ARID1A mutations in lung cancer: biology, prognostic role, and therapeutic implications.

Mutations in the AT-interacting domain-rich protein 1A (ARID1A) gene, a critical component of the switch/sucrose nonfermentable (SWI/SNF) complex, are frequently found in most human cancers. Approximately 5-10% of lung cancers carry ARID1A mutations. ARID1A loss in lung cancer correlates with clinicopathological features and poor prognosis. Co-mutation of ARID1A and epidermal growth factor receptor (EGFR) results in the limited efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) but increases the clinical benefit of immune checkpoint inhibitors (ICIs). ARID1A gene mutation plays a role in cell cycle regulation, metabolic reprogramming, and epithelial-mesenchymal transition. We present the first comprehensive review of the relationship between ARID1A gene mutations and lung cancer and discuss the potential of ARID1A as a new molecular target.

Cell-Cell Interactions Drive Metastasis of Circulating Tumor Microemboli.

Circulating tumor cells are the cellular mediators of distant metastasis in solid malignancies. Their metastatic potential can be augmented by clustering with other tumor cells or nonmalignant cells, forming circulating tumor microemboli (CTM). Cell-cell interactions are key regulators within CTM that convey enhanced metastatic properties, including improved cell survival, immune evasion, and effective extravasation into distant organs. However, the cellular and molecular mechanism of CTM formation, as well as the biology of interactions between tumor cells and immune cells, platelets, and stromal cells in the circulation, remains to be determined. Here, we review the current literature on cell-cell interactions in homotypic and heterotypic CTM and provide perspectives on therapeutic strategies to attenuate CTM-mediated metastasis by targeting cell-cell interactions.

ATM inhibitor KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake in aggressive cancer cells with sustained activation of Akt.

Enhanced glucose uptake is coupled with elevated aerobic glycolysis (the Warburg effect) in cancer cells and is closely correlated with increased tumor aggressiveness and poor prognosis. We previously discovered that ATM, a protein kinase deficient in Ataxia-telangiectasia (A-T) disease, is an insulin-responsive protein that participates in insulin-mediated glucose uptake in muscle cells by stimulating glucose transporter 4 (GLUT4) translocation. However, the role of ATM in glucose uptake and tumorigenesis of cancer cells is unclear. In the present study, we found that aggressive breast and prostate cancer cell lines with overactivated Akt activity exhibit enhanced glucose uptake and GLUT1 translocation upon insulin treatment, and KU-55933, a specific inhibitor of ATM, inhibits insulin-mediated glucose uptake by blocking translocation of GLUT1 to the cell surface. KU-55933 also inhibits aerobic glycolysis and ATP production in these cells. Moreover, KU-55933 induces apoptosis and inhibits motility of cancer cells by inhibiting glucose uptake. Our results showed that while high concentration of glucose and insulin promote the expression of a mesenchymal biomarker (vimentin) in these cancer cells, KU-55933 strongly inhibits its expression as well as epithelial to mesenchymal transition. The roles of ATM in stimulating glucose uptake, glycolysis, motility, and proliferation of cancer cells were demonstrated by knocking-down ATM in these cells. KU-55933 treatment also inhibits tumor growth and metastasis in vivo in mouse mammary tumors through inhibition of GLUT1 translocation and vimentin expression. These results suggest that ATM acts as a promoter of tumorigenesis in cancer cells with overactivated Akt, and KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake and glycolysis in these cancer cells, which may lead to the use of KU-55933 and its analogs as new preventive or therapeutic agents against cancer.

Combining brain-computer interface and virtual reality for rehabilitation in neurological diseases: A narrative review.

BACKGROUND: The traditional rehabilitation for neurological diseases lacks the active participation of patients, its process is monotonous and tedious, and the effects need to be improved. Therefore, a new type of rehabilitation technology with more active participation combining brain-computer interface (BCI) with virtual reality (VR) has developed rapidly in recent years and has been used in rehabilitation in neurological diseases. OBJECTIVES: This narrative review analyzed and characterized the development and application of the new training system (BCI-VR) in rehabilitation of neurological diseases from the perspective of the BCI paradigm, to provide a pathway for future research in this field. METHODS: The review involved a search of the Web of Science-Science Citation Index/Social Sciences Citation Index and the China National Knowledge Infrastructure databases; 39 papers were selected. Advantages and challenges of BCI-VR - based neurological rehabilitation were analyzed in detail. RESULTS: Most BCI-VR studies included could be classified by 3 major BCI paradigms: motor imagery, P300, and steady-state visual-evoked potential. Integrating VR scenes into BCI systems could effectively promote the recovery process from nervous system injuries as compared with traditional methods. CONCLUSION: As compared with rehabilitation based on traditional BCI, rehabilitation based on BCI-VR can provide better feedback information for patients and promote the recovery of brain function. By solving the challenges and continual development, the BCI-VR system can be broadly applied to the clinical treatment of various neurological diseases.

