Background: Tumor-associated macrophages (TAMs) are prevalent in advanced ovarian cancer tissues and ascites, significantly influencing disease prognosis. However, the mechanisms driving TAM polarization and their tumor-promoting effects remain poorly understood. Methods: The subcellular distribution of SNX10 in ovarian cancer tissues was analyzed using single-cell datasets (GSE147082, GSE58937). The Kaplan–Meier Plotter and GEPIA2 databases were used to evaluate SNX10’s prognostic relevance. Lentivirus-mediated SNX10 overexpression in THP-1 cells was employed in tumor cell–macrophage co-culture experiments. Transwell assays and flow cytometry assessed SNX10’s effects on ovarian cancer cell metastasis and cisplatin-induced apoptosis. RNA sequencing, Western blotting, lysosomal pH detection, lipid droplet staining, and RT-qPCR were performed to explore SNX10’s molecular mechanisms in TAM polarization and immune modulation. Results: SNX10 was specifically expressed in TAMs, promoting their polarization into the M2 phenotype. This enhanced the migration and invasion of ovarian cancer cell lines A2780 and A2780/CP70 while reducing cisplatin-induced apoptosis. SNX10 decreased lipid droplet content, downregulated p-mTOR1, and impaired lysosomal function in TAMs. Additionally, SNX10 differentially modulated PD-L1 mRNA expression in platinum-sensitive and platinum-resistant ovarian cancer cells. Conclusions: SNX10 regulates the mTOR1/lysosome pathway in TAMs, influencing lipid metabolism and indirectly modulating ovarian cancer cell metastasis. It also alters PD-L1 mRNA expression, suggesting a role in shaping the tumor immune microenvironment.

BACKGROUND:Depression and anxiety are common among asthmatic patients and are associated with asthma control. However, there is limited research on the nationwide prevalence of mental disorders and the association of depression/anxiety with asthma outcomes, remission and allergic comorbidities. OBJECTIVE:Our study aimed to evaluate the effect of depression/anxiety on asthma outcomes and allergic comorbidities. METHODS:This study used data from 231,460 adults (19,195 current asthma, 11,972 ever asthma, 200,293 never asthma) participated in the National Health Interview Survey 2010-2022. Depression/anxiety were identified based on self-reported frequency and intensity of mental symptoms. Multivariable logistic regressions and trend tests were employed. RESULTS:Compared with never asthma group, the morbidities of depression/anxiety among participants with current asthma (13.82 % with depression, 25.43 % with anxiety) and ever asthma (8.44 % with depression, 19.12 % with anxiety) were much higher. Depression and anxiety were associated with increased asthma risk (depression: OR 1.34, 95%CI 1.25-1.44; anxiety: OR 1.45, 95%CI 1.38-1.52) and reduced likelihood of asthma remission (depression: OR 1.19, 95%CI 1.04-1.35; anxiety: OR 1.17, 95%CI 1.06-1.28). Patients with depression/anxiety experienced more exacerbations (depression: OR 1.31, 95%CI 1.15-1.50; anxiety: OR 1.30, 95%CI 1.17-1.44), and more comorbid allergic diseases (depression: 1.15 vs 0.99, p = 0.018; anxiety: 1.20 vs 0.95, p < 0.001), including respiratory, skin and food allergy, compared to those without depression/anxiety. CONCLUSION:Depression and anxiety were associated with an increased risk of asthma, poorer symptoms control and a reduced likelihood of clinical remission. Asthmatic patients experiencing psychological distress were also at an elevated risk of developing comorbid allergic conditions.

