ASS1 Enhances Anoikis Resistance via AMPK/CPT1A-mediated Fatty Acid Metabolism in Ovarian Cancer.

Metastasis is the leading cause of death in ovarian cancer (OC), with anoikis resistance being a crucial step for detached OC cells survival. Despite extensive research, targeting anoikis resistance remians a challenge. Here, we identify argininosuccinate synthase 1 (ASS1), a key enzyme in urea cycle, is markedly upregulated in OC cells in detached culture and is associated with increased anoikis resistance and metastasis. Disruption of the AMP/ATP balance by elevated ASS1 activates AMPK and its downstream factor, CPT1A. Then, ASS1 enhances FAO, leading to higher ATP generation and lipid utilization. Inhibition of CPT1A reverses ASS1-induced FAO. Our study gives some new functional insights into OC metabolism and represents a shift from traditional views, expanding ASS1's relevance beyond nitrogen metabolism to fatty acid metabolism. It uncovers how ASS1-induced FAO disrupts the AMP/ATP balance, leading to AMPK activation. By identifying the ASS1/AMPK/CPT1A axis as crucial for OC anoikis resistance and metastasis, our study opens up new avenues for therapeutic interventions.

Macrophage-Derived GSDMD Plays an Essential Role in Atherosclerosis and Cross Talk Between Macrophages via the Mitochondria-STING-IRF3/NF-κB Axis.

BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE-/- and Gsdmd-/- ApoE-/- mice, bone marrow transplantation, and AAV (adeno-associated virus serotype 9)-F4/80-shGSDMD (shRNA-GSDMD) were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd-/- attenuates the atherosclerotic lesion area in high-fat diet-fed ApoE-/- mice. We performed single-cell RNA sequencing of ApoE-/- and Gsdmd-/- ApoE-/- mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 (GSDMD inhibitor Y1) can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.

Emodin attenuates cardiomyocyte pyroptosis in doxorubicin-induced cardiotoxicity by directly binding to GSDMD.

BACKGROUND: Doxorubicin (Dox), which is an anticancer drug, has significant cardiac toxicity and side effects. Pyroptosis occurs during Dox-induced cardiotoxicity (DIC), and drug inhibition of this process is one therapeutic approach for treating DIC. Previous studies have indicated that emodin can reduce pyroptosis. However, the role of emodin in DIC and its molecular targets remain unknown. HYPOTHESIS/PURPOSE: We aimed to clarify the protective role of emodin in mitigating DIC, as well as the mechanisms underlying this effect. METHODS: The model of DIC was established via the intraperitoneal administration of Dox at a dosage of 5 mg/kg per week for a span of 4 weeks. Emodin at two different doses (10 and 20 mg/kg) or a vehicle was intragastrically administered to the mice once per day throughout the Dox treatment period. Cardiac function, myocardial injury markers, pathological morphology of the heart, level of pyroptosis and mitochondrial function were assessed. Protein microarray, biolayer interferometry and pull-down assays were used to confirm the target of emodin. Moreover, GSDMD-overexpressing plasmids were transfected into GSDMD-/- mice and HL-1 cells to further verify whether emodin suppressed GSDMD activation. RESULTS: Emodin therapy markedly enhanced cardiac function and reduced cardiomyocyte pyroptosis in mice induced by Dox. Mechanistically, emodin binds to GSDMD and inhibits the activation of GSDMD by targeting the Trp415 and Leu290 residues. Moreover, emodin was able to mitigate Dox-induced cardiac dysfunction and myocardial injury in GSDMD-/- mice overexpressing GSDMD, as shown by increased EF and FS, decreased serum levels of CK-MB, LDH and IL-1ß and mitigated cell death and cell morphological disorder. Additionally, emodin treatment significantly reduced GSDMD-N expression and plasma membrane disruption in HL-1 cells overexpressing GSDMD induced by Dox. In addition, emodin reduced mitochondrial damage by alleviating Dox-induced GSDMD perforation in the mitochondrial membrane. CONCLUSION: Emodin has the potential to attenuate DIC by directly binding to GSDMD to inhibit pyroptosis. Emodin may become a promising drug for prevention and treatment of DIC.

