Mutation status of the KMT2 family associated with immune checkpoint inhibitors (ICIs) therapy and implicating diverse tumor microenvironments.

Mounting evidence suggests a strong association between tumor immunity and epigenetic regulation. The histone-lysine N-methyltransferase 2 (KMT2) family plays a crucial role in the methylation of histone H3 at lysine 4. By influencing chromatin structure and DNA accessibility, this modification serves as a key regulator of tumor progression and immune tolerance across various tumors. These findings highlight the potential significance of the KMT2 family in determining response to immune checkpoint inhibitor (ICI) therapy, which warrants further exploration. In this study, we integrated four ICI-treated cohorts (n = 2069) across 10 cancer types and The Cancer Genome Atlas pan-cancer cohort and conducted a comprehensive clinical and bioinformatic analysis. Our study indicated that patients with KMT2 family gene mutations benefited more from ICI therapy in terms of overall survival (P < 0.001, hazard ratio [HR] = 0.733 [95% confidence interval (CI): 0.632-0.850]), progression-free survival (P = 0.002, HR = 0.669 [95% CI: 0.518-0.864]), durable clinical benefit (P < 0.001, 54.1% vs. 32.6%), and objective response rate (P < 0.001, 40.6% vs. 22.0%). Through a comprehensive analysis of the tumor microenvironment across different KMT2 mutation statuses, we observed that tumors harboring the KMT2 mutation exhibited enhanced immunogenicity, increased infiltration of immune cells, and higher levels of immune cell cytotoxicity, suggesting a propensity towards a "hot tumor" phenotype. Therefore, our study indicates a potential association between KMT2 mutations and a more favorable response to ICI therapy and implicates different tumor microenvironments associated with ICI therapy response.

Role of hepatitis B core-related antigen in predicting the occurrence and recurrence of hepatocellular carcinoma in patients with chronic hepatitis B: A systemic review and meta-analysis.

BACKGROUND AND AIM: The purpose of the current study was to investigate the predictive value of hepatitis B core-related antigen (HBcrAg) on the occurrence and recurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). METHODS: We searched PubMed, Embase, Scopus, and Web of Science from database inception to April 6, 2023. Pooled hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was calculated for the occurrence and recurrence of HCC. RESULTS: Of the 464 articles considered, 18 articles recruiting 10 320 patients were included. The pooled results showed that high serum HBcrAg level was an independent risk factor for the occurrence of HCC in CHB patients (adjusted HR = 3.12, 95% CI: 2.40-4.06, P < 0.001, I2 = 43.2%, P = 0.043; OR = 5.65, 95% CI: 3.44-5.82, P < 0.001, I2 = 0.00%, P = 0.42). Further subgroup analysis demonstrated that the predictive ability of HBcrAg for the occurrence of HCC is not influenced by the hepatitis B e antigen (HBeAg) status or the use of nucleoside/nucleotide analogs (NAs). In addition, our meta-analysis also suggests that HBcrAg is a predictor of HCC recurrence (adjusted HR = 1.71, 95% CI: 1.26-2.32, P < 0.001, I2 = 7.89%, P = 0.031). CONCLUSIONS: For patients with CHB, serum HBcrAg may be a potential predictive factor for the occurrence of HCC, regardless of HBeAg status or NA treatment. It may also serve as a novel prognostic biomarker for the recurrence of HCC. More studies are needed to confirm our conclusions.

MALAT1/ mir-1-3p mediated BRF2 expression promotes HCC progression via inhibiting the LKB1/AMPK signaling pathway.

BACKGROUND: The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to play a vital role in the occurrence and development of various tumors. However, the underlying mechanism of MALAT1 in hepatocellular carcinoma (HCC) has not been thoroughly elucidated. METHODS: The expression levels of MALAT1 in HCC tissues and different cell lines were detected by qRT-PCR. Antisense oligonucleotides (ASO)-MALAT1 transfected cells were used to explore the biological effects of MALAT1 in HCC cells by cell counting kit 8 (CCK-8), colony formation, transwell, wound healing, and flow cytometry analysis. Western blotting was performed to measure AMPK and apoptosis-related protein levels. Dual-luciferase reporter assay was performed to verify the relationship between MALAT1 and its specific targets. RESULTS: We found that MALAT1 was upregulated in HCC, and MALAT1 knockdown in HCC cells inhibited cell proliferation, migration, and invasion and inhibited apoptosis in vitro. Further studies demonstrated that MALAT1 positively regulated the expression of transcription factor II B­related factor 2 (BRF2), which was associated with tumor recurrence, large tumor size, and poor prognosis in HCC. Mechanistically, MALAT1 was found to act as a competitive endogenous RNA to sponge has-miR-1-3p, which upregulated BRF2 expression. Knockdown of BRF2 inhibited the progression of HCC by activating the LKB1/AMPK signaling pathway. Overexpression of BRF2 reversed the inhibitory effect of MALAT1 knockdown on HCC cell viability. Moreover, ASO targeting MALAT1 inhibited the growth of xenograft tumors. CONCLUSIONS: Our results demonstrate a novel MALAT1/miR-1-3p/BRF2/LKB1/AMPK regulatory axis in HCC, which may provide new molecular therapeutic targets for HCC in the future.

