Li Zhang

Dysregulated BARD1 Contributes to Paclitaxel Resistance in Ovarian Cancer via Up-regulating CYP2C8

Ovarian cancer remains one of the most lethal gynaecological malignancies, with paclitaxel resistance being a major therapeutic challenge that limits treatment efficacy and patient survival. We found that although the BARD1 level was not signi­ficantly altered in patients with ovarian cancer (OC), patients with higher BARD1 levels had increased survival time, suggesting that the down-regulation of BARD1 may be related to the paclitaxel sensitivity. Through examining the expression of BARD1 in tumour samples from paclitaxel responders and non-responders, we observed that the BARD1 level was significantly reduced in non-responders. CYP2C8 was up-regulated in non-responders. Also, the BARD1 level was negatively correlated with the level of CYP2C8. BARD1 over-expression in OC cells could repress the CYP2C8 expression, while knockdown of BARD1 could up-regulate CYP2C8 expression, which could be rescued by H2A-Ub. Results from gain and loss of functional experiments indicated that BARD1 functions as a tumour suppressor during paclitaxel treatment, and BARD1 down-regulation increased the IC50 of paclitaxel from 2.46 nM to 5.33 nM in SK-OV-3 cells and from 3.11 nM to 7.51 nM in CaoV-3 cells. We are the first to demonstrate that the down-regulation of BARD1 contributes to paclitaxel resistance via up-regulating CYP2C8 in patients with OC, which provides a potent target for clinical OC treatment.

Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models

The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition–activated tumor cells and matrix metallopeptidase 11 (MMP-11) + cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer.

First case report of acute generalized exanthematous pustulosis (AGEP) caused by mifepristone

A histone acetylation-based predictive model for immunotherapy response and combinatorial targeting in cervical cancer

Histone acetylation, a fundamental component of epigenetic modification, plays a pivotal role in the progression, treatment, and prognosis of numerous cancers. In this study, we systematically investigated, for the first time, the clinical value of histone acetylation (HAT) modification in the prognostic assessment of cervical cancer. Utilizing the GSE44001 and The Cancer Genome Atlas-CESC databases, a HAT-associated prognostic model comprising 7 pivotal genes was formulated through Lasso-Cox regression analysis. The integration of multiple bioinformatics algorithms (including Cibersort, ESTIMATE, ssGSEA, and TIDE) has enabled the profound delineation of immune microenvironmental characteristics among disparate risk groups. Utilizing molecular docking technology, we conducted a screening process that identified 2 potential target drugs. The prognostic model’s predictive efficacy was successfully validated in an independent cohort. The analysis has revealed that the high-risk group exhibits a pronounced immunosuppressive phenotype. The study identified 2 additional factors that contribute to the prognosis of cervical cancer: CPE and PGK1. These factors have been shown to be significantly associated with poor clinical outcomes. In addition, we have identified 2 drugs that may target CPE and PGK1, namely Z-LLNle-CHO and OSU-03-012. The discovery of these drugs has opened up a new potential pathway for overcoming resistance to immunotherapy. This study addresses a significant research gap concerning HAT in the prognostic assessment of cervical cancer. Furthermore, it offers a crucial molecular basis for clinical decisions regarding individualized therapeutic interventions.

Immune Checkpoint Inhibitor–Induced Ureteritis and Cystitis in Patients With Lung Cancer and Uterine Malignancies: A Case Series and Literature Review

Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy across various cancers but can cause immune-related adverse events (irAEs). While common irAEs such as dermatitis, pneumonitis, and colitis are well-documented, rare events like cystitis and ureteritis remain underrecognized. We report 3 cases of ICI-induced cystitis and ureteritis. The first case involves a 67-year-old female with lung cancer who developed immune-related cystitis and ureteritis after 3 cycles of pembrolizumab, with recurrence 8 months after discontinuation. Both episodes presented with hematuria, urinary frequency, and dysuria, and were responsive to corticosteroid treatment. The second case involves a 37-year-old female with cervical cancer who developed a truncal rash, hematuria, urinary frequency, and dysuria after the first cycle of cadonilimab, a PD-1/CTLA-4 bispecific antibody. Her condition worsened with rising serum creatinine levels. Imaging revealed bladder wall thickening and ureteral dilation. Partial symptom relief followed oral corticosteroids, but complete resolution was achieved with intravesical corticosteroid irrigation. The third case describes a 35-year-old female with endometrial cancer who presented with similar urinary symptoms and flank pain after 4 cycles of pembrolizumab. Rapid creatinine elevation necessitated ureteral stent placement, which failed to alleviate symptoms. After exclusion of infectious etiologies, immune-related cystitis/ureteritis was diagnosed. Symptoms resolved with intravenous corticosteroids. This report underscores the importance of early recognition and management of rare urinary irAEs to avoid unnecessary interventions and prolonged interruption of anti-tumor therapy. It also highlights intravesical methylprednisolone as a potential treatment modality that warrants further investigation.

Bone marrow stromal cells-derived microRNA-181-containing extracellular vesicles inhibit ovarian cancer cell chemoresistance by downregulating MEST via the Wnt/β-catenin signaling pathway

Cisplatin (DDP)-based strategies are the first-line treatment for cancers; however, resistance to DDP remains a major obstacle to cancer treatment. The current study set out to investigate the effects of microRNA-181c (miR-181c) on the resistance of ovarian cancer cells to DDP. Ovarian cancer-associated miRs as well as the target messenger RNAs were screened using microarray-based analysis followed by determining the expression patterns of miR-181c and mesoderm-specific transcript (MEST) in ovarian cancer tissues with RT-qPCR and Western blot analysis. Subsequently, dual-luciferase reporter gene assay was performed to confirm the targeting relation between miR-181c and MEST. Through gain- or loss-of-function experiments, the study explored the mechanism by which miR-181 regulated MEST to influence the resistance of ovarian cancer cells to DDP via the Wnt/β-catenin signaling pathway. Afterwards, extracellular vesicles (EVs) were isolated from bone marrow stromal cells (BMSCs) and co-cultured with ovarian cancer cells to further investigate the effects of overexpressed miR-181 delivered by BMSCs-derived EVs on ovarian cancer cell resistance to DDP. miR-181c was significantly downregulated, while MEST was up-regulated in ovarian cancer. miR-181c was verified to specifically bind to MEST. Overexpressed miR-181c depleted the expression of MEST to attenuate the resistance of ovarian cancer cells to DDP by inactivating the Wnt/β-catenin signaling pathway. Furthermore, the delivery of overexpressed miR-181c by BMSCs-derived EVs was found to suppress the resistance of ovarian cancer cells to DDP. These findings demonstrate that miR-181c delivered by BMSCs-derived EVs down-regulates MEST, to inactivate the Wnt/β-catenin signaling pathway, thus repressing the resistance of ovarian cancer cells to DDP.

RETRACTED: Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K/AKT/mTOR pathway

AbstractObjectivesTanshinone I (Tan‐I) is one of the vital fatsoluble monomer components, which extracted from Chinese medicinal herb Salvia miltiorrhiza Bunge. It has been shown that Tan‐I exhibited anti‐tumour activities on different types of cancers. However, the underlying mechanisms by which Tan‐Ⅰ regulates apoptosis and autophagy in ovarian cancer remain unclear. Thus, this study aimed to access the therapy effect of Tan‐Ⅰ and the underlying mechanisms.MethodsOvarian cancer cells A2780 and ID‐8 were treated with different concentrations of Tan‐Ⅰ (0, 1.2, 2.4, 4.8 and 9.6 μg/mL) for 24 hours. The cell proliferation was analysed by CCK8 assay, EdU staining and clone formation assay. Apoptosis was assessed by the TUNEL assay and flow cytometry. The protein levels of apoptosis protein (Caspase‐3), autophagy protein (Beclin1, ATG7, p62 and LC3II/LC3I) and PI3K/AKT/mTOR pathway were determined by Western blot. Autophagic vacuoles in cells were observed with LC3 dyeing using confocal fluorescent microscopy. Anti‐tumour activity of Tan‐Ⅰ was accessed by subcutaneous xeno‐transplanted tumour model of human ovarian cancer in nude mice. The Ki67, Caspase‐3 level and apoptosis level were analysed by immunohistochemistry and TUNEL staining.ResultsTan‐Ⅰ inhibited the proliferation of ovarian cancer cells A2780 and ID‐8 in a dose‐dependent manner, based on CCK8 assay, EdU staining and clone formation assay. In additional, Tan‐Ⅰ induced cancer cell apoptosis and autophagy in a dose‐dependent manner in ovarian cancer cells by TUNEL assay, flow cytometry and Western blot. Tan‐Ⅰ significantly inhibited tumour growth by inducing cell apoptosis and autophagy. Mechanistically, Tan‐Ⅰ activated apoptosis‐associated protein Caspase‐3 cleavage to promote cell apoptosis and inhibited PI3K/AKT/mTOR pathway to induce autophagy.ConclusionsThis is the first evidence that Tan‐Ⅰ induced apoptosis and promoted autophagy via the inactivation of PI3K/AKT/mTOR pathway on ovarian cancer and further inhibited tumour growth, which might be considered as effective strategy.

