Combining cisplatin with Pinellia pedatisecta Schott lipid-soluble extract induces tumor immunogenic cell death in cervical cancer.

BACKGROUND: Pinellia pedatisecta Schott extract (PE) is extracted from Pinellia pedatisecta Schott (PPS), a traditional Chinese medicinal plant with the potential for direct anticancer effects or eliciting an anti-tumor response by activating the immune system. PURPOSE: To explore PE's ability and mechanism to reconstruct cisplatin's immunogenicity. METHODS: Cervical cancer cells were treated with cisplatin (CDDP) and/or PE. The exposure of calreticulin (CRT) on cell membrane was investigated by flow cytometry. The extracellular of ATP and HMGB1 was investigated by Western blot analysis, immunofluorescence and ELISA assay. Changes in immune profiles were using flow cytometry in vaccination and anti-tumor assays in vivo. Lastly, the mechanism of PE influenced the ROS/ERS pathway was examined by ROS assay kit, flow cytometry and Western blotting. RESULTS: PE treatment induced translocation of CRT from the endoplasmic reticulum to the cell membrane of tumor cells, concomitantly triggering immunogenic cell death (ICD). In terms of mechanisms, endoplasmic reticulum (ER) stress relievers could impede the ability of PE to induce immunogenicity. This indicates that PE is activated by ER stress, leading to subsequent induction of ICD. Upon analyzing RNA-seq data, it was observed that PE primarily induces programmed cell death in tumors by impeding upstream antioxidant mechanisms. Additionally, it transforms dying tumor cells into vaccines, activating a series of immune responses. CONCLUSIONS: This study observed for the first time that PE-induced CRT exposure on the membrane of cervical cancer cells compensates for the defect of nonimmunogenic cell death inducer CDDP thereby stimulating potent ICD. This ability restores the immunogenicity of CDDP through ER stress induced by the ROS signal. ROS played a role in PE's ability to induce ICD, leading to increased expression of ER stress-related proteins, including ATF3 and IRE-1α. PE exerted anti-cancer effects by increasing the ROS levels, and ROS/ERS signaling may be a potential avenue for cervical cancer treatment. Hence, the synergistic use of PE and CDDP holds potential for enhancing immunochemotherapy in cancer treatment.

A real-world disproportionality analysis of ospemifene: data mining of the public version of FDA adverse event reporting system.

BACKGROUND: Ospemifene has been authorized for the treatment of vulvovaginal atrophy (VVA). This study wasto evaluate adverse events (AEs) associated with ospemifene by data mining the US Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: The signals of AEs linked to ospemifene were measured using disproportionality analyses, such as the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms. RESULTS: There were 2283 events of ospemifene being the 'primary suspected (PS)' AE out of the 12,692,824 reports from the FAERS database. Ospemifene-induced AEs hit 25 organ systems. There were 726 severely disproportional preferred terms (PTs) that complied with the four algorithms. The investigation turned up a number of anticipated adverse drug reactions (ADRs), and significant unanticipated ADRs linked to eye and renal problems were found, indicating potential side effects not yet included in the prescription instructions. CONCLUSION: We detected novel AEs signals for ospemifene, and the results of our investigation were compatible with clinical observations. This suggests that further prospective clinical trials are required to confirm these findings and demonstrate their link. Our findings might be useful supporting data for ospemifene safety research in the future.

Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer.

