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Experimental and clinical data have shown that the nervous system can significantly stimulate the initiation and progression of melanoma. In support of this, approaches that reduce the transmission of signals from peripheral nerves to effector tissues reduce the recurrence of melanoma. Therefore, we investigated the effect of topical application of the local anesthetic Pliaglis (7% lidocaine and 7% tetracaine) on the growth of melanoma induced by intradermal application of B16F0 cells in mice without treatment and in mice treated with the anti-PD-1 antibody. We found that application of Pliaglis to melanoma significantly reduced its growth and this effect was even pronounced in mice treated with the anti-PD-1 antibody. To determine the mechanisms and pathways responsible for the observed effect, the in vitro effect of incubating melanoma cells with lidocaine and/or tetracaine and the in vivo gene expression of cancer and immune-related factors, percentage of immune cells, gene expression of selected neurotransmitter receptors and nerve growth factors in melanoma tissue were studied. We found that lidocaine and tetracaine significantly reduced the viability of B16F0 cells in vitro. In mice with melanoma, Pliaglis potentiated the effect of anti-PD-1 antibody on gene expression of COX-2, IL-1β, IL-6, CCL11, F4/80, CD206, and NCR1. In addition, Pliaglis increased the gene expression of α9nACHR and 5-HT2a receptors and decreased the gene expression of nerve growth factor receptor (p75NTR) and p53. We also observed Pliaglis-mediated changes in myeloid populations. Topical application of this local anesthetic cream decreased the CD11b+Gr1- population and increased the CD11b+Gr1high population. Our data suggest that Pliaglis reduces melanoma growth through a direct effect on melanoma cells as well as through modulation of the immune response. The involvement of nervous system-related signaling in the inhibitory effect of Pliaglis on melanoma is inconclusive from our data.

In sinonasal squamous cell carcinoma (SNSCC), the prognostic relevance of p16INK4a (p16) expression has been reported rarely. This study aims to examine the immunohistochemical expression of p16 and investigate the possibility of p16 as a prognostic factor for SNSCC. The medical records of 173 individuals with SNSCC between 2010 and 2022 were retrospectively reviewed. The researchers examined patients' demographics, p16 status, staging, tumor histological subtypes, treatment details, recurrence, metastasis, and survival outcomes. p16 was found in 22.0% (38/173) of SNSCC patients, and there was no difference between inverted papilloma-SNSCC (19.6%) and de novo SNSCC (23.0%). p16 status did not correlate with all the cases' age, gender, clinical stage, or therapy features. p16-positive patients had a considerably superior 5-year overall survival (OS) rate (80.7% vs. 57.5%, p=0.039) and a slight tendency in progression-free survival (PFS) rate (68.1% vs. 52.0%, p=0.15), except in stage T4b cases. In maxillary sinus lesions, p16-positive SNSCC had a better 5-year OS (87.4% vs. 49.2%, p=0.03) rate and PFS (79.1% vs. 40.7%, p=0.01) rate than p16-negative SNSCC. Among patients without skull base involvement (82.9% vs. 57.7%, p=0.037) or orbital invasion (86.9% vs. 57.3%, p=0.02), p16-positive SNSCC confers benefits in OS rates more than p16-negative SNSCC. Immunohistochemical p16 expression may be a predictive predictor in individuals with maxillary sinus SCC, non-T4b stage, without skull base involvement, and without orbital invasion.

Circular RNA (circ)_0000326 has been reported in bladder cancer and cervical cancer and is concerned to be involved with the development of cancerous cells. Whereas, there have been no reports concentrating on the influences of circ_0000326 in breast cancer (BC). Therefore, the latent modulatory mechanisms of circ_0000326 in BC are researched. circ_0000326 expression in BC tissues and correlative cells was evaluated via RT-qPCR, and the relevance between circ_0000326 expression and overall survival and the clinicopathological feature was also investigated. After a series of transfection, the effects of circ_0000326, microRNA-9-3p (miR-9-3p), and Yes-associated protein 1 (YAP1) in BC cell growth, invasion, and stemness were studied by CCK-8, flow cytometry, Transwell, and sphere-forming assays. The binding sites and correlation of circ_0000326, miR-9-3p, and YAP1 were certified via starBase website, luciferase reporter assay, and Pearson's χ2 test. The in vivo experiment was evaluated by establishing a subcutaneous tumorigenesis model. High-expressed circ_0000326 in BC tissues and cells was discovered, which was connected with an undesirable prognosis. Silencing of circ_0000326 visibly inhibited MCF-7 and BT549 cell growth, invasion, stemness, meanwhile declining the protein levels of SRY-related high-mobility group box gene 2 (SOX2) and octamer binding transcription factor 4 (OCT4). miR-9-3p was a sponger of circ_0000326, which was negatively regulated by circ_0000326. Moreover, YAP1 was confirmed as a target gene of miR-9-3p. circ_0000326 affected BC cell behaviors via mediating miR-9-3p and YAP1. Furthermore, circ_0000326 silencing prohibited tumor growth of BC in vivo. The research uncovered that circ_0000326 facilitated BC development via mediating the miR-9-3p/YAP1 axis.

