Targeting TCF19 sensitizes MSI endometrial cancer to anti-PD-1 therapy by alleviating CD8+ T cell exhaustion via TRIM14-IFN-ß axis.

Immune checkpoint blockade (ICB) therapies display clinical efficacy in microsatellite instable (MSI) endometrial cancer (EC) treatment, the key mechanism of which is reversing T cell exhaustion and restoration of anti-tumor immunity. Here, we demonstrate that transcription factor 19 (TCF19), one of the most significantly differentially expressed genes between MSI and microsatellite stable (MSS) patients in The Cancer Genome Atlas (TCGA)-EC cohort, is associated with poor prognosis and immune exhaustion signature. Specifically, TCF19 is significantly elevated in MSI EC, which in turn promotes tripartite motif-containing 14 (TRIM14) transcription and correlates with hyperactive signaling of the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3)-interferon ß (IFN-ß) pathway. The TCF19-TRIM14 axis promotes tumorigenicity under non-immunological background, and the enhanced downstream secretion of IFN-ß facilitates CD8+ T cell exhaustion through cell differentiation reprogramming. Finally, using humanized models, we show that a combination of TCF19 inhibition and ICB therapy demonstrates more effective anti-tumor responses. Together, our study indicates that targeting TCF19 is a potent strategy for alleviating CD8+ T cell exhaustion and synergizing with ICB in tumor treatment.

Oncolytic adenovirus with MUC16-BiTE shows enhanced antitumor immune response by reversing the tumor microenvironment in PDX model of ovarian cancer.

The improved survival rate of ovarian cancer (OC) is related to the action of infiltrating cytotoxic T lymphocytes (CTLs). Recently, oncolytic adenoviruses (OAds) have emerged as a key player in treating solid tumors; however, the immunosuppressive tumor microenvironment (TME) and the body-mediated antiviral immune response limit their therapeutic effect. In this study, we tested the hypothesis that bispecific T-cell engagers (BiTEs) could activate and redirect CTLs to increase the anti-tumor effect of OAds. We modified the parental OAd to express a MUC16-targeting BiTE antibody (OAd-MUC16-BiTE), which retained its oncolytic properties and replication ability in vitro. This BiTE secreted from infected tumor cells into the microenvironment binds to MUC16 on target cells and cross-links them to CD3 on T cells, leading to activation, proliferation, and toxicity of T cells against MUC16+ tumor cells. In cell coculture assays, OAd-MUC16-BiTE-mediated oncolysis enhanced T-cell-mediated tumor cell killing and bystander effect. In ex vivo tumor cultures freshly derived from OC patients, OAd-MUC16-BiTE overcame the suppressed immune TME, achieving stronger toxicity than the parental virus. Moreover, in the cell-derived xenograft and patient-derived xenograft model, OAd-MUC16-BiTE showed stronger antitumor activity and increased the number of CTLs, compared with the parental virus. Further, we demonstrated that the OAd-MUC16-BiTE-mediated anti-tumor activity is related to the reversal of the TME and improved MHC I antigen presentation. Overall, our results show how arming OAds with BiTE can overcome limitations in oncolytic virotherapy, yielding a potent therapy that is ready for clinical assessment.

Clinical features and prognostic factors analysis of intravenous leiomyomatosis.

Background: The treatment and prognostic factors of intravenous leiomyomatosis (IVL) remain lacking systematic evidence. Methods: A retrospective study was conducted on IVL patients from the Qilu Hospital of Shandong University, and IVL cases were published in PubMed, MEDLINE, Embase and Cochrane Library databases. Descriptive statistics were used for the basic characteristics of patients. The Cox proportional hazards regression analysis was used to assess the high-risk factors related to the progression-free survival (PFS). The comparison of survival curves was performed by Kaplan-Meier analysis. Results: A total of 361 IVL patients were included in this study, 38 patients from Qilu Hospital of Shandong University, and 323 patients from the published literature. Age ≤45 years was observed in 173 (47.9%) patients. According to the clinical staging criteria, stage I/II was observed in 125 (34.6%) patients, and stage III/IV was observed in 221 (61.2%) patients. Dyspnea, orthopnea, and cough were observed in 108 (29.9%) patients. Completed tumor resection was observed in 216 (59.8%) patients, and uncompleted tumor resection was observed in 58 (16.1%) patients. Median follow-up period was 12 months (range 0-194 months), and 68 (18.8%) recurrences or deaths were identified. The adjusted multivariable Cox proportional hazard analysis showed age ≤45 years (vs. >45) (hazard ratio [HR] = 2.09, 95% confidence interval [CI] 1.15-3.80, p = 0.016), and uncompleted tumor resection (vs. completed tumor resection) (HR = 22.03, 95% CI 8.31-58.36, p < 0.001) were high-risk factors related to the PFS. Conclusion: Patients with IVL have a high probability of recurrence after surgery and a poor prognosis. Patients younger than 45 years and with uncompleted tumor resection are at higher risk of postoperative recurrence or death.

Splicing Factor DDX23, Transcriptionally Activated by E2F1, Promotes Ovarian Cancer Progression by Regulating FOXM1.