SPOCK2 and SPRED1 function downstream of EZH2 to impede the malignant progression of lung adenocarcinoma in vitro and in vivo.

Enhancer of zeste homolog 2 (EZH2) is an important epigenetic regulator, and is associated with the malignant progression of lung cancer. However, the mechanisms of EZH2 on lung adenocarcinoma (LUAD) remain unclear. The relationship between EZH2 and SPOCK2 or SPRED1 was confirmed by dual-luciferase reporter assay. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to examine the expression of SPOCK2 and SPRED1 and their prognostic values of LUAD. The effects of SPOCK2 and SPRED1 on the biological characters of LUAD cells were identified on functional assays in vitro and in vivo. Our results showed that EZH2 suppressed the expression and transcriptional activity of SPOCK2 and SPRED1, and these effects were reversed by the EZH2 inhibitor, Tazemetostat. SPOCK2 and SPRED1 were expressed at low levels in LUAD patients, and a high expression level of SPOCK2 or SPRED1 predicted better survival. Moreover, overexpression of SPOCK2 or SPRED1 could inhibit tumoral proliferation, migration ratio, and invasion activity in vitro as well as retard tumor growth in vivo. However, EZH2 elevation could rescue these impacts and accelerate LUAD progression. Our findings reveal that SPOCK2 and SPRED1 are epigenetically suppressed by EZH2 and may act as novel regulators to inhibit the proliferation, migration, and invasion of LUAD cells.

A novel NGS-based diagnostic algorithm for classifying multifocal lung adenocarcinomas in pN0M0 patients.

The classification of multifocal lung adenocarcinomas (MLAs), including multiple primary lung adenocarcinomas (MPLAs) and intrapulmonary metastases (IPMs), has great clinical significance in staging and treatment determination. However, the application of molecular approaches in pN0M0 MLA diagnosis has not been well investigated. Here, we performed next-generation sequencing (NGS) analysis in 45 pN0M0 MLA patients (101 lesion pairs) who were initially diagnosed as having MPLA by comprehensive histologic assessment (CHA). Five additional patients with intrathoracic metastases were used as positive controls, while 197 patients with unifocal lung adenocarcinomas (425 random lesion pairs) were used as negative controls. By utilizing a predefined NGS criterion, all IPMs in the positive control group could be accurately classified, whereas 13 lesion pairs (3.1%) in the negative control cohort were misdiagnosed as IPMs. Additionally, 14 IPM lesion pairs were diagnosed in the study group, with at least 7 misdiagnoses. We thus developed a refined algorithm, incorporating both NGS and histologic results, that could correctly diagnose all the known MPLAs and IPMs. In particular, all IPMs identified by the refined algorithm were diagnosed to be IPMs or suspected IPMs by CHA reassessment. The refined algorithm-diagnosed MPLAs patients also had significantly better progression-free survival than the refined algorithm-diagnosed IPMs (p < 0.0001), which is superior to conventional NGS or CHA diagnoses. Overall, we developed an NGS-based algorithm that could accurately distinguish IPMs from MPLAs in MLA patients. Our results demonstrate a promising clinical utility of NGS to complement traditional CHA-based MLA diagnosis and help determine patient staging and treatment.

Optimal Regulation Strategy for Nonzero-Sum Games of the Immune System Using Adaptive Dynamic Programming.

This article investigates the optimal control strategy problem for nonzero-sum games of the immune system based on adaptive dynamic programming (ADP). First, the main objective is approximating a Nash equilibrium between the tumor cells and the immune cell population, which is governed through chemotherapy drugs and immunoagents guided by the mathematical growth model of the tumor cells. Second, a novel intelligent nonzero-sum games-based ADP is put forward to solve the optimization control problem by reducing the growth rate of tumor cells and minimizing chemotherapy drugs and immunotherapy drugs. Meanwhile, the convergence analysis and iterative ADP algorithm are specified to prove feasibility. Finally, simulation examples are listed to account for availability and effectiveness of the research methodology.