PURPOSE:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal cancer lacking effective treatment. Its genomic mutations and tumor microenvironment need further exploration. METHODS:We performed whole-exome sequencing or gene panel test to explore the SMARCA4 mutation spectrum in SCCOHT (15 samples). Single-cell RNA sequencing was conducted on one primary lesion with matched normal ovarian tissue and one recurrent lesion to investigate the intra-tumoral heterogeneity and immune microenvironment. Multiplex immunofluorescence staining validated T cell infiltration and PD-1 expression. RESULTS:13/15 (86.7%) patients harbored SMARCA4 mutations. The loss of heterozygosity (LOH) occurred in 10/15 (66.7%) patients. Cancer cells and immune cells were observed in SCCOHT tumors. Cancer cells were further divided into seven subtypes and one from recurrent lesion exhibited the highest stemness accompanied by high expression of genes related to cell mitosis (AURKB, CHEK2, CCNB1, WEE1), DNA repair (BRCA1, RAD51) and epigenetic (EZH2, DNMT1). Immune cells mainly included macrophages and T cells. Lipid-associated tumor-associated macrophages (TAMs) was mainly in primary lesion while inflammatory cytokine-enriched TAMs in recurrent lesion. CD4+/ CD8+ T cell infiltration was observed in SCCOHT tumor and a certain proportion of T cells expressed PD-1. CONCLUSIONS:SCCOHT exhibits universal SMARCA4 LOH and significant intra-tumoral heterogeneity, suggesting potential therapeutic targets, including CHEK2, CCNB1, and WEE1. Exhausted T cells and distinct TAM subsets infiltrate tumors. Targeting macrophage polarization or cytokine signaling may also be promising. These findings provide insights for developing novel therapies to improve outcomes in SCCOHT. CLINICAL TRIAL NUMBER:Not applicable.

Background: N6-methyladenosine (m6A) modification plays a crucial role in the regulation of diverse cellular processes influenced by environmental factors. Nevertheless, the involvement of m6A-modified long noncoding RNAs (lncRNAs) in the pathogenesis of lung injury induced by particulate matter (PM) remains largely unexplored. Methods: Here, we establish a mouse model of PM-induced lung injury. We utilized m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq) to identify differentially expressed m6A peaks on long non-coding RNAs (lncRNAs). Concurrently, we performed lncRNA sequencing (lncRNA-seq) to determine the differentially expressed lncRNAs. The candidate m6A-modified lncRNAs in the lung tissues of mice were identified through the intersection of the data obtained from these two sequencing approaches. Results: A total of 664 hypermethylated m6A peaks on 644 lncRNAs and 367 hypomethylated m6A peaks on 358 lncRNAs are confirmed. We use bioinformatic tools to analyze the potential functions and pathways of these m6A-modified lncRNAs, revealing their involvement in regulating inflammation, immune response, and metabolism-related pathways. Three key m6A-modified lncRNAs (lncRNA NR_003508, lncRNA uc008scb.1, and lncRNA ENSMUST00000159072) are identified through a joint analysis of the MeRIP-seq and lncRNA-seq data, and their validation is carried out using MeRIP-PCR and qRT-PCR. Analysis of the coding-non-coding gene co-expression network reveals that m6A-modified lncRNAs NR_003508 and uc008scb.1 participate in regulating pathways associated with inflammation and immune response. Conclusions: This study first provides a comprehensive transcriptome-wide analysis of m6A methylation profiling in lncRNAs associated with PM-induced lung injury and identifies three pivotal candidate m6A-modified lncRNAs. These findings shed light on a novel regulatory mechanism underlying PM-induced lung injury.