Umbilical cord blood-derived mesenchymal stem cells in treating a critically ill COVID-19 patient.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic is spreading rapidly. Critically ill cases of COVID-19 can rapidly progress to acute respiratory distress syndrome and multiple organ failures. However, no effective drugs have been available till now, leading to more than 300,000 deaths up to 29 April 2020. Here, we present a critically ill case utilizing umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs). CASE PRESENTATION: A 72-year-old man was admitted, with the diagnosis of COVID-19, ARDS, type-2 diabetes, diabetic nephropathy, renal insufficiency, and hypertension. His clinical condition continually developed to be life-threatening even receiving various treatment options including antiviral therapy and extracorporeal membrane oxygenation. Between 28 February and 8 March 2020, the patient was given 5-time intravenous infusions of UCB-MSCs. His hematological and biochemical indexes, including lymphocytes and renal function improved. Pulmonary static compliance increased significantly and PaO2/FiO2 ratio maintained stable. On March 10, he received lung transplantation. CONCLUSIONS: Our current findings suggested that UCB-MSCs therapy may show some positive effect in treating critical COVID-19 to some extent, for its delaying deterioration of the disease and efficacy in respiratory and renal function, though limited.

Ferritin Light Chain (FTL) competes with long noncoding RNA Linc00467 for miR-133b binding site to regulate chemoresistance and metastasis of colorectal cancer.

Although the colorectal cancer (CRC) mortality rates are decreasing in virtue of CRC screening and improved therapeutic methods, CRC is still a leading cause of cancer deaths. One of the main causes is chemoresistance occurrence in CRC. Understanding of the molecular mechanisms of chemoresistance benefits to CRC diagnosis and treatment. In this study, gene expression was determined by western blot and qRT-PCR. The biological functions of genes in CRC cells were studied by knocking down or overexpressing the gene in CRC cells and then analyzing cell sensitivity to 5-Fu by the MTT assay and the flow cytometry, and analyzing cell migration and invasion by transwell assays. The luciferase reporter assay was used to examine microRNA regulation of target gene expression, and biotin pull-down assay was performed to detect interaction between RNA molecules. This study found that ferritin light chain (FTL) and long intergenic noncoding RNA Linc00467 were both upregulated in CRC tissues and cell lines, and inversely correlated to CRC patient survival. FTL and Linc00467 promoted CRC cells abilities to resistance against 5-fluor-ouracil (5-Fu), migration and invasion. These effects were compromised by miR-133b which targeted both FTL and Linc00467. miR-133b interacted with Linc00467 and miR-133b inhibitor prevented Linc00467 knockdown-induced alternations of FTL expression and biological functions. Both FTL and Linc00467 are oncogenes in CRC. FTL expression upregulated in CRC via Linc00467/ miR-133b axis, and leads to CRC cell resistance against 5-FU treatment and promotes CRC metastasis. FTL expression upregulated in CRC via Linc00467/miR-133b axis, and leads to CRC cell resistance to 5-FU treatment and promotes CRC metastasis.

Potential Role of Glucose Transporter-1 Expression in Gastric Cancer: A Meta-Analysis and Systematic Review.

BACKGROUND: Glucose transporter-1 (GLUT-1) has been differentially expressed in various malignancies including gastric cancer (GC). Several previous meta-analyses of GLUT-1 have some significant limitations, such as researching the association between GLUT-1 and various cancer types with no specificity, not studying clinicopathological parameters with GLUT-1, existing conspicuous heterogeneity and so forth. Therefore, we performed a meta-analysis to evaluate the association between GLUT-1 expression and survival of gastric cancer patients, as well as clinicopathological characteristics. METHODS: We systematically searched PubMed, Embase, Web of Science and China National Knowledge Infrastructure for relevant studies in accordance with the applicable criteria up to Aug 2017. Hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were used as the effective measures. RESULTS: A total of 13 studies involving 1972 patients were included in this meta-analysis. The results demonstrated that there was a significant association between GLUT-1 expression and overall survival (OS) (HR=1.45, 95% CI=1.13-1.87) or disease-free survival (DFS) (HR=2.18, 95% CI=1.46-3.25). Moreover, GLUT-1 expression was significantly correlated with worse tumor nodes metastases (TNM) stage (OR=0.34, 95% CI=0.28-0.43), presence of lymph node metastasis (OR=2.88, 95% CI=1.34-6.19), intestinal type of Lauren classification (OR=3.84, 95% CI=2.57-5.74) and invasion of serosa (OR=0.25, 95% CI=0.18-0.35). CONCLUSION: Our meta-analysis showed that GLUT-1 was significantly correlated with poor OS and DFS in gastric cancer. Additionally, GLUT-1 was also a potential prognostic indicator of aggressive clinicopathological parameters in gastric cancer.