The prognostic significance of prognostic nutritional index in gastrointestinal stromal tumors: A systematic review and meta-analysis.

BACKGROUND: Risk assessment before treatment is important for gastrointestinal stromal tumors (GISTs), which will determine the priority of surgery or preoperative treatment. The prognostic nutritional index (PNI) is an integrated parameter consisting of serum albumin and lymphocyte count. Immunonutritional status defined in this manner is well-known to be closely linked to the prognosis of several other cancers. Nevertheless, the prognostic value of PNI specifically in GISTs has not been well-established. This study aimed to verify the prognostic role of PNI in patients with GISTs. METHODS: A comprehensive literature search was conducted on medical databases up to June, 2022, and the raw data (hazard ratios and 95% confidence intervals [CIs]) focusing on the prognostic value of PNI in patients with GISTs regarding recurrence-free survival were extracted and synthesized adopting the random-effects model. This review was registered in the PROSPERO database (CRD42022345440). RESULTS: A total of 8 eligible studies including 2627 patients with GISTs was analyzed and the pooled results confirmed that an elevated PNI was associated with a better recurrence-free survival (hazard ratio: 0.52, 95% CI: 0.40-0.68), with a moderate heterogeneity (I-square, 38%). The findings from subgroup analysis were consistent with the overall pooled results, and a sensitivity analysis, not the subgroup analysis, identified the source of heterogeneity. CONCLUSION: Elevated pretreatment PNI may be a useful indicator for assessing risk of recurrence in patients from China with GISTs. Studies in other countries and regions are needed to further verify the prognostic value of PNI in GISTs.

In vitroapplication of drug-loaded hydrogel combined with 3D-printed porous scaffolds.

Titanium mesh and three-dimensional titanium alloy scaffolds play a key role in addressing oral and maxillofacial bone defects, which can provide a specific environment and structure for bone growth and development. The two main causes of implant surgery failure are aseptic loosening and bacterial-induced implant-associated infections. To make bone defect implants effective for a long time, the ideal scaffold should take into account the two functions of osseointegration and anti-infection. Therefore, on the basis of the low-elastic-modulus Ti-10Ta-2Nb-2Zr (TTNZ) alloys developed by the research group in the early stage, this study intends to combine the vancomycin-loaded hydrogel with the 3D-printed through-hole porous titanium alloy scaffold to endow 3D-printed TTNZ scaffolds with antibacterial properties. The antibacterial properties of the complex were investigated by the zone of inhibition test and the adhesion/free antibacterial test. The effects of the composite system on osseointegration were investigated from the aspects of cell adhesion, cell proliferation and osteogenesis-related gene expression. The results showed that loading 2.5 wt.% and 5 wt.% vancomycin did not affect the structure of chitosan-hyaluronic acid hydrogel. The properties of the hydrogels were examined by scanning electron microscopy, Fourier-transform infrared, degradation experimentin vitroand vancomycin release experimentin vitro. When combined with porous scaffolds, the drug-loaded hydrogels exhibited slower drug release rates and longer release times. In addition,in vitrostudies found that the TTNZ scaffolds loaded with 5 wt.% vancomycin had a certain effect on the expression of osteogenesis-related genes in cells, but the antibacterial effect was the best. The porous scaffolds loaded with 2.5 wt.% vancomycin hydrogel TTNZ scaffolds did not inhibit cell proliferation, adhesion, alkaline phosphatase activity, and osteogenesis-related gene ex-pression, but the antibacterial effect on free bacteria was not as good as that of TTNZ scaffolds loaded with 5 wt.% vancomycin. This study, complementing the advantages of the two and controlling the local release rate of vancomycin, provides a new idea for future 3D printing of titanium alloy stents for anti-infection.