Survival after minimally invasive radical hysterectomy without using uterine manipulator for early-stage cervical cancer: A systematic review and meta-analysis.

BACKGROUND: Minimally invasive radical hysterectomy has been reported to increase the risk of cancer relapse and death compared with open surgery in women with early-stage cervical cancer. The use of a uterine manipulator is considered one of the risk factors. OBJECTIVES: To investigate whether women with early-stage cervical cancer treated with minimally invasive radical hysterectomy without using uterine manipulator have oncological outcomes similar to those of open surgery. SEARCH STRATEGY: Searches were performed in MEDLINE, Embase and CENTRAL from their inception until 31 March 2022. SELECTION CRITERIA: Inclusion criteria were: (1) randomised controlled trials or observational cohort studies published in English, (2) studies comparing minimally invasive radical hysterectomy without using a uterine manipulator with open radical hysterectomy in women with early-stage cervical cancer, and (3) studies comparing survival outcomes. DATA COLLECTION AND ANALYSIS: Two authors independently conducted data extraction and assessed study quality. We calculated the hazard ratios (HR) and the 95% confidence intervals (CI) using the inverse variance approach for survival outcome. MAIN RESULTS: Six observational studies with 2150 women were included. The minimally invasive surgery group had a significantly higher risk of cancer relapse compared with open surgery group (HR 1.55, 95% CI 1.15-2.10). CONCLUSIONS: Minimally invasive radical hysterectomy without using a uterine manipulator resulted in an inferior recurrence-free survival compared with open radical hysterectomy in the treatment of women with early-stage cervical cancer.

Prognostic value of human papillomavirus cell-free DNA in cervical cancer patients: A systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aimed to investigate the association between circulating human papillomavirus (HPV) cell-free DNA and oncological outcomes of cervical cancer patients. METHODS: Searches were performed in MEDLINE, Embase, and CENTRAL from their inception until 26 November 2023. Inclusion criteria were: (1) pathologically confirmed cervical cancer with available HPV test results; (2) detection of HPV cell-free DNA was performed in serum/plasma before or at end of treatment; (3) studies reported oncological outcomes of cervical cancer patients according to the levels of HPV cell-free DNA. Data extraction and study quality assessment were performed independently by two authors. Pooled hazard ratios and 95% confidence intervals were calculated using the inverse-variance method for survival outcomes. RESULTS: Five studies were finally included in this meta-analysis. Blood samples were collected from 167 patients before treatment, with 150 individuals available for analysis at the end of treatment. Furthermore, 82 patients with available samples at 3 months post-treatment were included in the analysis. The pooled results indicated a significant association between positive HPV cell-free DNA at end of treatment and worse progression-free survival in patients with cervical cancer (pooled hazard ratio: 5.49; 95 % confidence interval: 2.85-10.58; I2: 0 %). Similar findings were observed in patients with detectable HPV cell-free DNA at 3 months post-treatment (pooled hazard ratio: 7.86; 95 % confidence interval: 3.32-18.60; I2: 0 %). However, the detection of HPV cell-free DNA before treatment was not significantly associated with progression-free survival (pooled hazard ratio: 0.97; 95 % confidence interval: 0.55-1.71; I2: 0 %). CONCLUSION: Cervical cancer patients testing positive for HPV cell-free DNA at the end of treatment or 3 months post-treatment displayed significantly poorer oncological outcomes compared to those testing negative. Thus, personalized monitoring of HPV cell-free DNA holds promise as a prognostic biomarker for patients with cervical cancer.

Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts.

BACKGROUND: The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. METHOD: We analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. RESULTS: Our study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. CONCLUSIONS: RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.