Background: Bronchial provocation test (BPT) plays a crucial role in diagnosing airway hyper-responsiveness (AHR) among patients with asthma-like symptoms. Given that BPT may induce severe bronchospasm, baseline spirometric parameters are expected to help predict a positive outcome, guiding the decision of referring a patient to BPT. Methods: Baseline spirometry and BPT conducted on suspected asthmatics between July 2011 and 2013 at Department of Pulmonary Medicine, Zhongshan Hospital, were retrospectively collected. Baseline characteristics from positive and negative BPT groups were compared. The predictive accuracy of single parameter for AHR was evaluated by plotting receiver operating characteristic curve, and a composite model was developed to improve the accuracy by the logistic regression. The relationships of FEV1/FVC, FEV1 %predicted, and forced expiratory flow at 50% of FVC exhaled (FEF50 %predicted) with the provocation dose causing a 20% fall in FEV1 (PD20-FEV1) were examined. Results: The positive BPT group exhibited reduced FEV1 %predicted, FEV1/FVC, and small airway function parameters compared with the negative group. Among these parameters, FEF50 %predicted, forced expiratory flow at 75% of FVC exhaled (FEF75 %predicted), and forced expiratory flow between 25% and 75% (FEF25-75 %predicted) demonstrated significant accuracy. Notably, females and younger subjects were more prone to a positive outcome. A predictive model that combined FEV1 %predicted (cutoff 98.65%, area under the curve 0.714, sensitivity 39.10%, specificity 88.10%), FEV1/FVC (cutoff 79.22%, area under the curve 0.690, sensitivity 32.80%, specificity 90.50%), and FEF50 %predicted (cutoff 74.45%, area under the curve 0.761, sensitivity 50.50%, specificity 84.60%) with age and gender was found to enhance the accuracy for a positive BPT (area under the curve 0.786, 95% CI 0.758-0.814, sensitivity 52.27%, specificity 86.14%). Moreover, FEV1/FVC, FEF50 %predicted, and FEF25-75 %predicted showed differences among groups with varying AHR levels. The significant correlations between these 3 parameters and PD20-FEV1 were exclusively demonstrated in the severe AHR group. Conclusions: This study revealed that FEV1 %predicted, FEV1/FVC, and FEF50 %predicted along with age and gender were predictors of AHR in subjects with suspected asthma. Their combination improved the predictive accuracy over using FEF50 %predicted alone, thus offering a complement for clinical decision-making regarding referrals to BPT.

Background Lymphangioleiomyomatosis (LAM) is a rare disease which is easily misdiagnosed. Vascular endothelial growth factor D (VEGF-D), as the most common biomarker, however, is not so perfect for the diagnosis and severity assessment of LAM. Materials and methods The isobaric tags for relative and absolute quantitation (iTRAQ)-based method was used to identify a cytoskeleton protein, moesin. 84 patients with LAM, 44 patients with other cystic lung diseases (OCLDs), and 37 healthy control subjects were recruited for collecting blood samples and clinical data. The levels of moesin in serum were evaluated by ELISA. The relationships of moesin with lymphatic involvement, lung function, and treatment decision were explored in patients with LAM. Results The candidate protein moesin was identified by the proteomics-based bioinformatic analysis. The serum levels of moesin were higher in patients with LAM [219.0 (118.7–260.5) pg/mL] than in patients with OCLDs (125.8 ± 59.9 pg/mL, P < 0.0001) and healthy women [49.6 (35.5–78.9) ng/mL, P < 0.0001]. Moesin had an area under the receiver operator characteristic curve (AUC) of 0.929 for predicting LAM diagnosis compared to healthy women (sensitivity 81.0%, specificity 94.6%). The combination of moesin and VEGF-D made a better prediction in differentiating LAM from OCLDs than moesin or VEGF-D alone. Moreover, elevated levels of moesin were related to lymphatic involvement in patients with LAM. Moesin was found negatively correlated with FEV 1 %pred, FEV 1 /FVC, and DLCO%pred ( P = 0.0181, r = − 0.3398; P = 0.0067, r = − 0.3863; P = 0.0010, r = − 0.4744). A composite score combining moesin and VEGF-D improved prediction for sirolimus treatment, compared with each biomarker alone. Conclusion Higher levels of moesin in serum may indicate impaired lung function and lymphatic involvement in patients with LAM, suggest a more serious condition, and provide clinical guidance for sirolimus treatment.