Gasdermin D mediates doxorubicin-induced cardiomyocyte pyroptosis and cardiotoxicity via directly binding to doxorubicin and changes in mitochondrial damage.

Doxorubicin (Dox), as a widely used anthracycline antitumor drug, can cause severe cardiotoxicity. Cardiomyocyte death and inflammation are involved in the pathophysiology of Dox-induced cardiotoxicity (DIC). Gasdermin D (GSDMD) is known as a key executioner of pyroptosis, which is a pro-inflammatory programmed cell death. We aimed to investigate the impact of GSDMD on DIC and systematically reveal its underlying mechanisms. Our findings indicated that Dox induced cardiomyocyte pyroptosis in a GSDMD-dependent manner by utilizing siRNA or overexpression-plasmid technique. We then generated GSDMD global knockout mice via CRISPR/Cas9 system and found that GSDMD deficiency reduced Dox-induced cardiomyopathy. Dox induced the activation of inflammatory caspases, which subsequently mediated GSDMD-N generation indirectly. Using molecular dynamics simulation and cell-free systems, we confirmed that Dox directly bound to GSDMD and facilitated GSDMD-N-mediated pyroptosis. Furthermore, GSDMD also mediated Dox-induced mitochondrial damage via Bnip3 and mitochondrial perforation in cardiomyocytes. These findings provide fresh insights into the mechanism of how Dox-engaged GSDMD orchestrates adverse cardiotoxicity and highlight the prospects of GSDMD as a potential target for DIC.

A role for the NPM1/PTPN14/YAP axis in mediating hypoxia-induced chemoresistance to sorafenib in hepatocellular carcinoma.

BACKGROUND: Tumor microenvironments are characterized by resistance to chemotherapeutic agents and radiotherapy. Hypoxia plays an important role in the development of tumor resistance, as well as the generation of metastatic potential. YAP also participates in the regulation of hypoxia-mediated chemoresistance, and is negatively regulated by protein tyrosine phosphatase non-receptor type 14 (PTPN14). METHODS: The PTPN14 expression in hepatocellular carcinoma (HCC) tissues were evaluated by qRT-PCR, western blot and tissue microarrays. The effect of PTPN14 on HCC progression was investigated in vitro and in vivo. RESULTS: Here, we report that PTPN14 expression was downregulated in HCC tissues and cell lines. Silencing PTPN14 significantly enhanced proliferation, migration, invasion of HepG2 cells in vitro and tumor growth and metastasis in vivo, whereas overexpression of PTPN14 significantly inhibited these abilities in SK-Hep1 cells. We also found that hypoxia-induced nuclear translocation and accumulation of PTPN14 led to resistance to sorafenib in HCC cells. Further mechanistic studies suggested that NPM1 regulates PTPN14 localization, and that NPM1 regulates YAP by retaining PTPN14 in the nucleus under hypoxic conditions. CONCLUSIONS: These data suggest that a therapeutic strategy against chemoresistant HCC may involve disruption of NPM1-mediated regulation of YAP by retaining PTPN14 in the nucleus under hypoxic conditions.

Validation of a modified Caprini risk assessment model in lung cancer patients undergoing surgery: Results of a multicenter cross-sectional observational study.

BACKGROUND AND OBJECTIVES: Lung cancer patients slated for surgery are at high risk of venous thromboembolism (VTE). Precise risk assessment is necessary for providing proper thromboprophylaxis and reducing morbidity and mortality of VTE. METHODS: A multicenter, observational, cross-sectional cohort study, involving patients with primary lung cancer undergoing surgery, was carried out from August 2016 to December 2019. All patients were assessed according to the Caprini risk assessment model (RAM) and a modified scoring system incorporating elevated D-dimer and new stratification of surgical time. The endpoint was confirmed VTE or patient discharge. RESULTS: Out of 1205 patients, 87 (7.2%) were diagnosed with VTE. The area under the curve of modified scores for VTE was 0.759, which was larger than that of the original one (0.589) (p < 0.05). By modified Caprini scoring system, a higher score was associated with increased VTE risk (odds ratio [OR], 1.345; 95% confidence interval [CI], 1.197-1.512; p < 0.001), and there was an increased OR of 4.090 (95% CI, 2.472-6.768, p < 0.001) for VTE in high-risk category patients. CONCLUSION: Modified Caprini RAM showed an improved prediction of high-risk patients with an elevated likelihood of postoperative VTE compared to the original one.