BACKGROUND: Novel therapies are needed to treat recurrent and advanced cervical cancer (CC), as their prognosis remains very poor. Although therapies targeting the programmed cell death protein 1 (PD-1) pathway have been approved for CC, a large subset of patients exhibit innate resistance. Using checkpoint inhibitors in combination could enhance their efficacy. METHODS: Blood samples, tumor specimens, and peritumorous (PT) tissues were obtained from patients with CC. The inhibitory receptor expression and phenotypical analysis of CD8+ T cells in CC specimens were analyzed by flow cytometry. The ligands of CD96 expressed by tumor cells were measured by immunohistochemistry and immunofluorescence. Sensitivity to pembrolizumab was evaluated by an ex vivo treatment assay based on the single-cell culture of CC specimens. The efficacies of PD-1 and/or CD96 blockades were explored using an ex vivo treatment assay and an human papillomavirus-positive TC-1 xenograft mouse model in vivo. RESULTS: We found that CD96 expression was elevated on CD8+ tumor-infiltrating lymphocytes (TILs) from patients with CC who were insensitive to the PD-1 blockade. These CD96-expressing CD8+ TILs often coexpressed PD-1. The ratio of the CD96+CD8+/CD96-CD8+ T-cell gene signature from the scRNA-seq data was significantly associated with the poor survival of patients with cervical squamous cell carcinoma and endocervical adenocarcinoma. The costimulatory receptor CD226, which competes with CD96, was downregulated in tumors compared with blood and PT tissue. CD96 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) were upregulated on intratumoral CD8+ T cells. The CD226/CD96/TIGIT signaling ligands were widely expressed in CC tumor tissues. Phenotypical profiling showed that PD-1+CD96+CD8+ TILs exhibited a terminally exhausted effector phenotype with high levels of T-cell immunoglobulin mucin receptor 3 (TIM-3) and granzyme B (GZMB) and extremely low levels of proinflammatory cytokines and cytotoxic molecules. PD-1+CD96 cells exhibited a precursor exhausted phenotype with TCF-1 positivity. CD96 was further upregulated by CD8+ TILs on PD-1 blockade. Treatment with the CD96 blockade significantly enhanced the PD-1 blockade to blunt tumor growth and improve the function of CD8+ TILs in both mouse and CC specimen models. CONCLUSIONS: Our findings showed that CD96 and PD-1 cooperatively and negatively regulate the function of CD8+ TILs, and CD96 blockade has promise for use in combination with PD-1 blockade for the treatment of CC.

Accumulation of dysfunctional tumor-infiltrating PD-1+ DCs links PD-1/PD-L1 blockade immunotherapeutic response in cervical cancer.

Various predictive biomarkers are needed to select candidates for optimal and individualized treatments. Tumor-infiltrating immune cells have gained increasing interest in cancer research for the prediction of therapeutic response and survival. However, the role of dendritic cells (DCs) in PD-1 blockade immunotherapy remains unclear. In this study, we identified a population of PD-1+ DCs in the tumor microenvironment (TME) of cervical cancer (CC). The accumulation of PD-1+ DCs in cervical tumors was correlated with advanced stages, elevated preoperative squamous cell carcinoma antigen levels and lymph-vascular space invasion. PD-1 expression was induced on activated tumor-associated DCs (TADCs) in vitro compared with their resting counterparts. This PD-1+ DC population was characterized by reduced secretion of cytokines (IL-12, TNF-α, and IL-1ß) and dysfunctional induction of T cell proliferation and cytotoxic reaction. PD-1 blockade significantly reinvigorated PD-1+ DCs to release IL-12, TNF-α, and IL-1ß compared with PD-1- DCs. TILs from samples with higher PD-1+ DC infiltration could be induced to achieve a greater killing effect of PD-1 blockade treatment. Our findings suggested a role for PD-1+ DCs in immune surveillance dysfunction and CC progression. PD-1+ DC density in the TME may serve as a diagnostic factor for predicting the optimal beneficiaries of PD-1/PD-L1 blockade immunotherapy in CC.

Clinical analysis of uterine intravenous leiomyomatosis: A retrospective study of 260 cases.

METHODS: We collected the clinical data of 260 patients admitted to the hospital from April 2003 to September 2019 with pathologically confirmed intravenous leiomyomatosis (IVL) and followed up with these patients regularly. Univariate and multivariate logistic regression analyses were carried out on the relevant recurrence factors. RESULTS: A total of 166 patients were regularly followed up, the median follow-up time was 36 (range 2-168) months, 14 (5.4%) patients eventually relapsed, and the median recurrence time was 8.5 (range 2-42) months. The univariate analysis showed that age (p = 0.003) and surgical type (p < 0.001) were associated with recurrence, and multivariate regression analysis demonstrated that surgical type was the only factor associated with recurrence (p < 0.001, OR 20.01). CONCLUSIONS: The use of gonadotrophin releasing hormone agonist (GnRHa) cannot reduce the postsurgical recurrence rate of patients with UIVL. Compared to total hysterectomy and bilateral salpingo-oophorectomy (TH-BSO), total hysterectomy (TH) does not increase the odds of recurrence, but the chance of recurrence with tumorectomy (TE) is 20 times higher than that of TH-BSO.