In this article, we describe the gene-directed enzyme prodrug therapy, also known as the "Trojan Horse" therapy mediated by exosomes - small extracellular vesicles (sEVs) secreted from mesenchymal stem/stromal cells (MSCs) and cancer cells. MSC-EVs possess strong migrating tropism toward tumor sites. EVs derived from tumor cells mimic the parental cells in an invasive metastatic growth trait and the capability to reprogram the recipient cells. The behavior of these EVs when modified with the suicide gene predestinates them to be a drug with guided intracellular action. EVs with therapeutic suicide gene are prepared from cells with integrated retrovirus vector containing its genetic message. These EVs are internalized by tumor cells and the product of the gene converts the non-toxic prodrug into a cytotoxic drug inside the cell causing its suicide. The action of two suicide gene systems are described: the yCD::UPRT-MSC/5-FC system and the HSVTK-MSC-GCV system. Suicide gene EVs either MSCs or tumor cell origin due to their intrinsic targeting capabilities, high modification flexibility, as well as biological barrier permeability represent potential drugs for tumors untreatable with present standard cancer therapies.

The role of radiotherapy in borderline resectable (BRPC) and locally advanced pancreatic carcinoma (LAPC) remains controversial. In our study, we retrospectively evaluated 48 patients with BRPC (14; 29.2%) and LAPC (34; 70. 8%) who underwent 6-8 cycles of induction mFOLFIRINOX chemotherapy alone (23; 47.9%) or 4-6 cycles of mFOLFIRINOX followed by hypofractionated radiotherapy (up to the total dose of 39.9 Gy in 15 fractions) (25; 52.1%). Survival parameters were evaluated using the Gehan-Breslow-Wilcoxon Test and compared by using the long-rank test. The addition of radiotherapy was not associated with better survival (16.9 months for chemotherapy only versus 15.9 months for the combined therapy; p=0.486), as well as for both subgroups (13.5 months vs. 18.3 months; p=0.679) and (20.7 months vs. 13.8 months; p=0.425) for BRPC and LAPC, respectively. A higher resection rate was seen in the BRPC group compared to the LAPC group (43% vs. 17.6%, respectively). Our study revealed a significantly higher rate of lung metastases in patients after the combination therapy compared to those treated by chemotherapy only (19% vs. 0%, respectively; p=0.045). Such a borderline result, however, prevents us from drawing clear conclusions about whether this is an artifact caused by the low number of patients or whether radiotherapy leads to a selection of stem cells with a predilection to the generalization to the lungs.

Hepatocellular carcinoma (HCC) is a malignant tumor, which seriously threatens the life of patients. LncRNA SLC7A11-AS1 was reported to be abnormally expressed in HCC. Here, the functions and relative molecular regulatory mechanism of SLC7A11-AS1 in HCC were investigated. Nude mice and HCC cells were used as the experimental subjects. Knockdown or overexpression of exogenous genes was conducted in HCC cells. RT-qPCR, IHC, and western blot were employed to evaluate the abundance of genes and proteins. The malignant behaviors were evaluated using CCK-8, clone formation, wound-healing, and Transwell. The locations of SLC7A11-AS1 and KLF9 in cells were determined by FISH and IF assays. The total m6A level was evaluated by dot-blot assay. m6A modification of SLC7A11-AS1 was detected using RNA MeRIP. The interactions among molecules were validated by RIP, ChIP, dual luciferase reporter assay, and co-IP. SLC7A11-AS1 was elevated apparently in HCC cells and HCC tissues from mice. SLC7A11-AS1 silencing could suppress HCC progression, which was validated in in vivo and in vitro experiments. Furthermore, METTL3 mediated m6A modification of SLC7A11-AS1 to elevate its expression. In addition, SLC7A11-AS1 downregulated KLF9 expression by affecting STUB1-mediated ubiquitination degradation and KLF9 enhanced PHLPP2 expression to inactivate the AKT pathway. Eventually, rescue experiments revealed that KLF9 knockdown abolished SLC7A11-AS1 silencing-mediated suppression of HCC progression in vivo and in vitro. Our results unveiled that m6A-modified SLC7A11-AS1 promoted HCC progression by regulating the STUB1/KLF9/PHLPP2/AKT axis, indicating that targeting SLC7A11-AS1 might alleviate HCC progression.