LncRNA-SNHG6 promotes the progression of hepatocellular carcinoma by targeting miR-6509-5p and HIF1A.

BACKGROUND: Accumulating evidences have been reported that long noncoding RNAs play crucial roles in the progression of hepatocellular carcinoma (HCC). SnoRNA host gene 6 (SNHG6) is believed to be involved in several human cancers, but the specific molecular mechanism of SNHG6 in HCC is not well studied. METHODS: In this study, we experimentally down-regulated the SNHG6 in two hepatocellular carcinoma cell lines in vitro, and then measured the proliferation, migration and invasion abilities and the apoptotic levels. Also, we performed the xenograft assay to investigate the function of SNHG6 during the tumor growth in vivo. RESULTS: We found SNHG6 was highly expressed in HCC tissues. Next, using Hep3B and Huh7 cells, we confirmed knockdown of SNHG6 reduced the proliferation, migration and invasion abilities in vitro. Also, by bioinformatics analysis, further molecular and cellular experiments, we found miR-6509-5p bound to SNHG6 directly, and the expression level of HIF1A was regulated through SNHG6/miR-6509-5p axis. Finally, we found that down-regulation of SNHG6 dramatically reduced the tumor growth ability of Huh7 cells in vivo. CONCLUSIONS: We concluded that SNHG6/miR-6509-5p/HIF1A axis functioned in the progression of hepatocellular carcinoma, and could be the promising therapeutic targets during the development of hepatocellular carcinoma drugs.

Sialic acid-engineered mesoporous polydopamine nanoparticles loaded with SPIO and Fe3+ as a novel theranostic agent for T1/T2 dual-mode MRI-guided combined chemo-photothermal treatment of hepatic cancer.

Hepatic cancer is a serious disease with high morbidity and mortality. Theranostic agents with effective diagnostic and therapeutic capability are highly needed for the treatment of hepatic cancer. Herein, we aimed to develop a novel mesoporous polydopamine (MPDA)-based theranostic agent for T1/T2 dual magnetic resonance imaging (MRI)-guided cancer chemo-photothermal therapy. Superparamagnetic iron oxide (SPIO)-loaded MPDA NPs (MPDA@SPIO) was firstly prepared, followed by modifying with a targeted molecule of sialic acid (SA) and chelating with Fe3+ (SA-MPDA@SPIO/Fe3+ NPs). After that, doxorubicin (DOX)-loaded SA-MPDA@SPIO/Fe3+ NPs (SA-MPDA@SPIO/DOX/Fe3+) was prepared for tumor theranostics. The prepared SAPEG-MPDA@SPIO/Fe3+ NPs were water-dispersible and biocompatible as evidenced by MTT assay. In vitro photothermal and relaxivity property suggested that the novel theranostic agent possessed excellent photothermal conversion capability and photostability, with relaxivity of being r1 = 4.29 mM-1s-1 and r2 = 105.53 mM-1s-1, respectively. SAPEG-MPDA@SPIO/Fe3+ NPs could effectively encapsulate the DOX, showing dual pH- and thermal-triggered drug release behavior. In vitro and in vivo studies revealed that SA-MPDA@SPIO/DOX/Fe3+ NPs could effectively target to the hepatic tumor tissue, which was possibly due to the specific interaction between SA and the overexpressed E-selectin. This behavior also endowed SA-MPDA@SPIO/DOX/Fe3+ NPs with a more precise T1-T2 dual mode contrast imaging effect than the one without SA modification. In addition, SAPEG-MPDA@SPIO/DOX/Fe3+ NPs displayed a superior therapeutic effect, which was due to its active targeting ability and combined effects of chemotherapy and photothermal therapy. These results demonstrated that SAPEG-MPDA@SPIO/DOX/Fe3+ NPs is an effective targeted nanoplatform for tumor theranostics, having potential value in the effective treatment of hepatic cancer.

