MAL, a potential immunotherapy target, is associated with poor prognosis in cancer patients.

The MAL gene encodes Myelin and Lymphocyte Protein, mainly expressed in T cells with immunomodulatory effects, showing the potential as a target for immunotherapy. However, the mechanism of MAL in the regulation of immune infiltration and its association with the prognosis in pan-cancer patients remain elusive. We used the TCGA, TIMER2.0, GTEx, UCSC, and TISCH databases and the R programming tool to explore the role of MAL in cancers. MAL was differently expressed in the majority of malignancies relative to the matched healthy controls. Patients with low MAL levels had adverse survival outcomes in the BRCA and LUAD cohorts. In all cancer types, MAL showed a significant correlation to specific immune-subpopulation abundance in particular T cells as well as B cells. MAL was also implicated in immunological pathways in BRCA and LUAD, suggesting the important role of MAL in cancer immune regulation. In conclusion, the pan-cancer study indicates that MAL with excellent prognostic value is a potential immunotherapy target in multiple cancers.

PFKFB4 negatively regulated the expression of histone acetyltransferase GCN5 to mediate the tumorigenesis of thyroid cancer.

Thyroid cancer (TC) is the most common malignant endocrine tumor, and its incidence has progressively increased over several decades. Accumulating evidence has suggested that PFKFB4, a critical regulatory enzyme of glycolysis, has been implicated in various solid cancers. However, the exact effect of PFKFB4 on TC remains unclear. Hence, the objective of this work was to investigate the role of PFKFB4 in TC and explore the underlying regulatory mechanisms. Here, we provide evidence that mRNA levels of PFKFB4 were upregulated in TC patients' thyroids and cell lines. Downregulation of PFKFB4 reduced TC cell viability and inhibited colony formation. In addition, the migration and invasion of TC cells were suppressed by PFKFB4 knockdown, suggesting that PFKFB4 is positively correlated with tumorigenesis of TC. Molecularly, knockdown of PFKFB4 significantly inhibited expression of GCN5 and phosphorylation of PI3K/AKT. Moreover, the suppressive role of shPFKFB4 in TC cell growth was reversed by upregulation of GCN5. Finally, the in vivo experiment indicated that downregulation of PFKF4B suppressed tumor growth in xenografts TC model mice. In total, our results suggested that PFKFB4-mediated TC tumorigenesis by positively regulating GCN5 and PI3K/AKT signaling. These findings provide new research directions and therapeutic options considering PFKF4B as a novel diagnosis marker and therapeutic target.

lncRNA SNHG6 functions as a ceRNA to up-regulate c-Myc expression via sponging let-7c-5p in hepatocellular carcinoma.

Emerging evidence has revealed that dysregulation of lncRNAs correlate with the development and progression of hepatocellular carcinoma (HCC). In the present study, we globally investigated the expression of SNHG6 in 31 cancer type, and we found that SNHG6 was highly expressed in various cancers, especially in HCC. High expression of SNHG6 was associated with progression and poor prognosis in patients with HCC. Gain of function and loss of function assays showed that SNHG6 promoted HCC cell proliferation. Gene Set Enrichment Analysis (GSEA) and correlation analysis suggested that SNHG6 positively correlated with c-Myc and its downstream targets. Ectopic overexpression of SNHG6 markedly increased the expression of c-Myc and its downstream targets, whereas silencing SNHG6 had the opposite effect on the expression of c-Myc and its downstream targets. Mechanistic assays revealed that SNHG6 acted as a competing endogenous RNA (ceRNA) to sponge let-7c-5p and thereby modulating the depression of c-Myc by let-7c-5p. Taken together, SNHG6 promotes HCC cell proliferation via competitively binding let-7c-5p in hepatocellular carcinoma.

Novel SiC Trench MOSFET with Improved Third-Quadrant Performance and Switching Speed.