We have identified that NUDT21 plays a vital role in MDS transformations, while the transcription factor RUNX1 is essential for normal hematopoiesis, which is a high expression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and we aim to explore the linkage between the two genes and new pathways for MDS transformation to AML. Prediction of RUNX1 expression levels and its relationship with NUDT21 in AML and MDS patients was performed using bioinformatics techniques and validated in patients. Using lentiviral packaging technology, NUDT21 knockdown and overexpression models were developed in AML and MDS cell lines. These models were validated using quantitative polymerase chain reaction (qPCR) and western blotting. The cell cycle, apoptosis, differentiation, and cytokines were examined by flow cytometry, CCK-8 analyzed proliferation, and the intracellular localization of NUDT21 and RUNX1 was examined by immunofluorescence. mRNA transcriptome sequencing was performed on THP-1, MUTZ-1, and Dapars analyzed SKM-1 cell lines and the sequencing data to observe the knockdown effect of NUDT21 on RUNX1. qPCR and western blot revealed a positive correlation between NUDT21 and RUNX1; both were located in the nucleus. Overexpression of NUDT21 reduced apoptosis, promoted cell proliferation, and possibly increased the invasive ability of cells. It also altered the APA site in the RUNX1 3'-UTRs region. NUDT21 regulates RUNX1 gene expression and promotes AML transformation in MDS through an APA mechanism.

The regulation of protein kinase B (AKT) phosphorylation by Tripartite motif-containing protein 31 (TRIM31) is implicated as an essential mechanism in the progression of many malignant tumors. Nevertheless, the function of the TRIM31/AKT pathway in oral squamous cell carcinoma (OSCC) remains elusive. Here, immunohistochemistry analysis of human OSCC tissue microarrays indicated significantly higher levels of TRIM31 and phosphorylated AKT (p-AKT) in OSCC tumors than in adjacent tissue samples. Also, we detected a positive association between TRIM31 expression and clinical OSCC development. In in vitro studies, TRIM31 knockdown severely impaired OSCC cell growth, invasion, and migration. By contrast, TRIM31 overexpression improved these cell behaviors, while subsequent AKT inhibition abrogated the effect. In vivo tumorigenesis experiments using nude mice also validated the effects of TRIM31/AKT signaling in tumor growth. Furthermore, TRIM31 upregulation facilitated glucose uptake, as well as lactate and adenosine triphosphate production of OSCC cells, while such positive effects on glycolysis and malignant cell phenotypes were reversed by treatment with AKT or glycolysis inhibitors. In conclusion, TRIM31 may improve OSCC progression by enhancing AKT phosphorylation and subsequent glycolysis. Hence, TRIM31 has the potential as a treatment target in OSCC.

Six cycles of docetaxel in addition to androgen deprivation therapy (ADT) are currently one of the treatment options for patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC). Since the outcomes in patients with high-volume (HV) disease remain modest, we aimed to identify patients for more intensified treatment. We report a cohort of 73 consecutive patients with de novo mHSPC treated with early docetaxel at the Department of Oncology and Radiotherapy, University Hospital of Split, Croatia, from October 2015 until March 2020. The outcomes analyzed were the occurrence of castration-resistant disease (CRPC) and death from any cause (OS). The median follow-up was 54 (50-73) months. Forty-six (63%) patients developed CRPC and 34 (47%) died during the follow-up. The median time to CRPC and median OS were 16.2 and 58.4 months, respectively. The risk of CRPC was higher for patients with high (above median) values of serum alkaline phosphatase (ALP) (HR=2.4; 95% CI [1.4-4.5]), lactate dehydrogenase (LDH) (HR=1.98; 95% CI [1.1-3.7]), prostate-specific antigen (PSA) (HR=1.8; 95% CI [1.1-3]), ECOG performance status >1 (HR=2; 95% CI [1.2-3.3]) and HV disease (HR=1.9; 95% CI [1.1-3.1]). The risk of any-cause death was higher in patients with high values of ALP, LDH, and ECOG performance status >1. The predictive value of LDH was independent of disease volume. A set of baseline characteristics could be used in conjunction with disease volume in deciding on the optimal treatment strategy for patients with de novo mHSPC.