Introduction: Poly (ADP-ribose) polymerase (PARP) inhibitor has been widely used in ovarian cancer patients carrying BRCA mutations. However, resistance to PARP inhibitor is present in some patients, and no effective treatment is available for these patients. TH-302 is a hypoxia-activated prodrug, which releases the bis-DNA alkylator bromo-isophosphoramide mustard (Br-IPM) under hypoxic condition. The present study aims to determine whether TH-302 is effective in treating PARP inhibitor resistance.Methods: The in vitro cytotoxicity of TH-302 was assessed by short-term proliferation assay (50% inhibitory concentration, IC50) or long-term clonogenic assay (90% inhibitory concentration, IC90) under various oxygen concentrations. In vivo efficacy of TH-302 was assessed in PARP inhibitor resistance, partially responsive and sensitive patient-derived xenograft (PDX) or cell line-derived xenograft (CDX) models. Antitumor activity via homologous recombination (HR) pathway for TH-302 was evaluated using DLD1 BRCA2 knockout cell line and BRCA/RAD51D deleterious mutant PDX/CDX models. Breaks of double-strand DNA and hypoxia fraction in tumors were determined by gamma histone 2AX (gamma H2AX) and pimonidazole immunohistochemistry in H460 CDX model following treatment.Results: Cytotoxicity was significantly enhanced under hypoxia in 12 human cancer cell lines including four ovarian cancer cell lines. The cytotoxicity was 70 times higher in human colon cancer cell line with BRCA2 knock out compared to wild type under hypoxia following TH-302 treatment. gamma H2AX staining revealed that the cytotoxicity of TH-302 was associated with DNA damage. In addition, administration of TH-302 with olaparib led to better antitumor activities than either single drug/prodrug in olaparib-resistant PDX models.Conclusion: TH-302 exhibits hypoxia-dependent cytotoxicity across a wide range of human cancer cell lines, and may be a drug candidate to treat ovarian cancer, bladder cancer, and pancreatic cancer with HR deficiencies with or without resistance to PARP inhibitor. TH-302 may be effective in recurrent epithelial ovarian cancer (EOC) with homologous recombination deficiency (HRD) or in EOC patients resistant to PARP inhibitors.

RAD51D mutations have been implicated in the transformation of normal fallopian tube epithelial (FTE) cells into high-grade serous ovarian cancer (HGSOC), one of the most prevalent and aggressive gynecologic malignancies. Currently, no suitable model exists to elucidate the role of RAD51D in disease initiation and progression. Here, we established organoids from primary human FTE and introduced TP53 as well as RAD51D knockdown to enable the exploration of their mutational impact on FTE lesion generation. We observed that TP53 deletion rescued the adverse effects of RAD51D deletion on the proliferation, stemness, senescence, and apoptosis of FTE organoids. RAD51D deletion impaired the homologous recombination (HR) function and induced G2/M phase arrest, whereas concurrent TP53 deletion mitigated G0/G1 phase arrest and boosted DNA replication when combined with RAD51D mutation. The co-deletion of TP53 and RAD51D downregulated cilia assembly, development, and motility, but upregulated multiple HGSOC-associated pathways, including the IL-17 signaling pathway. IL-17A treatment significantly improved cell viability. TP53 and RAD51D co-deleted organoids exhibited heightened sensitivity to platinum, poly-ADP ribose polymerase inhibitors (PARPi), and cell cycle-related medication. In summary, our research highlighted the use of FTE organoids with RAD51D mutations as an invaluable in vitro platform for the early detection of carcinogenesis, mechanistic exploration, and drug screening.

Oxidative stress and endoplasmic reticulum stress (ERS) was associated with the development of asthma. Edaravone (EDA) plays a classical role to prevent the occurrence and development of oxidative stress-related diseases. Herein, we investigated the involvement and signaling pathway of EDA in asthma, with particular emphasis on its impact on type 2 innate lymphoid cells (ILC2) and CD4+T cells, and then further elucidated whether EDA could inhibit house dust mite (HDM)-induced allergic asthma by affecting oxidative stress and ERS. Mice received intraperitoneally injection of EDA (10 mg/kg, 30 mg/kg), dexamethasone (DEX) and N-acetylcysteine (NAC), with the latter two used as positive control drugs. DEX and high dose of EDA showed better therapeutic effects in alleviating airway inflammation and mucus secretion in mice, along with decreasing eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF) than NAC. Further, the protein levels of IL-33 in lung tissues were inhibited by EDA, leading to reduced activation of ILC2s in the lung. EDA treatment alleviated the activation of CD4+ T cells in lung tissues of HDM-induced asthmatic mice and reduced Th2 cytokine secretion in BALF. ERS-related markers (p-eIF2 alpha, IRE1 alpha, CHOP, GRP78) were decreased after treatment of EDA compared to HDM group. Malondialdehyde (MDA), glutathione (GSH), hydrogen peroxide (H2O2), and superoxide dismutase (SOD) were detected to evaluate the oxidant stress in lung tissues. EDA showed a protective effect against oxidant stress. In conclusion, our findings demonstrated that EDA could suppress allergic airway inflammation by inhibiting oxidative stress and ERS, suggesting to serve as an adjunct medication for asthma in the future.

