Chen Zhang

Low‐Density Lipoprotein Contributes to Endometrial Carcinoma Cell Proliferation, Migration, and Invasion by Activating the JAK–STAT Signaling Pathway

Background. Cholesterol‐rich low‐density lipoprotein (LDL) particles have been demonstrated to regulate breast cancer cell proliferation and migration, but their biological function and relevant mechanisms in endometrial carcinoma (EC) remain unclear Methods. Serum and tissue samples were collected from EC patients (n = 50) and patients with benign endometrial hyperplasia (n = 50). Ishikawa and RL95‐2 cells were stimulated with different concentrations of LDL, followed by treatment with a JAK2 inhibitor (SD‐1029). LDL concentrations were determined by ELISA. The in vitro biological behavior of cells was examined using the CCK‐8 assay, EdU staining, and Transwell assay. The tumorigenicity of LDL in vivo was examined using a xenograft mouse model. western blotting, immunofluorescence, and immunohistochemistry studies were performed to measure related protein expression. Results. The LDL concentrations and levels of p‐JAK2 and p‐STAT3 expression were elevated in the clinical samples. Similar trends in expression were detected in EC cells after LDL stimulation. LDL treatment significantly promoted EC cell proliferation, migration, and invasion, and also upregulated p‐JAK2 and p‐STAT3 expression in a dose‐dependent manner. Moreover, SD‐1029 dramatically blocked the LDL‐mediated effects on EC cells. Intravenous injection of LDLs promoted tumor growth in the xenograft nude mice, and also increased p‐JAK2, p‐STAT3, and Ki‐67 expression, and downregulated caspase‐3 expression. Conclusions. These findings indicate that LDLs exert an oncogenic effect in EC cells by activating the JAK/STAT signaling pathway, and also suggest the JAK/STAT pathway as a possible therapeutic target for EC.

The treatment of intravascular leiomyomatosis with different clinical manifestations: Two case reports

Rationale: Intravascular/intravenous leiomyomatosis (IVL) is a rare benign smooth muscle cell tumor with malignant biological behavior. The early diagnosis of IVL is challenging, and the range of treatment options is extensive. Patient concerns: Herein, we present 2 cases of IVL that present markedly different clinical presentations. These cases underscore the importance of vigilance in the diagnosis of IVL. A further objective of this study is to demonstrate the similarities and differences in treatment modalities. Patient 1 was registered for lower abdominal discomfort and a palpable pelvic mass, with a high preoperative suspicion of IVL. Patient 2 was characterized by severe vaginal bleeding during menstruation, accompanied by a palpable uterine mass, and an initial diagnosis of uterine adenomyosis or fibroids, with suspicion of IVL. Diagnoses: Both patients’ diagnoses were confirmed as IVL by histopathology. Interventions: Removal of the uterine lesion combined with bilateral salpingo-oophorectomy was performed in the former case, whereas total hysterectomy and bilateral salpingo-oophorectomy were performed in the latter case. Both were treated postoperatively with Qiu empirical formula, a traditional Chinese medicine herbal decoction. Outcomes: No recurrence was observed in either patient. Lessons: In the 2 cases examined in this study, following initial evaluation by imaging and complete resection of the lesion by surgical treatment initially, the patients demonstrated a more favorable prognosis following the application of herbal preparations in the long-term postoperative follow-up period. Our work provides additional information for clinicians to further study and better understand specific types of leiomyosarcoma.

Mannose Enhances Immunotherapy Efficacy in Ovarian Cancer by Modulating Gut Microbial Metabolites

Abstract The gut microbiome significantly influences the effectiveness of immune checkpoint blockade therapy. However, its clinical application is hindered by the absence of cost-effective production methods. In this study, we demonstrated that oral mannose supplementation inhibits ovarian tumor growth in immunocompetent mice through the enrichment of Faecalibaculum rodentium (F. rodentium). Administration of F. rodentium not only suppressed tumor progression but also enhanced antitumor immune responses. Mannose supplementation fostered an immune stimulatory tumor microenvironment, characterized by the expansion and differentiation of progenitor-exhausted CD8+ T cells (Tpex). Metabolomics analysis identified propionate and butyrate as critical metabolites driving the mannose-mediated tumor-suppressive effects, which was validated in vivo. Mechanistically, propionate and butyrate enhanced histone acetylation to promote Tpex-cell expansion. Moreover, a mannose-related gene signature was associated with favorable response to immune checkpoint blockade therapy across multiple cancer types. Supplementation with mannose also improved the efficacy of anti–PD-1 therapy and PARP inhibitor treatment. These findings highlight the role of F. rodentium–derived metabolites propionate and butyrate as key stimulators of Tpex-cell expansion, thereby activating antitumor immune responses. This underscores the therapeutic potential of mannose supplementation in enhancing cancer immunotherapy outcomes in high-grade serous ovarian cancer. Significance: Alterations to the gut microbiome induced by mannose engender an immune stimulatory tumor microenvironment responsive to immunotherapy, suggesting that mannose may be an effective and safe adjuvant therapy for stimulating immunotherapy sensitivity.