Ovarian carcinoma remains the most lethal gynecological carcinoma. Abnormal expression of splicing factors is closely related to the occurrence and development of tumors. The DEAD-box RNA helicases are important members of the splicing factor family. However, their role in the occurrence and progression of ovarian cancer is still unclear. In this study, we identified DEAD-box helicase 23 (DDX23) as a key DEAD-box RNA helicase in ovarian cancer using bioinformatics methods. We determined that DDX23 was upregulated in ovarian cancer and its high expression predicted poor prognosis. Functional assays indicated that DDX23 silencing significantly impeded cell proliferation/invasion in vitro and tumor growth in vivo. Mechanistically, transcriptomic analysis showed that DDX23 was involved in mRNA processing in ovarian cancer cells. Specifically, DDX23 regulated the mRNA processing of FOXM1. DDX23 silencing reduced the production of FOXM1C, the major oncogenic transcript of FOXM1 in ovarian cancer, thereby decreasing the FOXM1 protein expression and attenuating the malignant progression of ovarian cancer. Rescue assays indicated that FOXM1 was a key executor in DDX23-induced malignant phenotype of ovarian cancer. Furthermore, we confirmed that DDX23 was transcriptionally activated by the transcription factor (TF) E2F1 in ovarian cancer using luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays. In conclusion, our study demonstrates that high DDX23 expression is involved in malignant behavior of ovarian cancer and DDX23 may become a potential target for precision therapy of ovarian cancer.

FBLN5 is targeted by microRNA­27a­3p and suppresses tumorigenesis and progression in high­grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecological malignancies; however, the precise molecular mechanisms have not been fully characterized. Fibulin­5 (FBLN­5) is an extracellular matrix (ECM) glycoprotein, and plays a crucial role in maintaining the stability of ECM structures, regulating cell proliferation and tumorigenesis. In the present study, the expression of FBLN­5, as determined by western blot analysis and immunohistochemistry, was significantly increased in normal fallopian tube (FT) samples compared with that in HGSOC samples, and decreased FBLN5 expression was associated with unfavorable prognosis of HGSOC. Functional characterization revealed that FBLN5 overexpression significantly inhibited migration, invasion and proliferation abilities of ovarian cancer cells in vitro. Furthermore, micro (mi)RNA­27a­3p (miR­27a­3p) was revealed to be increased in HGSOC, and dual­luciferase reporter assay indicated that miR­27a­3p was functioned as a negative regulator of FBLN5 by directly binding with its 3'­untranslated region. Collectively, FBLN5 expression was associated with prognosis, proliferation, and metastasis in HGSOC. We hypothesized that FBLN5 was targeted by miR­27a­3p and may serve as a biomarker and provide a new therapeutic approach for the treatment of HGSOC.

A case of unplanned pregnancy at 2 months after uterine curettage in a patient with a hydatidiform mole.

Whether an unplanned pregnancy should be terminated during follow-up of a hydatidiform mole is controversial. We report a patient who had an unplanned pregnancy with a hydatidiform mole at 2 months after uterine curettage when the human chorionic gonadotropin level had decreased to a negative value. Hydatidiform mole was confirmed by histopathology. Uterine curettage was performed twice and regular follow-ups were performed after surgery. The patient achieved a full-term pregnancy. The Apgar score of the newborn was 10 at 1, 5, and 10 minutes, and the newborn had no malformations. We conclude that the pregnancy outcome might be good in an unplanned pregnancy when the human chorionic gonadotropin level is negative.

Rare case of uterine neoplasm: cervical sarcoma with endometrial carcinoma.

Multiple primary malignant tumors (MPMTs) refer to two or more primary malignant neoplasms that simultaneously or successively occur in one or more organs in the same individual. Cervical sarcoma concomitant with endometrial carcinoma is rare. A 46-year-old woman was admitted because of increased menstrual volume for 4 years and irregular vaginal bleeding with discharge for 6 months. The diagnosis of endometrial carcinoma at stage II was made on the basis of results of ultrasound, pelvic magnetic resonance imaging, and hysteroscopic curettage. Extensive total abdominal hysterectomy + bilateral adnexectomy + bilateral ovarian arteriovenous high ligation + pelvic adhesion separation + pelvic lymphadenectomy +abdominal aortic lymphadenectomy via the abdomen were performed. Postoperative diagnosis of cervical sarcomas with endometrial carcinoma in stage IIIC1 was made according to the results of pathology and immunohistochemistry. Six cycles of cisplatin-epirubicin-isocyclophosphamide treatment were provided after the operation. Most clinical manifestations of cervical sarcomas are abnormal vaginal bleeding. Use of preoperative imaging and hysteroscopy is difficult for diagnosing cervical sarcomas, and postoperative pathological examinations and immunohistochemical diagnosis are mainly used instead. The possibility of MPMTs should be considered for endometrial carcinoma, especially if the cervical lesion is larger than that of the uterine cavity.

One case report of giant atypical leiomyoma of the ovary.

RATIONALE: Ovarian leiomyoma is a rare ovarian tumor that occurs in 20-65 year-old women, and is mostly misdiagnosed as malignant tumor. In most reports on this type of tumor, ovarian myoma has a benign histology. Herein,we describe a case of ovarian atypical leiomyoma. PATIENT CONCERNS: The patient is a 58-year-old woman. At the age of 40 years old, the patient underwent hysterectomy due to "hysteromyoma" and secondary anemia. The patient was admitted to our hospital due to palpation of lower abdominal mass and abdominal distention. DIAGNOSES: A mass was revealed at the left uterine appendage by pelvic ultrasound and CT.Pathology and immunohistochemistry confirmed the diagnosis of the left ovarian atypical leiomyoma. INTERVENTIONS: Pelvic cavity resection and right adnexectomy were performed during laparotomy for the patient. OUTCOMES: Without radiotherapy or chemotherapy, there were no signs of tumor recurrence in a 9-month follow-up period. LESSONS: When a solid mass appears in ovarian tissues, ovarian leiomyoma should be considered. Patients with this type of tumor are mostly asymptomatic. Preoperative diagnosis was difficult, intraoperative frozen section would be helpful for determining the scope of the surgery, and the correct diagnosis was made by identifying the properties of smooth muscles through postoperative pathology and immunohistochemistry.