A new biosensor detection system to overcome the Debye screening effect: dialysis-silicon nanowire field effect transistor.

Background: A silicon nanowire field effect transistor biosensor has four advantages in the detection of small biomolecules. It is mark-free, immediately responsive, highly sensitive, and specific. However, because of environments with a high salt concentration, the Debye screening effect has been a major issue in biological detection. Objective: To overcome Debye screening effect, realize the clinical application of silicon nanowire field effect transistor and verify its specificity and sensitivity. Materials and methods: The test solution was desalted by miniature blood dialyzer, and then the tumor markers were detected by silicon nanowire field effect transistor. Results: Tumor markers in serum were detected successfully and their sensitivity and specificity were verified. Conclusion: This method was found to effectively promote the development of semiconductor materials in biological solution detection.

Apocynin ameliorates diabetic retinopathy in rats: Involvement of TLR4/NF-κB signaling pathway.

Diabetic retinopathy is a diabetes complication. During diabetic retinopathy development, the TLR4/NF-κB pathway is up-regulated. Apocynin is a nicotinamide adenine dinucleotide phosphate oxidase blocker which can reduce the superoxide radicals. It is demonstrated that apocynin can inhibit TLR4/NF-κB pathway in rats. We aim to figure out whether apocynin treatment is benefit for the diabetic retinopathy in rat model. The diabetes in rats was induced by streptozotocin. The treatment of apocynin (16 mg/kg/day) or vehicle in diabetic rat model was maintained for 12 weeks. The expression levels of relative genes in this research were shown through Western blot and qRT-PCR. Morphology of the retinas was shown by Hematoxylin-Eosin staining. The treatment of apocynin ameliorated biochemical indexes in diabetic rats and rescued the morphology of the retinas. After a 12 weeks apocynin treatment, the cell apoptosis, oxidative stress, and inflammatory in retina was reduced in diabetic rats. TLR4/NF-κB signaling pathway activity in diabetic rat retina was inhibited by apocynin. Based on our study, the treatment of apocynin ameliorates diabetic retinopathy in rats. The TLR4/NF-κB signaling pathway inhibition by apocynin is involved in this process. This result indicated a great therapeutic potential of apocynin in diabetic retinopathy treatment.

The association of intraocular pressure with metabolic syndrome and its components: a Meta-analysis and systematic review.

AIM: To perform a Meta-analysis to explore the correlation between metabolic syndrome and intraocular pressure (IOP). METHODS: We searched PubMed and Embase in November 2017 for studies discussing the relationship between metabolic syndrome components and IOP in patients. Pearson correlation coefficients, odds ratios and standardized betas were extracted from inclusive studies. Heterogeneity and publication bias were checked. RESULTS: Of 295 articles, 10 met inclusion criteria and provided sufficient data for Meta-analysis. Results showed a significant positive relation between metabolic syndrome and IOP (Z=0.47, 95%CI: 0.15-0.79, P=0.005). The five components [waist circumference, hypertriglyceridemia, high blood pressure, high fasting glucose and low high density lipoprotein (HDL)-cholesterol] of metabolic syndrome all showed positive correlation with IOP except the low HDL-cholesterol which had no statistical significance. The pooled Z was 0.08 (95%CI: 0.04-0.12), 0.16 (95%CI: 0.11-0.21), 0.16 (95%CI: 0.10-0.22), 0.30 (95%CI: 0.20-0.40) and 0.12 (95%CI: 0.08-0.16), respectively. Begg's test and Egger's test showed no evidence of significant publication bias of this Meta-analysis. CONCLUSION: Our findings suggest that metabolic syndrome and its components are significantly associated with IOP, besides the HDL-cholesterol. This association may be used to control IOP by intervening the occurrence of metabolic syndrome.

Prostaglandin E2 Activates NLRP3 Inflammasome in Endothelial Cells to Promote Diabetic Retinopathy.