Attenuation of Sialylation Augments Antitumor Immunity and Improves Response to Immunotherapy in Ovarian Cancer

Abstract Aberrant sialylation functions as an important modulator of all steps of malignant transformation. Therefore, targeting sialylation regulators, such as sialyltransferases and neuraminidases, is a potential strategy for treating cancer. Here, we found that elevated α2,3-sialyltransferase III (St3gal3) was associated with dismal prognosis in high-grade serous ovarian carcinoma (HGSC). St3gal3 knockdown antagonized subcutaneous tumor growth in immunocompetent, but not immunodeficient mice, with enhanced accumulation of functional CD8+ T cells and antitumor immune gene signatures. St3gal3 knockdown inhibited intraperitoneal tumor growth and repolarized tumor-associated macrophages from a protumorigenic M2-like to a tumor-suppressive M1-like phenotype. In vitro, St3gal3 knockdown tumor cells guided bone marrow–derived macrophages (BMDM) toward the M1-like phenotype under both direct contact and distant Transwell coculture conditions. Depletion of macrophages rescued the suppressed tumor growth induced by St3gal3 knockdown and completely suppressed infiltration of functional CD8+ T cells that rely on macrophage-derived CXCL10. St3gal3 engendered an immunosuppressive HGSC microenvironment characterized by an abundance of pro-tumorigenic macrophages and reduced cytotoxic T-cell infiltration. In vivo, St3gal3 knockdown improved effectiveness of dual immune checkpoint blockade (ICB) with αPD-1 and αCTLA4 antibodies. Preclinical inhibition of sialylation with ambroxol resulted in decreased tumor growth and prolonged the survival of tumor-bearing mice, which was enhanced by the addition of dual ICB. These findings indicate that altered sialylation induced by St3gal3 upregulation promotes a tumor-suppressive microenvironment in HGSC and targeting α2,3-sialylation may reprogram the immunosuppressive tumor microenvironment and improve the efficacy of immunotherapy. Significance: Blocking sialylation augments antitumor immunity and enhances response to immune checkpoint blockade therapy, highlighting a potential therapeutic approach for treating patients with high-grade serous ovarian cancer.

Identification and validation of potential mRNA- microRNA- long-noncoding RNA (mRNA-miRNA-lncRNA) prognostic signature for cervical cancer

Cervical cancer is one of the most common causes of cancer deaths in women due to poor prognosis and high mortality rates. A novel mRNA-miRNA-lncRNA signature linked to prognosis of cervical cancer is needed to help clinicians judge the prognosis of individual patients more accurately. On the basis of GEO datasets, a total of 161 upregulated and 242 downregulated DE-mRNAs were identified firstly. Among them, eight potential biomarkers were found to have prognostic values with cervical cancer and miRNAs-lncRNAs related to these biomarkers were then analyzed to create mRNA-miRNA-lncRNA networks in cervical cancer. Moreover, in vitro experiments such as qRT-PCR, western blot and Edu assays were also performed to validate these promising targets. On the basis of these findings, a total of eight mRNA-miRNA-lncRNA subnetworks were finally established as a novel mRNA-miRNA-lncRNA signature and independent prognostic indicator of clinically relevant parameters by ROC analysis, univariate and multivariate Cox regression. Since some work of validation was done, it is believed that this mRNA-miRNA-lncRNA prognostic signature may be applied as a potential clinical judgment to estimate the prognosis of cervical cancer.

Automatic segmentation for plan-of-the-day selection in CBCT-guided adaptive radiation therapy of cervical cancer

Abstract Objective. Plan-of-the-day (PoD) adaptive radiation therapy (ART) is based on a library of treatment plans, among which, at each treatment fraction, the PoD is selected using daily images. However, this strategy is limited by PoD selection uncertainties. This work aimed to propose and evaluate a workflow to automatically and quantitatively identify the PoD for cervix cancer ART based on daily CBCT images. Approach. The quantification was based on the segmentation of the main structures of interest in the CBCT images (clinical target volume [CTV], rectum, bladder, and bowel bag) using a deep learning model. Then, the PoD was selected from the treatment plan library according to the geometrical coverage of the CTV. For the evaluation, the resulting PoD was compared to the one obtained considering reference CBCT delineations. Main results. In experiments on a database of 23 patients with 272 CBCT images, the proposed method obtained an agreement between the reference PoD and the automatically identified PoD for 91.5% of treatment fractions (99.6% when considering a 5% margin on CTV coverage). Significance. The proposed automatic workflow automatically selected PoD for ART using deep-learning methods. The results showed the ability of the proposed process to identify the optimal PoD in a treatment plan library.