A SiC double-trench MOSFET embedded with a lower-barrier diode and an L-shaped gate-source in the gate trench, showing improved reverse conduction and an improved switching performance, was proposed and studied with 2-D simulations. Compared with a double-trench MOSFET (DT-MOS) and a DT-MOS with a channel-MOS diode (DTC-MOS), the proposed MOS showed a lower voltage drop (VF) at IS = 100 A/cm2, which can prevent bipolar degradation at the same blocking voltage (BV) and decrease the maximum oxide electric field (Emox). Additionally, the gate-drain capacitance (Cgd) and gate-drain charge (Qgd) of the proposed MOSFET decreased significantly because the source extended to the bottom of the gate, and the overlap between the gate electrode and drain electrode decreased. Although the proposed MOS had a greater Ron,sp than the DT-MOS and DTC-MOS, it had a lower switching loss and greater advantages for high-frequency applications.

A Novel 4H-SiC Asymmetric MOSFET with Step Trench.

In this article, a silicon carbide (SiC) asymmetric MOSFET with a step trench (AST-MOS) is proposed and investigated. The AST-MOS features a step trench with an extra electron current path on one side, thereby increasing the channel density of the device. A thick oxide layer is also employed at the bottom of the step trench, which is used as a new voltage-withstanding region. Furthermore, the ratio of the gate-to-drain capacitance (Cgd) to the gate-to-source capacitance (Cgs) is significantly reduced in the AST-MOS. As a result, the AST-MOS compared with the double-trench MOSFET (DT-MOS) and deep double-trench MOSFET (DDT-MOS), is demonstrated to have an increase of 200 V and 50 V in the breakdown voltage (BV), decreases of 21.8% and 10% in the specific on-resistance (Ron,sp), a reduction of about 1 V in the induced crosstalk voltage, and lower switching loss. Additionally, the trade-off between the resistance of the JFET region (RJFET) and the electric field in the gate oxide (Eox) is studied for a step trench and a deep trench. The improved performances suggest that a step trench is a competitive option in advanced device design.

Estrogen-mediated DNMT1 and DNMT3A recruitment by EZH2 silences miR-570-3p that contributes to papillary thyroid malignancy through DPP4.

BACKGROUND: Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. Studies have indicated that estrogen can regulate the expression of miRNAs in numerous malignancies. MiR-570-3p has been shown to have a regulatory function in various cancers. However, studies of the regulatory function of miR-570-3p and a direct link between estrogen (especially estradiol E2) and miR-570-3p in PTC have not been done. METHODS: Expression of miR-570-3p and its downstream target DPP4 in PTC tissues and cells was predicted using bioinformatics and validated by qRT-PCR and western blot assays. We then performed a series of gain-and-loss experiments to assess the functional significance of miR-570-3p/DPP4 axis in PTC progression in vitro and in vivo. Additionally, the methylation of the miR-570-3p promoter region was examined via bioinformatics analysis and MSP. Finally, the effects of E2 on PTC progression and the correlation between DNMT1/DNMT3A and EZH2 were predicted by bioinformatic tools and proved by luciferase reporter, ChIP, and co-IP assays. RESULTS: In PTC tumor tissues and cell lines, there was a lower expression level and a higher methylation level of miR-570-3p compared to normal tissues and cell lines. DPP4 was identified as the downstream target of miR-570-3p. Overexpression of miR-570-3p reduced the proliferative, migratory, and invasive capabilities, and promoted apoptosis, while overexpression of DPP4 reversed these effects in PTC cells. It was also discovered that DNMT1 and DNMT3A increased the CpG methylation level of the miR-570-3p promoter in an EZH2-dependent manner, which led to decreased expression of miR-570-3p. Furthermore, we observed that estrogen (E2) enhanced the methylation of miR-570-3p and suppressed its expression levels, resulting in augmented tumor growth in vivo in PTC. CONCLUSION: Estrogen regulates the EZH2/DNMTs/miR-570-3p/DPP4 signaling pathway to promote PTC progression.

Circ_0011373 promotes papillary thyroid carcinoma progression by regulating miR-1271/LRP6 axis.