Conditional survival rate estimates of lobectomy, segmentectomy and wedge resection for stage IA1 non-small cell lung cancer: A population-based study.

Conditional survival rate (CSR) is defined as the dynamic possibility of survival, considering the changes in the survival risk over time. The present study aimed to compare the CSR of the surgical procedures for stage IA1 non-small cell lung cancer (NSCLC). Overall, data for 2,535 patients with stage IA1 NSCLC after lobectomy, segmentectomy or wedge resection were obtained from the Surveillance, Epidemiology and End Results database, and the overall survival (OS) rates were subsequently compared. CSR estimates, the possibility of patients who had already survived × years, to survive further y years, was calculated as CSR=S(x+y)/S(x), where S is the survival rate at a particular point in time. A Cox regression model and propensity-score matching were used to adjust confounding factors. There were no statistical differences in the OS among the three surgical procedures, except that OS of patients who underwent a lobectomy was improved compared with the wedge resection. The CSR of surviving to the 5th year after operation improved gradually over time. The 3-year CSR of lobectomy or segmentectomy was higher compared with that of the wedge resection. Moreover, the 3-year CSR of segmentectomy was higher compared with that of lobectomy from the 3rd year after surgery, particularly in some specific situations, such as female sex, patients ≥66 years old, patients with squamous cell carcinoma or patients with poor tumor differentiation. The present study is the first report to compare CSR following lobectomy, segmentectomy and wedge resection for patients with stage IA1 NSCLC, to the best of our knowledge. These findings indicated that lobectomy is the most conservative surgical procedure for stage IA1 NSCLC and raises questions regarding improved long-term prognosis of segmentectomy in some subsets of patients.

Endogenous thrombopoietin promotes non-small-cell lung carcinoma cell proliferation and migration by regulating EGFR signalling.

Thrombopoietin (TPO) is a haematopoietic cytokine mainly produced by the liver and kidneys, which stimulates the production and maturation of megakaryocytes. In the past decade, numerous studies have investigated the effects of TPO outside the haematopoietic system; however, the role of TPO in the progression of solid cancer, particularly lung cancer, has not been well studied. Exogenous TPO does not affect non-small-cell lung cancer (NSCLC) cells as these cells show no or extremely low TPO receptor expression; therefore, in this study, we focused on endogenous TPO produced by NSCLC cells. Immunohistochemical analysis of 150 paired NSCLC and adjacent normal tissues indicated that TPO was highly expressed in NSCLC tissues and correlated with clinicopathological parameters including differentiation, P-TNM stage, lymph node metastasis and tumour size. Suppressing endogenous TPO by small interfering RNA inhibited the proliferation and migration of NSCLC cells. Moreover, TPO interacted with the EGFR protein and delayed ligand-induced EGFR degradation, thus enhancing EGFR signalling. Notably, overexpressing TPO in EGF-stimulated NSCLC cells facilitated cell proliferation and migration, whereas no obvious changes were observed without EGF stimulation. Our results suggest that endogenous TPO promotes tumorigenicity of NSCLC via regulating EGFR signalling and thus could be a therapeutic target for treating NSCLC.

Integrated analyses identify miR-34c-3p/MAGI3 axis for the Warburg metabolism in hepatocellular carcinoma.