A novel ferroptosis-related gene signature for predicting outcomes in cervical cancer.

Ferroptosis, a newly discovered iron-dependent form of cell death, contributes to various pathologies; however, the prognostic value of ferroptosis-related genes (FRGs) in cervical cancer (CC) remains unclear. Herein, we identified 15 differentially expressed FRGs based on data from The Cancer Genome Atlas database. Ten FRGs that correlated with prognosis were screened by univariate Cox regression analysis. The least absolute shrinkage and selection operator regression model was performed to develop a novel prognostic signature. A four-gene model was built to separate samples into high-risk and low-risk groups. Overall survival was lower in the high-risk group than in the low-risk group (p < 0.05). Receiver operating characteristic curve showed a good diagnostic efficiency of the signature. The risk score was identified as an independent prognostic factor via multivariate Cox regression. A functional analysis further revealed a difference in the immune status between the two risk groups. To conclude, we constructed a novel prognostic signature based on FRGs. Targeting ferroptosis may represent a promising approach for the treatment of CC.

An Innovative Immune Score-Based Prognostic Nomogram for Patients with Cervical Cancer.

BACKGROUND: In the past few years, the immune system and tumor immune microenvironment are becoming increasingly popular as more work has been accomplished in this field. However, nomograms based on immune-related characteristics for prognosis prediction of cervical cancer have not been fully explored to our knowledge. We constructed a novel immune score-based nomogram to predict patients with high risk and poor prognosis. MATERIALS AND METHODS: 198 patients with cervical cancer from The Cancer Genome Atlas (TCGA) database were included in our study. Immune scores were generated with Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm, and clinic-pathological characteristics were also included for subsequent analysis. Cox proportional hazards regression models were performed for univariate and multivariate analyses to screen the significant factors, and a prognostic nomogram was built. Bootstrap resampling analysis was used for internal validation. The calibration curve and concordance index (C-index) were used to assess the predictive performance of the nomogram. RESULTS: Patients were split into three subgroups based on immune scores. We found that patients with high immune scores conferred significantly better overall survival (OS) compared with those with medium and low immune scores (hazard ratio (HR), 0.305; 95% confidence interval (CI), 0.108-0.869). A nomogram with a C-index of 0.720 had a favorable performance for predicting survival rate for clinical use by combining immune scores with other clinical features. The calibration curves at 3 and 5 years suggested a good consistency between the predicted OS and the actual OS probability. CONCLUSIONS: Our work highlights the potential clinical application significance of immune score-based nomogram in predicting the OS of cervical cancer patients.

The Alu-insertion progesterone receptor gene polymorphism is not associated with breast cancer: a meta-analysis.

BACKGROUND: The role of progesterone receptor (PGR) gene polymorphisms in breast cancer is still controversial. Here, we performed a meta-analysis to determine whether the Alu insertion is associated with an increased risk of breast cancer and, further, whether the Alu insertion contributes to the development of breast cancer. METHODS: Using database searches, we selected 10 controlled case studies that met a rigorous set of inclusion criteria; these studies included 2106 cases and 1660 controls. We generated odds ratios and 95% confidence intervals in order to determine the strength of the relationship between the Alu insertion and breast cancer incidence. We also performed additional subgroup analyses and sensitivity analyses to further clarify the relationship. RESULTS: Using a random effects model, we concluded that the Alu insertion was not associated with the risk of breast cancer under the dominant genetic model; the pooled OR was 1.025 (95% CI = 0.526-1.994, p = 0.943). When a subgroup analysis was performed according to ethnicity, we found that the Alu insertion was associated with breast cancer incidence in Indians and Indo-European mixed racial groups, but the association disappeared for patients of Caucasian or Latino decent. CONCLUSIONS: Our meta-analysis showed that the Alu-insertion progesterone receptor gene polymorphism was not associated with breast cancer. These results provide further information regarding the association between the Alu insertion in the PGR gene and the incidence of breast cancer.

