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This study focuses on exploring the role of Six2 in the progression of hepatocellular carcinoma (HCC) and its resistance to the chemotherapy drug 5-fluorouracil (5-FU). Using Hep3B and Huh7 cell lines, we analyzed how Six2 affects various cellular functions, including viability, proliferation, apoptosis, and invasion. Our research also delved into Six2's regulatory impact on DNMT1 levels, E-cadherin expression, and the methylation of the E-cadherin promoter, all of which are crucial for 5-FU resistance in HCC cells. Additionally, we examined the effects of Six2 knockdown on the PI3K/AKT/mTOR signaling pathway. Our findings indicate that overexpression of Six2 enhances cell viability and proliferation, encourages invasive behavior, increases methylation at the E-cadherin promoter, and reduces apoptosis. These changes correspond with increased levels of DNMT1 and decreased levels of E-cadherin, culminating in heightened resistance to 5-FU. Conversely, knocking down Six2 increases the sensitivity of HCC cells to 5-FU and reduces activation of the PI3K/AKT/mTOR pathway. These results suggest that Six2 plays a significant role in promoting HCC proliferation, invasion, and chemotherapy resistance, particularly through mechanisms involving DNMT1 and the PI3K/AKT/mTOR pathway, highlighting its potential as a target for HCC treatment.

Prostate cancer (PCa) is the most frequently diagnosed malignant tumor in males, and there are currently few effective therapeutic targets following hormone therapy resistance. Subunits of eukaryotic initiation factor 3 (eIF3) have been implicated in the progression of various cancers. This study aims to investigate the biological functions of the eIF3m subunit in PCa and assess its potential as a novel therapeutic target for treatment. We utilized open-access datasets and patient tissues to analyze the expression and prognostic value of eIF3m in PCa. To explore the role of eIF3m in PCa growth, we established eIF3m knockdown models in PC3 and 22Rv1 cells for both in vitro and in vivo studies. Gene set enrichment analysis (GSEA) was utilized to identify signaling pathways regulated by eIF3m in PCa. Additionally, western blotting and immunochemistry were used to confirm the regulation of c-Myc signaling by eIF3m in PCa. Our results indicated that eIF3m expression was elevated in PCa tissues, with higher levels correlating with an increased risk of biochemical recurrence following radical prostatectomy. Both in vitro and in vivo experiments demonstrated that inhibiting eIF3m significantly impeded the growth of PCa cells. GSEA and immunochemistry further revealed that high eIF3m expression contributed to the activation of c-Myc signaling in PCa patients. Notably, the downregulation of eIF3m resulted in a significant decrease in the expression of c-Myc mRNA and protein in PCa cells. Overall, our findings suggest that eIF3m inhibition significantly suppressed PCa cell growth and c-Myc signaling, indicating that eIF3m is a promising therapeutic target for PCa patients.

Effective treatment strategies for second-line therapy in extensive-stage small cell lung cancer (ES-SCLC) are currently lacking. For this reason, we collected and recorded efficacy and safety data from patients with ES-SCLC who had disease progression after first-line treatment and received albumin-bound paclitaxel, anlotinib, and immunotherapy. Preliminary data showed an objective response rate of 37.78%. Median progression-free survival and overall survival were 5 months and 10 months, respectively. Treatment-related adverse events were mostly tolerable. Subgroup analysis indicated that efficacy correlated with the interval from last chemotherapy to treatment initiation and specific drug-related adverse events. Further analysis of immune cell subtypes suggested that the mechanism may involve depletion of immune suppression to activate immune responses synergistically against tumors. With its promising efficacy and manageable adverse effects, this regimen holds potential as a significant option for second-line therapy in ES-SCLC. However, due to the limited sample size, further clinical validation is needed to ascertain its true clinical value.