Efficacy and safety of endostar combined with chemoradiotherapy versus chemoradiotherapy alone in locally advanced cervical cancer: A PRISMA-compliant systematic review and meta-analysis

Background: To evaluate the role and safety of endostar in cervical cancer by comparing the efficacy and adverse reactions of endostar combined with concurrent chemoradiotherapy in patients with locally advanced cervical carcinoma. Methods: The quality of the included literature was evaluated by searching the database for the comparison of endostar combined with concurrent radiotherapy and chemotherapy in cervical cancer patients; objective response rate (ORR) and disease control rate (DCR) were used as the main outcome indicators, and statistical analysis was performed using RevMan5.3 and State15.3 software. Results: A total of 13 studies were included in this study, including 1057 patients with locally advanced cervical cancer, suggesting that endostar combined with chemoradiotherapy can significantly improve the objective response rate (ORR: odds ratio 3.88, 95% confidence interval 2.77–5.45, P < .00001) and disease control rate (DCR: odds ratio 4.43, 95% confidence interval 2.78–7.04; P < .00001), and there was no significant increase in treatment-related adverse reactions. Conclusions: In this meta-analysis, endostar combined with concurrent chemoradiotherapy significantly improved ORR and DCR in patients with locally advanced cervical cancer without increasing toxicity. However, this study only analyzed the short-term efficacy of endostar, and its influence on overall survival and progression-free survival needs to be further verified in large randomized controlled trials with long-term follow-up.

Identification and validation of a prognostic signature related to hypoxic tumor microenvironment in cervical cancer

BackgroundHypoxia is a common microenvironment condition in most malignant tumors and has been shown to be associated with adverse outcomes of cervical cancer patients. In this study, we investigated the effects of hypoxia-related genes on tumor progress to characterize the tumor hypoxic microenvironment.MethodsWe retrieved a set of hypoxia-related genes from the Molecular Signatures Database and evaluated their prognostic value for cervical cancer. A hypoxia-based prognostic signature for cervical cancer was then developed and validated using tumor samples from two independent cohorts (TCGA-CESC and CGCI-HTMCP-CC cohorts). Finally, we validated the hypoxia prediction of ccHPS score in eight human cervical cancer cell lines treated with the hypoxic and normoxic conditions, and 286 tumor samples with hypoxic category (more or less) from Gene Expression Omnibus (GEO) database with accession GSE72723.ResultsA risk signature model containing nine hypoxia-related genes was developed and validated in cervical cancer. Further analysis showed that this risk model could be an independent prognosis factor of cervical cancer, which reflects the condition of the hypoxic tumor microenvironment and its remodeling of cell metabolism and tumor immunity. Furthermore, a nomogram integrating the novel risk model and lymphovascular invasion status was developed, accurately predicting the 1-, 3- and 5-year prognosis with AUC values of 0.928, 0.916 and 0.831, respectively. These findings provided a better understanding of the hypoxic tumor microenvironment in cervical cancer and insights into potential new therapeutic strategies in improving cancer therapy.