Oncolytic virus M1 functions as a bifunctional checkpoint inhibitor to enhance the antitumor activity of DC vaccine.

Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can downregulate SIRPα in DCs and CD47 in tumor cells. Since OVM upregulates PD-L1 in DCs, combining PD-L1 blockade with DC vaccines and OVM further enhances antitumor activity. Overall, OVM strengthens the antitumor efficacy of DC vaccines by targeting the SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.

Identification of Ferroptosis-Associated Genes in Prostate Cancer by Bioinformatics Analysis.

Background: In order to reveal the functions of ferroptosis in prostate cancer (PCa), a ferroptosis potential index (FPI) was built. This study researched the influence of ferroptosis on gene mutations, various cellular signaling pathways, biochemical recurrence (BCR), and drug resistance in both FPI-high and FPI-low groups. Methods: RNA-seq, somatic mutation data, and clinical data were obtained from The Cancer Genome Atlas (TCGA). FPI values were calculated. All samples were divided into FPI-high and FPI-low groups. The BCR-free survival rate, tumor mutation burden (TMB) value, cellular signaling pathway, differentially expressed genes (DEGs), and drug resistance in the two FPI groups were identified. Human PCa cells, LNCaP, were treated with ferroptosis inducer erastin or inhibitor ferrostatin-1. The expression of hub genes was detected by qRT-PCR and Western blot. Results: A high FPI level was significantly related to poor BCR-free survival. Also, higher TMB value was found in the FPI-high group, and FPI was shown to be associated with gene mutations. Then, genes in both groups were revealed to be enriched in different pathways. A total of 310 DEGs were identified to be involved in muscle system processes and neuroactive ligand-receptor interactions. A total of 101 genes were found to be related to BCR-free survival, and a protein-protein interaction (PPI) network was constructed. Two sub-modules were identified by MCODE, and eight hub genes were screened out, among which SYT4 had higher expression levels and poorer BCR-free survival in the FPI-high group, while the remaining hub genes had lower expression levels and poorer BCR-free survival. Drug sensitivity was revealed to be different in the two groups by study on the IC50 data of different molecules and ferroptosis regulator gene (FRG) expressions. Finally, erastin increased the expression of SYT4 in LNCaP and decreased the expression of the other four genes (ACTC1, ACTA1, ACTN2, and MYH6), while ferrostatin-1 led to the opposite results. The molecular experimental results were consistent with those of bioinformatics analysis, except TNNI1, TNNC2, and NRAP. Conclusion: The current research depicted the ferroptosis level and FRGs in PCa. Ferroptosis was related to TMB value, BCR-free survival, and drug resistance. This study will be beneficial to further research studies on ferroptosis-related molecular mechanisms.

Identification of the receptor of oncolytic virus M1 as a therapeutic predictor for multiple solid tumors.

Over the last decade, oncolytic virus (OV) therapy has shown its promising potential in tumor treatment. The fact that not every patient can benefit from it highlights the importance for defining biomarkers that help predict patients' responses. As particular self-amplifying biotherapeutics, the anti-tumor effects of OVs are highly dependent on the host factors for viral infection and replication. By using weighted gene co-expression network analysis (WGCNA), we found matrix remodeling associated 8 (MXRA8) is positively correlated with the oncolysis induced by oncolytic virus M1 (OVM). Consistently, MXRA8 promotes the oncolytic efficacy of OVM in vitro and in vivo. Moreover, the interaction of MXRA8 and OVM studied by single-particle cryo-electron microscopy (cryo-EM) showed that MXRA8 directly binds to this virus. Therefore, MXRA8 acts as the entry receptor of OVM. Pan-cancer analysis showed that MXRA8 is abundant in most solid tumors and is highly expressed in tumor tissues compared with adjacent normal ones. Further study in cancer cell lines and patient-derived tumor tissues revealed that the tumor selectivity of OVM is predominantly determined by a combinational effect of the cell membrane receptor MXRA8 and the intracellular factor, zinc-finger antiviral protein (ZAP). Taken together, our study may provide a novel dual-biomarker for precision medicine in OVM therapy.

Comparison of Transvaginal and Transumbilical Laparoscopic Single-Site Surgery for Ovarian Cysts.