Proliferative diabetic retinopathy (PDR) is the leading cause of blindness and accounts for approximately 12% of all new cases of blindness. Prostaglandin E2 (PGE2) and nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) inflammasomes have been long considered to be associated with PDR. Levels of pro-inflammatory mediators were examined by Enzyme-linked immunosorbent assay (ELISA) measurements. PGE2 levels were analyzed by using the Prostaglandin E2 Monoclonal EIA Kit. Human retinal microvascular endothelial cells (HRMECs) were stained with Annexin V/propidium iodide and analyzed by flow cytometry for testing the apoptosis. Expression levels of NLRP3 inflammasome components under various conditions were detected by Western blot and real-time PCR. Inflammasome markers and PGE2 were highly expressed in the vitreous of PDR patients. PGE2 and NLRP3 induced apoptosis of HRMECs. PGE2 upregulated the expression of NLRP3 inflammasome components and inflammatory chemokines. Knockdown of NLRP3 attenuated the expression of NLRP3 inflammasome components and inhibited the effect of PGE2. Our results suggest that PGE2 levels and NLRP3 inflammasome activation are closely related to the pathogenesis of PDR and nonsteroidal anti-inflammatory drugs may have a potential therapeutic effect on PDR.

Ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by inhibition of drug resistance.

It has been reported that ursolic acid has anti-tumor activity and it enhances the therapeutic effect of oxaliplatin in colorectal cancer (CRC). However, the underlying mechanisms remain unknown. In the present study, the mechanisms of the enhancement of therapeutic effects through use of ursolic acid were investigated. We treated CRC cell lines HCT8 and SW480 with ursolic acid and oxaliplatin and monitored the effects on cell proliferation, apoptosis, reactive oxygen species (ROS) production and drug resistance gene production. We discovered that treatment with a combination of ursolic acid and oxaliplatin resulted in significant inhibition of cell proliferation, significantly increased apoptosis and ROS production, and significant inhibition of drug resistance gene expression. Our study provided evidence that ursolic acid enhances the therapeutic effects of oxaliplatin in colorectal cancer by ROS-mediated inhibition of drug resistance.

Curcumin Suppresses the Colon Cancer Proliferation by Inhibiting Wnt/ß-Catenin Pathways via miR-130a.

Curcumin exhibits anti-tumor effects in several cancers, including colorectal carcinoma (CRC), but the detailed mechanisms are still unclear. Here we studied the mechanisms underlying the anti-tumor effect of curcumin in colon cancer cells. SW480 cells were injected into mice to establish the xenograft tumor model, followed by evaluation of survival rate with the treatment of curcumin. The expression levels of ß-catenin, Axin and TCF4 were measured in the SW480 cells in the absence or presence of curcumin. Moreover, miRNAs related to the curcumin treatment were also detected in vitro. Curcumin could suppress the growth of colon cancer cells in the mouse model. This anti-tumor activity of curcumin was exerted by inhibiting cell proliferation rather than promoting cell apoptosis. Further study suggested that curcumin inhibited cell proliferation by suppressing the Wnt/ß-catenin pathway. MiR-130a was down-regulated by curcumin treatment, and overexpressing miR-130a could abolish the anti-tumor activity of curcumin. Our study confirms that curcumin is able to inhibit colon cancer by suppressing the Wnt/ß-catenin pathways via miR-130a. MiR-130a may serve as a new target of curcumin for CRC treatment.

EZH2 is involved in silencing of WNT5A during epithelial-mesenchymal transition of colon cancer cell line.

PURPOSE: Transforming growth factor-ß (TGF-ß) induction of epithelial-mesenchymal transition (EMT) in SW480 was established as a system for studies of colon cancer metastasis. However, the epigenetic mechanisms underlying this process remain unknown. In mammal, polycomb repressive complex-2 (PRC2) is a highly conserved histone methyltransferase involved in epigenetic regulations. Enhancer of zeste Homolog 2 (EZH2) is the catalytic subunit of PRC2, which catalyzes methylation of lysine 27 of histone H3 (H3K27). METHODS: An inducible EMT system in colorectal cancer was utilized to study its mechanistic and phenotypic changes. Particularly, gene expression analysis was studied after immunoprecipitation. RESULTS: In this study, we reported that EZH2 is significantly enriched in the promoter region of WNT5A after TGF-ß induction in SW480 colon cancer cell line, which in turn silenced the expression of WNT5A. Furthermore, EZH2 inhibitor antagonized the TGF-ß-induced morphological conversion associated with epithelial-mesenchymal transition (EMT). Conversely, inhibition of histone H3K27me3 reader CBX does not affect the WNT5A expression level during TGF-ß-induced EMT. CONCLUSIONS: Our results indicate that EZH2 was essential for the silencing of WNT5A during TGF-ß-induced epithelial-mesenchymal transition of colon cancer cells.