Activated oncogenes and loss of tumor suppressors contribute to reprogrammed energy metabolism and induce aerobic glycolysis, also known as Warburg effect. MicroRNAs are profoundly implicated in human malignancies by inhibiting translation of multiple mRNA targets. Using hepatocellular carcinoma (HCC) molecular profiles from The Cancer Genome Atlas (TCGA), we identified a handful of dysregulated microRNA in HCC glycolysis, especially miR-34c-3p. Antagonization of miR-34c-3p inhibited the lactate production, glucose consumption, extracellular acidification rate (ECAR), and aggressive proliferation in HCC cells. Hijacking glycolysis by 2-deoxy-d-glucose or galactose largely abrogated the suppressive effects of miR-34c-3p inhibition in HCC. Membrane associated guanylate kinase, WW, and PDZ domain containing 3 (MAGI3) is then identified as a direct functional target of miR-34c-3p in regulating HCC glycolysis and oncogenic activities. Mechanistically, MAGI3 physically interacted with ß-catenin to regulate its transcriptional activity and c-Myc expression, which further facilitates the Warburg effect by increasing expression of glycolytic genes including HK2, PFKL, and LDHA. Moreover, overexpressed miR-34c-3p and reduced MAGI3 predicted poor clinical outcome and was closely associated with the maximum standard uptake value (SUVmax) in HCC patients who received preoperative 18 F-FDG PET/CT. Our findings elucidate critical several microRNAs implicated in HCC glycolysis and reveal a novel function of miR-34c-3p/MAGI3 axis in Warburg effect through regulating ß-catenin activity.

Drug-eluting beads-transcatheter arterial chemoembolization with or without iodine-125 treatment is effective and tolerable in treating advanced non-small cell lung cancer patients: a pilot study.

BACKGROUND: This study aimed to explore the efficacy and safety of drug-eluting beads-transcatheter arterial chemoembolization (DEB-TACE) with or without iodine-125 (125I) seed implantation in treating advanced non-small cell lung cancer (NSCLC) patients. METHODS: A total of 25 advanced NSCLC patients underwent DEB-TACE were consecutively enrolled, among which 17 cases also received 125I seed implantation post DEB-TACE treatment. Treatment response, overall survival (OS), biochemical indexes and safety profiles were recorded and analyzed. RESULTS: Zero (0.0%), 13 (54.2%), 9 (37.5%) and 2 (8.3%) patients realized complete response (CR), partial response (PR), stable disease (SD) and progression disease (PD) respectively, and the objective response rate (ORR) and disease control rate (DCR) were 54.2% and 91.7%. The median OS was 12.6 (95% CI: 7.8-17.5) months. No difference of treatment response or OS was observed between DEB-TACE treatment alone and DEB-TACE plus 125I seed implantation. Predictive factors analysis revealed that tumor size correlated with worse OS. Besides, chest distress grade and dyspnea grade were decreased after DEB-TACE procedure, while clinical symptoms were not changed after 125I seed implantation. The common adverse events (AEs) were fever (32.0%), pain (12.0%) by DEB-TACE treatment, and common AE was pain (26.7%) by 125I seed implantation. CONCLUSIONS: DEB-TACE with or without 125I seed implantation is effective and tolerable in treating advanced NSCLC patients.

CPSF7 regulates liver cancer growth and metastasis by facilitating WWP2-FL and targeting the WWP2/PTEN/AKT signaling pathway.

Alternative splicing within a gene can create different versions of an mRNA, called isoforms. CFIm, composed of a small subunit CFIm25 and two large subunits CFIm68 and CFIm59 (also known as CPSF7), has been proposed as an enhancer-dependent activator of mRNA 3' processing. In this study, we investigated the role of CPSF7 in hepatocellular carcinoma. Experimental evidence suggests that the expression level of CPSF7 is higher in liver cancer cells and tissues than in non-tumor hepatic cells and tissues. Furthermore, knockdown of CPSF7 effectively suppressed cell proliferation, migration and colony formation in liver cancer cells by inhibiting PTEN/AKT signaling. CPSF7 promoted WWP2-FL due to the presence of PTEN ubiquitination sites in this longer transcript. Taken together, we identified that CPSF7 regulates liver cancer growth by targeting WWP2-FL that in turn regulates AKT activation in a PTEN-dependent manner.