BACKGROUND: Minimally invasive surgery is currently a preferred treatment for symptomatic ovarian cyst(s), with single-site techniques, such as transumbilical laparoendoscopic single-site surgery (TU-LESS) and transvaginal laparoendoscopic single-site surgery (TV-LESS), gaining increasing popularity. Although both methods have delivered positive outcomes, there is currently limited literature directly comparing TU-LESS and TV-LESS. OBJECTIVES: This study had two primary objectives: (1) to evaluate the safety and feasibility of TV-LESS and TU-LESS for the treatment of ovarian cysts and (2) to compare the surgical and postoperative outcomes of the two procedures. METHOD: This was a prospective observational clinical analysis of 81 patients with a diagnosis of benign ovarian cyst with indication for TV-LESS or TU-LESS. Surgeries were performed at a tertiary hospital between February 1, 2018 and January 31, 2020. Patients were divided into TV-LESS (n = 40) and TU-LESS groups (n = 40), with one excluded due to severe pelvic adhesive disease. Demographics, operation outcomes, and follow-up details were compared. RESULTS: All 80 patients underwent uncomplicated procedures. The two groups were demographically matched (except age), with no difference in operation time, intra-operative blood loss, hemoglobin loss, and hospitalization costs (P > 0.05). However, TV-LESS patients had significantly faster time to ambulation (P < 0.001), faster time to return of bowel function (P < 0.001), less postoperative pain level (P < 0.001), and shorter length of hospital stay (P < 0.001). The cosmetic scores at 1, 4, and 24 weeks after surgery were also higher for the TV-LESS group. CONCLUSION: Our preliminary experience suggested that TU-LESS and TV-LESS are both feasible and safe for ovarian cystectomy and salpingo-oophorectomy. However, TV-LESS may provide three main advantages including: (1) fewer postoperative complications (i.e. incisional hernia); (2) less postoperative pain; and (3) improved cosmetic satisfaction.

LNG-IUS combined with progesterone ameliorates endometrial thickness and pregnancy outcomes of patients with early-stage endometrial cancer or atypical hyperplasia.

OBJECTIVE: To determine the positive effect of levonorgestrel-releasing intrauterine system (LNG-IUS) combined with progesterone on endometrial thickness and pregnancy outcomes of patients with atypical endometrial hyperplasia (AEH) or early-stage endometrial cancer (EEC). METHODS: Patients with AEH or EEC admitted to our hospital were enrolled, and assigned to a control group (con group) and a combination group (com group). Patients in the con group were treated with LNG-IUS, while those in the com group were treated with LNG-IUS combined with progesterone. After treatment, the two groups were compared in efficacy, menstrual blood volume (pictorial blood loss assessment chart (PBAC) score), and changes in endometrial thickness. In addition, the incidence of adverse drug reactions and pregnancy outcomes of the patients were analyzed. RESULTS: Before treatment, there was no significant difference in PBAC score and endometrial thickness between patients with AEH or EEC in the con group and those in the com group, but after 3 months and 6 months of treatment, the com group got a better PBAC score and better changes of endometrial thickness than the con group, and the incidence of adverse drug reactions in the com group was also significantly lower than that in the con group. In addition, the follow-up results of pregnancy outcomes of patients showed that the fertility rate and total effective rate of the com group were both significantly higher than those of the con group (both P<0.05). CONCLUSION: LNG-IUS combined with progesterone is more effective in treating patients with AEH or EEC. It can effectively improve the endometrial thickness of patients and fertility rate of those with fertility requirements after treatment.

UriBLAD: A Urine-Based Gene Expression Assay for Noninvasive Detection of Bladder Cancer.

Bladder cancer is the most common urinary system neoplasm, with approximately 550,000 new cases per year worldwide. Current methods for diagnosis and monitoring of bladder cancer are often invasive and/or lack sensitivity and specificity. In this study, the authors aimed to develop an accurate, noninvasive urine-based gene expression assay for the detection of bladder cancer. Urine specimens were collected at five Chinese hospitals from patients with bladder cancer, and from healthy and other control subjects. The expression levels of 70 genes were characterized by quantitative RT-PCR in a training cohort of 211 samples. Machine learning approaches were used to identify a 32-gene signature to classify cancer status. The performance of this gene signature was further validated in a multicenter, prospective cohort of 317 samples. In the blind validation set, the 32-gene signature achieved encouraging performance of 90% accuracy, 83% sensitivity, and 95% specificity. The area under the receiver operating characteristic curve reached 0.93. Importantly, the 32-gene signature performed well in the detection of non-muscle invasive tumor and low-grade tumor with sensitivities of 81.6% and 81%, respectively. In conclusion, we present a novel gene expression assay using urine samples that can accurately discriminate patients with bladder cancer from controls. The results might prompt further development of this gene expression assay into an in vitro diagnostic test amenable to routine clinical practice.