AbstractBackgroundParkinson's disease (PD) and cholelithiasis are a huge public health burden. Although observational studies have suggested a potential link between PD and cholelithiasis, the causal relationship between the two remains uncertain. To address this gap, we performed a two‐sample bidirectional Mendelian randomization analysis using genetic tools.MethodGenome‐wide association study summary statistics for all traits were obtained from publicly available databases. We used strict control steps in instrumental variable selection to screen for single nucleotide polymorphisms (SNPs) from summary‐level genome‐wide association studies. In addition, all F‐statistics were >10, indicating no weak instrumental bias. The inverse variance weighting (IVW) method was the primary method used to assess causal associations. Four other MR methods (MR‐Egger, Weighted Median, Simple mode, and Weighted mode) were also used to complement IVW. Various sensitivity tests were also performed to assess reliability: (1) Cochrane's Q test for assessing heterogeneity, (2) MR‐Egger intercept test and MR‐PRESSO global test for assessing horizontal multiplicity, and (3) leave‐one‐out sensitivity test for determining stability.ResultsWe selected a total of 30 SNPs as instrumental variables. It was demonstrated that cholelithiasis had a causal effect on the risk of PD (OR = 1.146, 95% CI: 1.062–1.236, p < 0.001) in IVW method.ConclusionThe results of our analysis revealed an increased risk effect of cholelithiasis against PD, which may give light on new approaches to PD prevention and therapy.

Background: The effect of fibroblast growth factor 10 (Fgf10) against allergic asthma has remained unclear, despite its importance in lung development and homeostasis maintenance. The purpose of this study was to investigate the protective effect and potential mechanism of Fgf10 on asthma.Method: House Dust Mite (HDM)-induced asthma mice were administered recombinant Fgf10 intranasally during activation. Flow cytometry and ELISA were performed to determine type of inflammatory cells and type 2 cytokines levels in bronchoalveolar lavage fluid (BALF). Hematoxylin and eosin (H&E) and periodic acid -Schiff (PAS) staining of lung sections were conducted to evaluate histopathological assessment. Transcriptome profiling was analyzed using RNA-seq, followed by bioinformatics and network analyses to investigate the potential mechanisms of Fgf10 in asthma. RT-qPCR was also used to search for and validate differentially expressed genes in human Peripheral Blood Mononuclear Cells (PBMCs).Results: Exogenous administration of Fgf10 alleviated HDM-induced inflammation and mucus secretion in lung tissues of mice. Fgf10 also significantly inhibited the accumulation of eosinophils and type 2 cytokines (IL-4, IL-5, and IL-13) in BALF. The PI3K/AKT/NF-kappa B pathway may mediate the suppressive impact of Fgf10 on the asthma inflammation. Through RNA-seq analysis, the intersection of 71 differentially expressed genes (DEGs) was found between HDM challenge and Fgf10 treatment. GO and KEGG enrichment analyses indicated a strong correlation between the DEGs and different immune response. Immune infiltration analysis predicted the differential infiltration of five types of immune cells, such as NK cells, dendritic cells, monocytes and M1 macrophages. PPI analysis determined hub genes such as Irf7, Rsad2, Isg15 and Rtp4. Interestingly, above genes were consistently altered in human PBMCs in asthmatic patients.Conclusion: Asthma airway inflammation could be attenuated by Fgf10 in this study, suggesting that it could be a potential therapeutic target.