The effect of age, sex, and eastern cooperative oncology group performance status on the efficacy and safety of immune checkpoint inhibitors in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: The effect of age, sex, and eastern cooperative oncology group performance status (ECOG PS) on the efficacy and safety of immune checkpoint inhibitor (ICI) therapy among hepatocellular carcinoma (HCC) patients remains elusive. Thus, a meta-analysis was conducted to evaluate whether such effects exist. RESEARCH DESIGN AND METHODS: Eligible studies in PubMed, Embase, and Cochrane Library databases were retrieved. RESULTS: One-hundred-and-eleven studies involving 14,768 HCC patients were included. The findings indicated that the ECOG PS didn't have a significant effect on the ORR and PFS in ICI-treated HCC patients (higher ECOG PS vs. lower ECOG PS: ORR: OR = 0.78, 95%CI = 0.55-1.10; PFS: HR = 1.15, 95%CI = 0.97-1.35), while those patients with a higher ECOG PS may have a worse OS (HR = 1.52, 95% CI = 1.26-1.84). There is no significant evidence of the effect of age (older vs. younger) or sex (males vs. females) on the efficacy of ICI therapy in HCC. CONCLUSION: ICI therapy in HCC should not be restricted strictly to certain patients in age or sex categories, while HCC patients with higher ECOG PS may require closer medication or follow-up strategy during ICI therapy. PROSPERO REGISTRATION: CRD42024518407.

Survival after minimally invasive radical hysterectomy with protective colpotomy for early-stage cervical cancer: A systematic review and meta-analysis.

Minimally invasive surgery on treatment of early-stage cervical cancer is debatable. Traditional approaches of colpotomy are considered responsible for an inferior oncological outcome. Evidence on whether protective colpotomy could optimize minimally invasive technique and improve prognoses of women with early-stage cervical cancer remains limited. We produced a systematic review and meta-analysis to compare oncological outcomes of the patients treated by minimally invasive radical hysterectomy with protective colpotomy to those treated by open surgery according to existing literature. We explored PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception to December 2022. Inclusion criteria were: (1) randomized controlled trials or observational studies published in English, (2) studies comparing minimally invasive radical hysterectomy with protective colpotomy to abdominal radical hysterectomy in early-stage cervical cancer, and (3) studies comparing survival outcomes. Two reviewers performed the screening, data extraction, and quality assessment independently. A total of 8 retrospective cohort studies with 2020 women were included in the study, 821 of whom were in the minimally invasive surgery group, and 1199 of whom were in the open surgery group. The recurrence-free survival and overall survival in the minimally invasive surgery group were both similar to that in the open surgery group (pooled hazard ratio, 0.88 and 0.78, respectively; 95% confidence interval, 0.56-1.38 and 0.42-1.44, respectively). Minimally invasive radical hysterectomy with protective colpotomy on treatment of early-stage cervical cancer had similar recurrence-free survival and overall survival compared to abdominal radical hysterectomy. Protective colpotomy could be a guaranteed approach to modifying minimally invasive technique.

Systemic therapy with or without locoregional therapy for advanced hepatocellular carcinoma: A systematic review and network meta-analysis.

We aim to identify the optimal treatment option of systemic therapy with or without locoregional therapy for advanced hepatocellular carcinoma (HCC). Outcomes of interest include overall survival (OS), progression-free survival (PFS), objective response rate (ORR), grade 3-4 treatment-related adverse events (TRAEs), and incidence of treatment discontinuation due to AEs. The surface under the cumulative ranking curve (SUCRA) probability values were applied to rank the interventions. 23 randomized-controlled trials including 14,303 patients with advanced HCC were included. Lenvatinib plus transcatheter arterial chemoembolization (TACE) ranked best regarding OS benefit (SUCRA: 0.99). Immuno-oncology (IO)-multikinase inhibitor (MKI)/vascular endothelial growth factor (VEGF) inhibitor combinations had a higher probability of providing better OS than IO-IO combinations. IO monotherapies demonstrated superior safety profile while combination therapies caused more toxicity in general. We conclude that combination therapies achieve remarkable efficacy in patients with advanced HCC and clinical decision making requires a careful balance of efficacy versus risk.

Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism.

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by ß cells. By screening the expression and functional characterization of olfactory receptors (ORs) in pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a ß cell-macrophage circuit and a ß-arrestin-1-mediated CCL2 pathway, as evidenced by ß-arrestin-1-/- mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdx1-Cre+/-Olfr109fl/fl specifically alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic ß cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.