Genetic relationships and diversity among populations of Paris polyphylla assessed using SCoT and SRAP markers.

The genetic diversity of 33 Paris polyphylla samples collected from the Dabie Mountains was analyzed using SCoT and SRAP molecular markers, revealing the genetic relationships among Paris polyphylla resources in the Dabie Mountains at the molecular level and providing a theoretical basis for genetic improvement and conservation. As a result, a total of 134 bands were amplified with 9 SCoT primers, the percentage of polymorphic bands was 100%, the average number of primers amplified was 14.89, the PIC value was 94.83% and the genetic similarity coefficient ranged from 0.463 to 0.896. Ten pairs of SRAP primer combinations amplified 135 bands, including 129 polymorphic bands, and the percentage of polymorphic bands was 95.56%. The average number of polymorphic bands obtained with each pair of SRAP primer combinations was 12.9, the PIC value was 93.91%, and the genetic similarity coefficient ranged from 0.533 to 0.904. This study showed that both SCoT and SRAP markers were suitable for the genetic diversity analysis of P. polyphylla, which belongs to a genus in which SRAP marker technology has not previously been applied, despite its application in a variety of other plants.

Targeting TR4 nuclear receptor with antagonist bexarotene increases docetaxel sensitivity to better suppress the metastatic castration-resistant prostate cancer progression.

Prostate cancer (PCa) is the second leading cause of cancer death in men in America, and there are no curative options for metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (DTX) has been used as a standard chemotherapy for the mCRPC. However, resistance to DTX is a significant clinical problem as half of patients fail to respond to therapy. The TR4 nuclear receptor has been reported to play an important role in PCa progression, however, its linkage to the DTX resistance remains unclear. Here we found that TR4 was upregulated after DTX chemotherapy in the mCRPC cells and patients, and TR4 expression is correlated with DTX sensitivity with a higher level conferring chemo-resistance. Targeting TR4 with an antagonist bexarotene (Bex, a derivative of retinoid) suppressed the TR4 transactivation with increased DTX chemo-sensitivity. Mechanism dissection studies revealed that TR4 might alter the DTX chemo-sensitivity via modulating the TR4/lincRNA-p21/HIF-1α/VEGF-A signaling. Together, these results suggest that targeting this newly identified TR4/lincRNA-p21/HIF-1α/VEGF-A signaling with Bex, an FDA-approved drug, may increase the DTX chemo-sensitivity to better suppress the mCRPC progression.

Long noncoding RNA SOX2-OT facilitates prostate cancer cell proliferation and migration via miR-369-3p/CFL2 axis.

Accepted as crucial participators in human malignancies, long noncoding RNAs (lncRNAs) have been proven to exert significant function on the complicated processes of cancer progression. Although existing investigations have revealed the oncogenic role of lncRNA SOX2 overlapping transcript (SOX2-OT) in different kinds of cancers, such as osteosarcoma and cholangiocarcinoma, the potential role of it in prostate cancer (PC) is poorly understood. This study was the first attempt to decipher the underlying regulatory mechanism of SOX2-OT in PC. According to the data from this study, SOX2-OT expression was conspicuously elevated in PC tissues and cells. Silenced SOX2-OT could repress PC cell proliferation and migration. Besides, mechanism assays manifested that SOX2-OT bound with miR-369-3p and negatively correlated with miR-369-3p in PC. Additionally, miR-369-3p was confirmed to elicit suppressive impact on PC progression. What's more, cofilin 2 (CFL2) was testified to be a downstream target gene of miR-369-3p. Final rescue tests uncovered that CFL2 upregulation or miR-369-3p inhibition could largely restore SOX2-OT knockdown-mediated function on PC progression. To sum up, SOX2-OT accelerates cell proliferation and migration by targeting miR-369-3p/CFL2 axis in PC.

TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490-3p/vimentin signals.