Studies have shown that the occurrence and development of endometriosis are closely linked to long-term psychological stress. The specific contribution of chronic stress to the metabolic adaptations in patients with endometriosis is still unknown. Lesions were removed from ten endometriosis patients during an operation, and the participants were divided into two groups using a psychological questionnaire. An mRNA Human Gene Expression Microarray analysis was applied to compare the mRNA expression profiles between the chronic stress group and the control group. In addition, the reliability of the mRNA Human Gene Expression Microarray analysis was verified by using research on metabolites based on both the liquid chromatography (LC-MS/MS) technique and quantitative reverse transcription polymerase chain reaction (RT–PCR). A microarray analysis of significantly up-regulated, differentially expressed genes between the chronic stress and the control groups showed genes that were principally related to metabolism-related processes and immune-related processes, such as the immune response process, negative regulation of T cell proliferation, the leucine metabolic process, and the L-cysteine metabolic process (p < 0.05). LC-MS showed that the differential metabolites were primarily concerned with arginine and proline metabolism, D-glutamine and D-glutamate metabolism, aspartate metabolism, glycine, serine metabolism, and tyrosine metabolism (p < 0.05). The possibility of chronic stress blocks the endometriosis immune response through metabolic reprogramming. Chronic stress reduces the supply of energy substrates such as arginine and serine, down-regulates T immune cell activation, and affects the anti-tumor immune response, thereby promoting the migration and invasion of endometriosis lesions in patients with chronic stress.

BackgroundThe occurrence of chronic inflammation resulting from infection with human papillomaviruses is an important factor in the development of cervical cancer (CC); thus, deciphering the crosstalk between the tumor microenvironment and innate immune cells during the establishment of immune tolerance is vital for identifying potential treatment strategies.MethodsSingle-cell RNA sequencing data and primary tumor samples from patients with CC were used to evaluate the functional role of Siglec-10 on dendritic cells (DCs). Patient-derived tumor fragment platforms were used to examine the ability of Siglec-10 blockade to reinvigorate DC-mediate T-cell activation and tumor clearance.ResultsHere, we demonstrated that Siglec-10 is a prominent inhibitory checkpoint for DCs infiltrated in CC. CC epithelial cells use their aberrant surface sialylated structures to induce the transformation of conventional DCs into phenotypes characterized by low immunogenicity and high immunotolerance. Additionally, Siglec-10+DCs suppress the function of adaptive T cells via galectin-9 signaling to strengthen the immunosuppressive CC microenvironment. Disturbance of Siglec-10 signaling restored the DC-mediated tumoricidal response and increased adaptive T cells sensitivity to programmed cell death protein 1 inhibition.ConclusionOur study confirms the checkpoint role of Siglec-10 on DCs and proposes that targeting Siglec-10 may be a promising avenue for immunotherapy against CC.

BackgroundPinellia 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.PurposeTo explore PE's ability and mechanism to reconstruct cisplatin's immunogenicity.MethodsCervical 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.ResultsPE 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.ConclusionsThis 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.

BackgroundOspemifene 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).MethodsThe 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.ResultsThere 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.ConclusionWe 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.