The purpose of this study is to detect the vitamin D (VitD) levels in patients with renal cell carcinoma (RCC), bladder cancer (BC), and prostate cancer (PC) using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technology to assess the VitD status in subjects using different methods, to understand the true level of VitD in RCC, BC, and PC patients. A total of 170 subjects were included in this study, and their serum VitD metabolite levels were measured, including 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3], 3-epi-25-hydroxyvitamin D3 [C3-epi-25(OH)D3, C3-epi], and calculations for 25(OH)D, 25(OH)D2/25(OH)D3, and C3-epi/25(OH)D3 were made. The variations in serum VitD, calcium (Ca), inorganic phosphorus (IP), vitamin D receptor (VDR), and renal function indicators were measured, and their correlations were analyzed. The levels of 25(OH)D, 25(OH)D3, C3-epi, C3-epi /25(OH)D3, and free 25(OH)D [ F25(OH)D] in RCC, BC, and PC patients were significantly lower than that in the healthy control (HC) group (all p<0.05). The ratio of 25(OH)D2/25(OH)D3 was significantly higher in these groups compared to the HC group (all p<0.05). 25(OH)D3 distinguished the HC group from common cancers of the urinary system (including RCC, BC, and PC) in male patients and showed good diagnostic performance. The level of 25(OH)D3 in all three groups was positively correlated with F25(OH)D levels, and in the disease groups, C3-epi levels were positively correlated with both 25(OH)D3 and F25(OH)D levels. This study found that RCC, BC, and PC patients had lower serum levels of 25(OH)D3, C3-epi, and F25(OH)D compared to healthy individuals, with most RCC, BC, and PC patients displaying VitD deficiency.

Carcinoma of unknown primary (CUP) is defined as a metastatic carcinoma whose primary site cannot be determined, and the absence of a known primary tumor in CUP poses a significant challenge in treatment planning. The purpose of this study was to investigate the protein level of epithelial membrane proteins (EMP) 1, EMP 2, and EMP 3 in CUP and explore their clinical implications. Tissue microarrays were constructed using samples from 72 CUP cases. The histologic subtypes were adenocarcinoma (ADC) in 22% of cases, poorly differentiated carcinoma (PDC) in 15%, squamous cell carcinoma (SCC) in 19%, and undifferentiated carcinoma (UDC) in 14%. Clinically, 17 cases (23.6%) were of favorable type, and 55 cases (76.4%) were of unfavorable type. Immunohistochemical staining for EMP 1, EMP 2, and EMP 3 was performed on the tissue microarrays to investigate the correlation between staining results and clinicopathologic parameters. The investigation of EMP 1, EMP 2, and EMP 3 protein levels in CUP revealed that EMP 2 H-score was significantly higher (p=0.013) in the favorable type, and there was a higher proportion of stromal EMP 1-positivity (p=0.034) and high protein level of tumoral EMP 3 (p=0.002). A positive correlation was observed between EMP 1 and EMP 3 (r=0.425 and p<0.001). In conclusion, CUP exhibits EMP 1, EMP 2, and EMP 3 protein levels, and their protein levels are different according to the clinical subtype.

MYC-rearranged high-grade B-cell lymphoma (HGBCL) patients with concurrent BCL2 rearrangements (HGBCL-MYC/BCL2) often have a poor prognosis with standard chemoimmunotherapy and may benefit from more intensified regimens. Conventional fluorescence in situ hybridization (FISH) is the gold standard for detecting rearrangements, but it has several limitations. This study compared DNA- and RNA-sequencing with FISH to detect clinically relevant rearrangements in HGBCL. Archived formalin-fixed, paraffin-embedded samples from 34 patients who underwent FISH testing were analyzed using targeted DNA- and RNA-sequencing. DNA- and RNA-sequencing identified six and five out of the 12 MYC rearrangements detected by FISH, 10 and 6 out of 10 FISH-detectable BCL2 rearrangements, and 13 and 10 out of the 18 FISH-detectable BCL6 rearrangements. When combining DNA- and RNA-sequencing (integrated NGS), the sensitivity for detecting MYC, BCL2, and BCL6 rearrangements was 58.3%, 100%, and 73.7%, respectively. Both DNA- and RNA-sequencing detected the EIF4A2::BCL6 fusion missed by FISH. FISH identified 12 HGBCL-MYC/BCL2 out of 34 cases, while the integrated NGS strategy identified 7 cases, with 5 cases showing discordant results (41.7%). Additionally, patients with DLBCL/HGBCL-MYC/BCL2 had significantly shorter overall survival than other patients. Our results suggest that an integrated NGS strategy should not replace FISH or be routinely used in the workup to detect the clinically relevant rearrangements in HGBCL. It may serve as a complement to FISH testing when FISH shows negative results.

Due to the delayed delivery of the request for a correction and the requirement from the Office of Zhejiang Chinese Medical University to standardize the institution's English translation, the editorial department of NEOPLASMA has issued a correction in response to the author's signed request: The affiliation of the first author has been changed from "Graduate School of Zhejiang University of Traditional Chinese Medicine" to "Graduate School, Zhejiang Chinese Medical University."

