.001). The unsuccessful catheterization decreased after ACTH stimulation. Time points within 20 min after ACTH stimulation were better for sampling, and the selectivity did not increase over longer periods. According to lateralization before and after ACTH stimulation, the patients could be divided into 3 groups (U, unilateral; B, bilateral): U/U , U/B or B/U, and B/B. Compared with the U/U group, in the U/B or B/U and B/B groups, the lateralization index (LI) was lower both at baseline and after ACTH stimulation (p<0.0001), the contralateral index (CLI) was higher after ACTH stimulation (p<0.003), the serum potassium level was higher (p<0.001), and the carbon dioxide combining power (CO2CP) and base excess (BE) levels were lower. In conclusion, in simultaneous bilateral AVS, ACTH stimulation had significant effects on increasing the catheterization selectivity. Lateralization change was observed after stimulation. After ACTH stimulation, fewer patients could be diagnosed with lateralized PA. Patients with consistent lateralized PA showed a more serious phenotype.

Advancements and Obstacles of CRISPR-Cas9 Technology in Translational Research.

The expanding CRISPR-Cas9 technology is an easily accessible, programmable, and precise gene-editing tool with numerous applications, most notably in biomedical research. Together with advancements in genome and transcriptome sequencing in the era of metadata, genomic engineering with CRISPR-Cas9 meets the developmental requirements of precision medicine, and clinical tests using CRISPR-Cas9 are now possible. This review summarizes developments and established preclinical applications of CRISPR-Cas9 technology, along with its current challenges, and highlights future applications in translational research.

PD-1/PD-L1 Inhibitors in Cervical Cancer.

Cervical cancer is one of the most common gynecological tumors, and the majority of early-stage cervical cancer patients achieve good recovery through surgical treatment and concurrent chemoradiotherapy (CCRT). However, for patients with recurrent, persistent, metastatic cervical cancer, effective treatment is rare, except for bevacizumab combined with chemotherapy. Programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors might be a novel choice to improve the clinical outcomes of these patients. Thus far, some pivotal trials, including Keynote 028, Keynote 158 and Checkmate 358, have indicated established clinical benefit of PD-1/PD-L1 inhibitors in cervical cancer. In light of these data, the FDA has approved pembrolizumab for patients with recurrent or metastatic cervical cancer with disease progression during or after chemotherapy. There are also some ongoing studies that may provide more evidence for the PD-1/PD-L1 pathway as a therapeutic target in cervical cancer. In this review, we have summarized the status and application of PD-1/PD-L1 inhibitors in clinical trials for the treatment of cervical cancer and suggested some future directions in this field.

Ionizing Radiation-Induced Cellular Senescence in Normal, Non-transformed Cells and the Involved DNA Damage Response: A Mini Review.

Cellular senescence is identified by a living cell in irreversible and persistent cell cycle arrest in response to various cellular stresses. Senescent cells secrete senescence-associated secretory phenotype factors that can amplify cellular senescence and alter the microenvironments. Radiotherapy, via ionizing radiation, serves as an effective treatment for local tumor control with side effects on normal cells, which can induce inflammation and fibrosis in irradiated and nearby regions. Research has revealed that senescent phenotype is observable in irradiated organs. This process starts with DNA damage mediated by radiation, after which a G2 arrest occurs in virtually all eukaryotic cells and a mitotic bypass is possibly necessary to ultimately establish cellular senescence. Within this complex DNA damage response signaling network, ataxia telangiectasia-mutated protein, p53, and p21 stand out as the crucial mediators. Senolytic agents, a class of small molecules that can selectively kill senescent cells, hold great potential to substantially reduce the side effects caused by radiotherapy while reasonably steer clear of carcinogenesis.