PURPOSE: This research aimed to explore the regulatory molecular mechanism among circular RNA (circ)_0011373, microRNA (miR)-1271, and lipoprotein receptor-related protein 6 (LRP6) in papillary thyroid carcinoma (PTC). METHODS: Quantitative real-time PCR (qRT-PCR) assay was adopted to measure the expression of circ_0011373, miR-1271, and LRP6 mRNA. Furthermore, cell cycle distribution, apoptosis, migration and invasion were investigated by flow cytometry and transwell assay, respectively. The target relationship between miR-1271 and circ_0011373 or LRP6 was predicted by using the Starbase website and DIANA TOOL and verified by dual-luciferase reporter and RIP assay. Protein expression levels of LRP6, p-mTOR, mTOR, p-AKT, AKT, p-PI3K, and PI3K were tested by Western blot. The function of circ_0011373 on PTC tumor growth was validated by the xenograft tumor model in vivo. RESULTS: Circ_0011373 and LRP6 were upregulated, while miR-1271 was downregulated in PTC tissues and cell lines. Moreover, knockdown of circ_0011373 inhibited cell cycle, migration, and invasion and promoted apoptosis. Of particular importance was the fact that circ_0011373 directly interacted with miR-1271 and miR-1271 inhibitor was able to reverse the effect of circ_0011373 knockdown on PTC cell progression. Meanwhile, LRP6 was directly targeted by miR-1271, and its expression was positively regulated by circ_0011373. We further confirmed that miR-1271 overexpression suppressed cell cycle, migration, and invasion and enhanced apoptosis by regulating LRP6. In addition, circ_0011373 knockdown restrained PTC tumor growth in vivo. CONCLUSION: Circ_0011373 might be able to regulate PTC cell cycle, migration, invasion, and apoptosis by regulating the miR-1271/LRP6 axis.

A Novel Super-Junction DT-MOS with Floating p Regions to Improve Short-Circuit Ruggedness.

A novel super-junction (SJ) double-trench metal oxide semiconductor field effect transistor (DT-MOS) is proposed and studied using Synopsys Sentaurus TCAD in this article. The simulation results show that the proposed MOSFET has good static performance and a longer short-circuit withstand time (tsc). The super-junction structure enables the device to possess an excellent compromise of breakdown voltage (BV) and specific on-resistance (Ron,sp). Under short-circuit conditions, the depletion of p-pillar, p-shield, and floating p regions can effectively reduce saturation current and improve short-circuit capability. The proposed device has minimum gate-drain charge (Qgd) and gate-drain capacitance (Cgd) compared with other devices. Moreover, the formation of floating p regions will not lead to an increase in process complexity. Therefore, the proposed MOSFET can maintain good dynamic and static performance and short-circuit ability together without increasing the difficulty of the process.

Identification of ALG3 as a potential prognostic biomarker in lung adenocarcinoma.