Ovarian cancer is the leading cause of gynecologic cancer-related death, and PARP inhibitors (PARPis) are becoming a promising treatment option, as demonstrated by recent clinical trials. After PARPi exposure, somatic reversion mutations in the homologous recombination genes may be a mechanism of PARPi resistance in ovarian carcinoma. We present an ovarian cancer case of a 61-year-old woman, who underwent routine tumor reduction surgery followed by platinum and PARPis. She demonstrated a good response to PARPis for 15 months before recurrence and secondary tumor reduction surgery. However, post-surgery platinum and PARPi treatment only kept the disease stable for 5 months. A potential molecular mechanism for PARPi resistance was investigated using next-generation sequencing, immunohistochemical (IHC) staining, and other functional assays. A germline RAD51D loss-of-function mutation was found in the reported case (LRG_516t1:c.270_271dup p1:p.(Lys91fs*13)). Subsequently, a secondary mutation (LRG_516t1:c.271_282 del) was identified in the same locus of the germline duplication in the post-progression biopsies and ctDNA. The IHC staining supported low expression of RAD51D in the initial tumor tissue, but the expression was restored after the correction of the open reading frame by the secondary mutation. The in vitro results supported that the loss-of-function mutation of RAD51D was the basis for the initial response to the platinum and PARPi therapy, while the newly acquired reversion mutation could be attributed to the observed PARPi resistance. An acquired mutation can reverse a loss-of-function change in RAD51D and can result in PARPi resistance in a hereditary ovarian cancer patient. Liquid biopsy could be considered for longitudinal monitoring in ovarian patients under PARPi-based therapy, which can identify acquired resistant mutations earlier and facilitate precision management.

Ovarian cancer is a major cause of death among all gynaecological cancers. Although surgery, chemotherapy and targeted therapy have yielded successful outcomes, the 5-year survival rate remains < 30%. Adoptive immunotherapy, particularly chimeric antigen receptor (CAR) T-cell therapy, has demonstrated improved survival in acute lymphoblastic leukaemia with manageable toxicity. We explored CAR T-cell therapy in a preclinical mouse model of ovarian cancer. Second-generation CAR T cells were developed targeting mesothelin (MSLN), which is abundantly expressed in ovarian cancer. Cytotoxicity experiments were performed to verify the lethality of CAR T cells on target cells via flow cytometry. The in vivo antitumour activity of MSLN CAR T cells was also verified using a patient-derived xenograft (PDX) mouse model with human tumour-derived cells. We also evaluated the potency of CAR T cells directed to MSLN following co-expression of a dominant-negative transforming growth factor- β receptor type II (dnTGF β RII). Our data demonstrate that anti-MSLN CAR T cells specifically eliminate MSLN-expressing target cells in an MSLN density-dependent manner. This preclinical research promises an effective treatment strategy to improve outcomes for ovarian cancer, with the potential for prolonging survival while minimizing risk of on-target off-tumour toxicity.

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-1β) 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-1β 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.

Background Although the use of PARP inhibitor has received considerable amount of attention in ovarian cancer, PARP inhibitor resistance still emerges with disease progression. PI3K/AKT pathway inhibitors have been proposed to synergize with PARP inhibition to slow tumor growth, but the exact molecular mechanisms are still elusive. Methods Utilizing tumor samples from recurrent EOC patients with platinum resistance and prior PARP inhibitor use, Mini PDX and PDX models were established to study the anti-tumor effect of AKT inhibitor (LAE003) and LAE003/PARP inhibitor (Olaparib) in combination. Five ovarian cancer cell lines were treated with Olaparib or LAE003 or in combination in vitro. Cell viability and apoptosis rate were measured after the treatments. Combination index by the Chou-Talalay was used to evaluate in vitro combination effect of Olaparib and LAE003. The protein expression level of PARP1 and PAR was measured by Western blot in cell lines and by immunohistochemistry in PDX tumor tissues. Results Tumor cells from two out of five platinum-resistant ovarian cancer patients previously treated with PARP inhibitor were sensitive to AKT inhibition in Mini-PDX study. Inhibition of AKT further increased the response of tumor cells to Olaparib in a PDX model derived from a recurrent platinum-resistant ovarian cancer patient. Additive anti-proliferation effect of LAE003 and Olaparib was also observed in three ovarian cancer cell lines with high PARP1 protein level. Interestingly, mechanism study revealed that AKT inhibition decreased PARP enzyme activity as measured by PAR level and/or reduced PARP1 protein level in the tumor cell lines and PDX tumor tissues, which may explain the observed combined anti-tumor effect of LAE003 and Olaparib. Conclusion Collectively, our results suggest that the combination of AKT inhibitor and PARP inhibitor could be a viable approach for clinical testing in recurrent ovarian cancer patients.