Gastric cancer is a globally common type of cancer with a dismal prognosis. Circle RNA_ 0001860 (circ_0001860) is dysregulated in several cancers and involved in cancer development. Its involvement in stomach cancer, however, remains unclear. AGS and HGC-27 cells were transfected with shRNA against circ_0001860 to knock down the circ_0001860 level. The function of circ_0001860 in gastric cancer was analyzed by cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, Transwell, ELISA, dual-luciferase reporter, RIP, RNA pull-down, and western blotting. Nude mice were subcutaneously inoculated with AGS cells with lentivirus-packaged sh-circ_0001860 to determine the role of sh-circ_0001860 in gastric cancer by immunohistochemistry assays. circ_0001860 was upregulated in gastric cancer, indicating a poor prognosis for gastric cancer patients. Knockdown of circ_0001860 reduced gastric cancer cells' viability, the percentage of EdU-positive cells, the numbers of invaded cells, and concentrations of IL-10 and TGF-β while fostering the concentrations of IFN-γ and IL-2. circ_0001860 sponged miR-618 to positively modulate the HMGA2 level in gastric cancer cells. The inhibitory role of sh-circ_0001860 on cell growth, invasion, and immune evasion of gastric cancer was abolished with the miR-618 knockdown or the HMGA2 overexpression. Besides, EIF4A3 positively modulated the circ_0001860 level in gastric cancer cells. In vivo, silencing of circ_0001860 reduced tumor size and weight and the expression of HMGA2 and IL-10 but enhanced the level of miR-618 and IFN-γ. Collectively, circle RNA_ 0001860 was induced by EIF4A3 to enhance proliferation, invasion, and immune evasion of gastric cancer through the miR-618/HMGA2 axis.

The aberrant activation of the hepatocyte growth factor receptor (c-Met) in malignant melanoma is associated with poor prognosis, fostering tumor progression, angiogenesis, and invasiveness. While therapeutic targeting of this pathway has shown promise in several tumors, our previous findings revealed increased tumorigenicity following tyrosine kinase inhibitor SU11274 treatment. Therefore, we hypothesized that administering c-Met inhibitors may elicit distinct effects in human melanoma cells. In this study, we investigated the influence of three c-Met inhibitors, SU11274, crizotinib, and PHA665752, on molecular characteristics, tumorigenicity, and metastatic behavior in three human melanoma cell lines, M4Beu, EGFP-A375 and its metastatic variant, EGFP-A375/Rel3 (Rel3). Crizotinib and PHA665752 induced upregulation of MET proto-oncogene, receptor tyrosine kinase (MET), alongside cancer stem cell marker Prominin 1 (CD133), pluripotency marker Nanog homeobox (Nanog), and genes encoding angiogenic factors and receptors in Rel3 cells, correlating with supportive effect on tumorigenicity in vivo. The increased tumorigenicity of the Rel3 cells following the SU11274 treatment correlated with the elevated phosphorylation of Akt, p70 S6 and RSK kinases. Our results demonstrate pleiotropic changes induced by small-molecule inhibitors of receptor tyrosine kinases in melanoma cell lines.

The incidence and mortality trends of lung cancer in Slovakia are not favorable. In our single-center, non-interventional retrospective cohort study, we provide comprehensive information about Slovakia's non-small cell lung cancer (NSCLC) patient population. We evaluated how the introduction of immunotherapy agents affected the survival of NSCLC patients and tried to identify whether the PD-L1 expression level was associated with a negative patient survival effect. The demographics, results of histological and immunohistochemical (PD-L1) examinations, and information about treatment (immunotherapy or standard of care (SOC)) were recorded. In males, squamous cell carcinomas occurred more often than adenocarcinomas (54.40% and 45.08%, respectively), in females, adenocarcinomas clearly dominated (71.88% vs. 27.08%, respectively). The overall proportion of adenocarcinomas was 53.98%. NSCLC patients with stage III and IV treated with SOC treatment (n=54) showed significantly worse overall survival than patients with immunotherapy (n=9) (p=0.026). The comparison of immunotherapy-treated (n=7) and SOC-treated (n=32) adenocarcinoma patients stage III and IV showed similar results (p=0.046). The negative effect of PD-L1 expression level on survival of females with NSCLC and females with adenocarcinoma was visible already at the TPS level of 20-25%. In males with NSCLC, the negative effect was visible at a TPS level of 70-90%. Our results confirm the positive impact of immunotherapy in real-world conditions and show different effects of PD-L1 expression level on patients' survival depending on sex and histology. Determination of different PD-L1 expression breaking points in males and females with NSCLC is a solid starting point for more research on this topic.