While TR4 nuclear receptor plays key roles to promote prostate cancer progression, its roles to alter the progression of clear cell renal cell carcinoma (ccRCC), remains unclear. Here, we demonstrate that TR4 can promote the ccRCC cell vasculogenic mimicry (VM) formation and its associated metastasis via modulating the miR490-3p/vimentin (VIM) signals. Mechanism dissection revealed that TR4 might increase the oncogene VIM expression via decreasing the miR-490-3p expression through direct binding to the TR4-response-elements (TR4REs) on the promoter region of miR-490-3p, which might then directly target the 3' UTR of VIM-mRNA to increase its protein expression. Preclinical studies using the in vivo mouse model with xenografted RCC Caki-1 cells into the sub-renal capsule of nude mice also found that TR4 could promote the ccRCC VM and its associated metastasis via modulating the miR490-3p/VIM signals. Together, results from preclinical studies using multiple RCC cell lines and the in vivo mouse model all conclude that TR4 may play a key role to promote ccRCC VM formation and metastasis and targeting the newly identified TR4/miR-490-3p/VIM signals with small molecules may help us to develop a new therapeutic approach to better suppress the ccRCC metastasis.

miR-199a-5p suppresses human bladder cancer cell metastasis by targeting CCR7.

BACKGROUND: C-C chemokine receptor type 7 (CCR7) overexpression correlated with lymphatic metastasis and poor prognosis is a major obstacle to bladder cancer treatment. Recent studies have revealed that miR-199a-5p was significantly abnormal expressed in several solid tumors and functioned as oncogene or tumor suppressor. This study was aimed to further investigate the effects of miR-199a-5p on the cell metastasis mediated by CCR7 in bladder cancer. METHODS: Quantitative Real Time PCR (qRT-PCR) was firstly performed to identified the expression of miR-199a-5p and CCR7 in human bladder cancer samples and cell lines. Following that, the effects of miR-199a-5p on cell migratory and invasive activities were assessed by wound healing and Matrigel invasion assays, respectively. Finally, luciferase reporter assay and western blot were employed to investigate whether CCR7 could directly interact with miR-199a-5p. RESULTS: miR-199a-5p downregulation and CCR7 upregulation were firstly observed in bladder cancer samples and cell lines. In addition, both miR-199a-5p downregulation and CCR7 upregulation were significantly involved in bladder cancer clinicopathological features. Moreover, overexpression of miR-199a-5p could inhibit baldder cancer cell migration and invasion. miR-199a-5p was confirmed to be able to target the 3' untranslated region (UTR) of CCR7 and regulate the expression of CCR7, Matrix metalloproteinases 9 (MMP-9) and Epithelial-Mesenchymal Transition (EMT)-related proteins. CONCLUSION: Our findings added newer insights into the multifaceted role played by miR-199a-5p/CCR7 in bladder cancer, prompting for the first time this miRNA/chemokine axis that regulates cell metastasis. The results strongly supported miR-199a-5p as a potential therapeutic agent and diagnostic marker of bladder cancer.

Androgen deprivation induces bladder histological abnormalities and dysfunction via TGF-ß in orchiectomized mature rats.

Symptomatic late-onset hypogonadism, one of the most common elder diseases, is defined as a syndrome associated with a deficiency in serum testosterone. Recent studies have indicated that androgen deficiency in men is also associated with lower urinary tract symptoms and bladder dysfunction. To determine the pathologic consequences of androgen deprivation in bladder histology and function, we addressed the underlying mechanism. Male rats were divided into 4 groups: emasculated rats (EMR), emasculated rats treated with testosterone, emasculated rats treated with anti- transforming growth factor-ß (TGF-ß) neutralizing antibody, and sham surgery rats. TGF-ß is a common profibrotic factor that mediates the pathologic process of fibrosis in multiple organs. Two months later, urodynamic evaluations were employed to determine the bladder function in vivo. And then rats were sacrificed, and the bladder tissues were collected. Histological studies were employed to determine the degree of bladder fibrosis. Real time PCR was used to evaluate the mRNA level of pro-collagen I, a fibrotic marker. We demonstrate here that androgen deficiency induces bladder fibrosis and decreases the bladder maximal volume and compliance. Androgen replacement treatment completely prevented the histological and functional abnormalities induced by androgen deficiency. Subsequently, we identified that androgen deprivation induced the induction of TGF-ß mRNA level. Importantly, treatment with anti-TGF-ß antibody abolished androgen deprivation-induced bladder fibrosis and dysfunction. Our study reveals an essential role of TGF-ß in the pathogenesis of androgen deprivation-induced bladder fibrosis and dysfunction and offers a potential target for prevention and treatment of bladder dysfunction associated with androgen deficiency.