No association between dopamine D3 receptor gene Ser9Gly polymorphism (rs6280) and risk of schizophrenia: an updated meta-analysis.

OBJECTIVE: Ser9Gly (rs6280) is a functional single-nucleotide polymorphism (SNP) in the dopamine receptor D3 (DRD3) gene that may be associated with schizophrenia. We performed a meta-analysis to determine whether Ser9Gly influences the risk of schizophrenia and examined the relationship between the Ser9Gly SNP and the etiology of schizophrenia. METHODS: Case-control studies were retrieved from literature databases in accordance with established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between Ser9Gly and schizophrenia. Subgroup analysis and sensitivity analysis were also performed. RESULTS: Seventy-three studies comprising 10,634 patients with schizophrenia (cases) and 11,258 controls were included in this meta-analysis. Summary results indicated no association between Ser9Gly and risk of schizophrenia. In the dominant genetic model, the pooled OR using a random effects model was 0.950 (95% CI, 0.847-1.064; P=0.374). CONCLUSION: Results of this meta-analysis suggest that the Ser9Gly SNP is not associated with schizophrenia. These data provide possible avenues for future case-control studies related to schizophrenia.

No association between the progesterone receptor gene polymorphism (+331G/a) and the risk of breast cancer: an updated meta-analysis.

BACKGROUND: Many published studies have estimated the association between the +331G/A (rs10895068) polymorphism in the progesterone receptor (PgR) gene and breast cancer risk. However, the results remain inconsistent and controversial. To address this inconsistency, we systematically interrogated the aforementioned association via a meta-analysis. METHODS: Through a literature search, we identified 13 case-control studies, including 12,453 cases and 14,056 case-free controls. The strengths of reported associations were evaluated using odds ratios (ORs) with 95% confidence intervals (95%CIs). RESULTS: An association was found between +331G/A polymorphism and +331G/A risk in the dominant model (p = 0.027). Via subgroup analysis, we found no association between +331G/A and breast cancer risk in Caucasians, Asians or mixed racial groups. CONCLUSIONS: Through meta-analysis, we were able to gain insight into previously reported associations between +331G/A polymorphism and breast cancer risk. However, further studies are still needed to provide more evidence.

Pleomorphic xanthoastrocytoma arising from the suprasellar region: A report of two cases.

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic neoplasm that usually arises in children and young adults. Typically, lesions of PXA are superficially located in the cerebral hemispheres. Herein, we report two extremely rare patients with PXA arising from suprasellar regions. One of the patients is a 29-year-old man admitted to our hospital with a history of progressive headache for 1month. The patient's brain MRI revealed a large tumor arising from the suprasellar cistern of the third ventricle. The second patient, a 52-year-old woman, presented with progressive dizziness and visual disturbance that had developed over the course of 1year. The MRI revealed a well-enhanced suprasellar solid mass measuring 1.4×1.2×1.4cm. Both patients underwent surgical removal of their tumors, and both patients showed similar microscopic structures and immunohistochemical phenotypes: the tumor cells were pleomorphic with mixtures of spindle-shaped, and multinuclear giant cells. In addition, eosinophilic granular bodies and xanthomatous cells were seen on section. Immunohistochemistry was positive for GFAP, S-100, and CD34, and was negative for IDH 1, CK, and Syn. The Ki-67 proliferation index was less than 1%. Silver impregnation revealed reticulin fibers surrounding the individual tumor cells, and small cell groups. Based on these findings, the two patients were diagnosed with PXA in the suprasellar region. To date, only five such patients have been reported in the literature. PXA should be included in the differential diagnosis for tumors arising in the sellar region.