Background: The abnormal expression of Alpha-1,3-mannosyltransferase (ALG3) has been implicated in tumor promotion. However, the clinical significance of ALG3 in Lung Adenocarcinoma (LUAD) remains poorly understood. Therefore, we aimed to assess the prognostic value of ALG3 and its association with immune infiltrates in LUAD. Methods: The transcriptional expression profiles of ALG3 were obtained from the Cancer Genome Atlas (TCGA), comparing lung adenocarcinoma tissue with normal tissues. To determine the prognostic significance of AGL3, Kaplan-Meier plotter, and Cox regression analysis were employed. Logistic regression was utilized to analyze the association between ALG3 expression and clinical characteristics. Additionally, a receiver operating characteristic (ROC) curve and a nomogram were constructed. To explore the underlying mechanisms, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA) was conducted. The relationship between AGL3A mRNA expression and immune infiltrates was investigated using the tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB). Furthermore, an in vitro experiment was performed to assess the impact of ALG3 mRNA on lung cancer stemness abilities and examine key signaling pathway proteins. Results: Our results revealed the ALG3 mRNA and protein expression in patients with LUAD was much higher than that in adjacent normal tissues. High expression of ALG3 was significantly associated with N stage (N0, HR = 1.98, P = 0.002), pathological stage (stage I, HR = 2.09, P = 0.003), and the number of pack years (<40, HR = 2.58, P = 0.001). Kaplan-Meier survival analysis showed that high expression of ALG3 was associated with poor overall survival (P < 0.001), disease-free survival (P < 0.001), and progression-free interval (P = 0.007). Through multivariate analysis, it was determined that elevated ALG3 expression independently impacted overall survival (HR = 1.325, P = 0.04). The Tumor Immune Estimation Resource discovered a link between ALG3 expression and tumor-infiltrating immune cells in LUAD. Additionally, ROC analysis proved that ALG3 is a reliable diagnostic marker for LUAD (AUC:0.923). Functional pathways analysis identified that ALG3 is negatively correlated with FAT4. We performed qRT-PCR to assess that knockdown ALG3 expression significantly upregulated FAT4 expression. Spheroid assay and flow cytometry analysis results showed that downregulated of ALG3 inhibited H1975 cell line stemness. Western blot analysis revealed that decreased ALG3 inhibited the YAP/TAZ signal pathway. Conclusion: High expression of ALG3 is strongly associated with poor prognosis and immune infiltrates in LUAD.

Cutoff value of IC50 for drug sensitivity in patient-derived tumor organoids in colorectal cancer.

Patient-derived tumor organoids (PDTOs) have the potential to be used to predict the patient response to chemotherapy. However, the cutoff value of the half-maximal inhibition concentration (IC50) for PDTO drug sensitivity has not been validated with clinical cohort data. We established PDTOs and performed a drug test in 277 samples from 242 CRC patients who received FOLFOX or XELOX chemotherapy. After follow-up and comparison of the PDTO drug test and final clinical outcome results, the optimal IC50 cutoff value for PDTO drug sensitivity was 43.26 µmol/L. This PDTO drug test-defined cutoff value could predict patient response with 75.36% sensitivity, 74.68% specificity, and 75% accuracy. Moreover, this value distinguished groups of patients with significant differences in survival benefit. Our study is the first to define the IC50 cutoff value for the PDTO drug test to effectively distinguish CRC patients with chemosensitivity or nonsensitivity and predict survival benefits.

Interference with KCNJ2 inhibits proliferation, migration and EMT progression of apillary thyroid carcinoma cells by upregulating GNG2 expression.

Papillary thyroid carcinoma is a common malignant tumor of the endocrine system. The specific role and molecular mechanism of potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) in papillary thyroid carcinoma remain unknown. In the present study, the underlying mechanism of KCNJ2 in papillary thyroid carcinoma was explored. KCNJ2 expression in thyroid cancer tissues was predicted using the Gene Expression Profiling Interactive Analysis database, and reverse transcription­quantitative PCR and western blot analyses were performed to detect KCNJ2 expression in papillary thyroid carcinoma cell lines. Cell transfection was performed to inhibit KCNJ2 and G protein subunit Î³2 (GNG2) expression. In addition, cell proliferation was detected via the colony formation and MTT assays. The wound healing and Transwell assays were performed to assess cell migration and invasion, respectively. Western blot analysis was performed to detect the expression levels of transport­related proteins and interstitial related proteins. The StarBase database was used to detect GNG2 expression in thyroid cancer. The results demonstrated that KCNJ2 expression was upregulated in papillary thyroid carcinoma cells. In addition, interfering with KCNJ2 expression inhibited the proliferation, invasion and migration of papillary thyroid carcinoma cells, and inhibited the epithelial­to­mesenchymal transition (EMT). These processes may be influenced by the upregulation of GNG2 expression induced by KCNJ2 knockdown. Overall , the results of the present study demonstrated that interference with KCNJ2 inhibited proliferation, migration and EMT progression of papillary thyroid carcinoma cells by upregulating GNG2 expression.