ACTL6A Promotes the Proliferation of Esophageal Squamous Cell Carcinoma Cells and Correlates with Poor Clinical Outcomes.

BACKGROUND: ACTL6A, a regulatory subunit of ATP-dependent chromatin-remodeling complexes SWI/SNF, has been identified as a central oncogenic driver in many tumor types. MATERIALS AND METHODS: We used immunohistochemistry (IHC) to detect ACTL6A expression in esophageal squamous cell carcinoma (ESCC) tissues. Then, the effect of ACTL6A on proliferation and DNA synthesis was explored by using cell counting kit 8 (CCK8) and EdU retention assays. The potential oncogenic mechanism of ACTL6A in ESCC cells was also analyzed by flow cytometry and Western blotting. We further established an ESCC xenograft mouse model to validate the in vitro results. RESULTS: ACTL6A expression, localized in cancer cell nuclei, was markedly higher in ESCC tissues than in the corresponding noncancerous tissues (P<0.001) and was positively associated with tumor size, histological differentiation, T stage and tumor-node-metastasis (TNM) stage. Kaplan-Meier analysis revealed that high ACTL6A expression was significantly associated with poor overall survival (OS) (P = 0.008, HR= 2.562, 95% CI: 1.241-5.289), and decision curve analysis (DCA) demonstrated that ACTL6A could increase the clinical prognostic efficiency of the original clinical prediction model. Further in vitro experiments showed that ACTL6A knockdown led to inhibition of cell proliferation and DNA synthesis in ESCC cell lines, while overexpression of ACTL6A had the opposite effects. ACTL6A knockdown resulted in G1 phase arrest, with downregulation of cyclin D1, CDK2 and S6K1/pS6 pathway proteins and upregulation of p21 and p27, while overexpression of ACTL6A facilitated the entry of more cells into S phase with upregulated cyclin D1, CDK2 and S6K1/pS6 pathway proteins and downregulated p21 and p27. Finally, a xenograft mouse model of ESCC cells validated the results in vitro. CONCLUSION: ACTL6A expression may affect the proliferation and DNA synthesis of ESCC cells by facilitating ESCC cell cycle redistribution via the S6K1/pS6 pathway. Therefore, ACTL6A may potentially become an alternative therapeutic target for ESCC.

Dimethyl 3,3'-[(4-nitro-phen-yl)methyl-ene]bis-(1H-indole-2-carboxyl-ate) ethanol hemisolvate.

There are two main molecules in asymmetric unit of the title compound, C27H21N3O6·0.5C2H5OH. In both, the indole ring systems are approximately perpendicular to each other, at dihedral angles of 69.3 (5) and 82.8(4)°. In the crystal, mol-ecules are linked by N-H⋯O and O-H⋯O hydrogen bonds into a three-dimensional supra-molecular architecture. The solvent ethanol mol-ecule acts as a donor, forming an O-H⋯O hydrogen bond, reinforcing the structure.

Vitamin C supplementation enhances compact morulae formation but reduces the hatching blastocyst rate of bovine somatic cell nuclear transfer embryos.

Vitamin C, an antioxidant that reduces reactive oxygen species (ROS) in cells, is capable of significantly improving the developmental competence of porcine and mouse somatic cell nuclear transfer (SCNT) embryos, both in vitro and in vivo. In the present study, the effects of vitamin C on the developmental competence of bovine SCNT embryos were investigated. The results indicated that vitamin C (40 µg/mL) positively affected the scavenging of intracellular ROS, cleavage rate at 24 h (76.67 vs. 68.26%, p<0.05), compact morulae formation (60.83 vs. 51.30%, p<0.05), and the blastomere apoptosis index (3.70 ± 1.41 vs. 4.43% ± 1.65, p<0.05) of bovine SCNT embryos. However, vitamin C supplementation did not significantly affect the blastocyst formation rate and proportion of inner cell mass over total cells per blastocyst on day 7. Moreover, vitamin C supplementation obviously impaired the total cell numbers per blastocyst (97.20 ± 11.35 vs. 88.57 ± 10.43, p<0.05) on day 7 and the hatching blastocysts formation rate on day 9 (26.51 vs. 50.65%, p<0.05) compared with that of the untreated group. Vitamin C supplementation preferentially improved the viability of bovine SCNT embryos prior to the blastocyst stage, but did not enhance the formation and quality of blastocysts in vitro. In conclusion, the effect of vitamin C on the development of bovine SCNT embryos is complex, and vitamin C is not a suitable antioxidant chemical for the in vitro culture of bovine SCNT embryos.