Association of composite dietary antioxidant index with depression and all-cause mortality in middle-aged and elderly population.

Current research has shown an increasing acceptance of interventions for depression through dietary modifications. However, whether composite dietary antioxidant index (CDAI) is associated with depression and all-cause mortality in middle-aged and elderly population remains unknown. This study aimed to explore those associations in American middle-aged and elderly population. Weighted logistic regression models and weighted Cox proportional hazard regression models were used to assess the association of CDAI, covariates, depression, and all-cause mortality, respectively. The stability of the results was also determined by a linear trend test based on CDAI quintiles. Restricted cubic spline curves were employed to test for non-linear relationships. In the model adjusted for all covariates, significant associations were found with the ORs (95% CI) for CDAI and depression [0.77 (0.67, 0.89)] and the HRs (95% CI) for CDAI with all-cause mortality[0.91 (0.83, 1.00)]. Upon conducting restricted cubic spline curves, we found that the association between CDAI and depression was linear, whereas the association between CDAI and all-cause mortality was non-linear with an inflection point of -0.19. Statistical significance was only found before the inflection point. In this study of middle-aged and elderly Americans, CDAI was linearly negatively associated with depression and non-linearly negatively associated with all-cause mortality.

Silver Nanoparticles Cause Neural and Vascular Disruption by Affecting Key Neuroactive Ligand-Receptor Interaction and VEGF Signaling Pathways.

Introduction: Silver nanoparticles (AgNP) are widely used as coating materials. However, the potential risks of AgNP to human health, especially for neural and vascular systems, are still poorly understood. Methods: The vascular and neurotoxicity of various concentrations of AgNP in zebrafish were examined using fluorescence microscopy. In addition, Illumina high-throughput global transcriptome analysis was performed to explore the transcriptome profiles of zebrafish embryos after exposure to AgNP. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to elucidate the top 3000 differentially expressed genes (DEGs) between AgNP-exposed and control groups. Results: We systematically investigated the neural and vascular developmental toxicities of AgNP exposure in zebrafish. The results demonstrated that AgNP exposure could cause neurodevelopmental anomalies, including a small-eye phenotype, neuronal morphology defects, and inhibition of athletic abilities. In addition, we found that AgNP exposure induces angiogenesis malformation in zebrafish embryos. Further RNA-seq revealed that DEGs were mainly enriched in the neuroactive ligand-receptor interaction and vascular endothelial growth factor (Vegf) signaling pathways in AgNP-treated zebrafish embryos. Specifically, the mRNA levels of the neuroactive ligand-receptor interaction pathway and Vegf signaling pathway-related genes, including si:ch73-55i23.1, nfatc2a, prkcg, si:ch211-132p1.2, lepa, mchr1b, pla2g4aa, rac1b, p2ry6, adrb2, chrnb1, and chrm1b, were significantly regulated in AgNP-treated zebrafish embryos. Conclusion: Our findings indicate that AgNP exposure transcriptionally induces developmental toxicity in neural and vascular development by disturbing neuroactive ligand-receptor interactions and the Vegf signaling pathway in zebrafish embryos.

Nuclear translocation of cGAS orchestrates VEGF-A-mediated angiogenesis.

Cyclic GMP-AMP synthase (cGAS) senses cytosolic incoming DNA and consequently activates stimulator of interferon response cGAMP interactor 1 (STING) to mount immune response. Here, we show nuclear cGAS could regulate VEGF-A-mediated angiogenesis in an immune-independent manner. We found VEGF-A stimulation induces cGAS nuclear translocation via importin-ß pathway. Moreover, nuclear cGAS subsequently regulates miR-212-5p-ARPC3 cascade to modulate VEGF-A-mediated angiogenesis through affecting cytoskeletal dynamics and VEGFR2 trafficking from trans-Golgi network (TGN) to plasma membrane via a regulatory feedback loop. In contrast, cGAS deficiency remarkably impairs VEGF-A-mediated angiogenesis in vivo and in vitro. Furthermore, we found strong association between the expression of nuclear cGAS and VEGF-A, and the malignancy and prognosis in malignant glioma, suggesting that nuclear cGAS might play important roles in human pathology. Collectively, our findings illustrated the function of cGAS in angiogenesis other than immune surveillance, which might be a potential therapeutic target for pathological angiogenesis-related diseases.

L1CAM promotes vasculogenic mimicry formation by miR-143-3p-induced expression of hexokinase 2 in glioma.

In recent decades, antiangiogenic therapy, which blocks the supply of oxygen and nutrition to tumor cells, has become a promising clinical strategy for the treatment of patients with tumors. However, recent studies revealed that vasculogenic mimicry (VM), which is the process by which vascular morphological structures are formed by highly invasive tumor cells, has been considered a potential factor for the failure of antiangiogenic therapy in patients with tumors. Thus, inhibition of VM formation might be a potential target for improving the outcome of antiangiogenic strategies. However, the mechanism underlying VM formation is still incompletely elucidated. Herein, we report that L1CAM might be a critical regulator of VM formation in glioma, and might be associated with the resistance of glioma to antiangiogenic therapy. We found that the tumor-invasion and tube-formation capabilities of L1CAM-overexpressing cells were significantly enhanced in vitro and in vivo. In addition, the results indicated that miR-143-3p, which might directly target the 3'UTR of the hexokinase 2 (HK2) gene to regulate its protein expression, was subsequently involved in L1CAM-mediated VM formation by glioma cells. Further study revealed that the regulation of MMP2, MMP9, and VEGFA expression was involved in this process. Moreover, we identified that activation of the downstream PI3K/AKT signaling pathway of the L1CAM/HK2 cascade is critical for VM formation by glioma cells. Furthermore, we found that the combined treatment of anti-L1CAM neutralizing monoclonal antibody and bevacizumab increases efficacy beyond that of bevacizumab alone, and suppresses glioma growth in vivo, indicating that the inhibition of L1CAM-mediated VM formation might efficiently improve the effect of antiangiogenic treatment for glioma patients. Together, our findings demonstrated a critical role of L1CAM in regulating VM formation in glioma, and that L1CAM might be a potential target for ameliorating tumor resistance to antiangiogenic therapy in glioma patients.

Par6 Enhances Glioma Invasion by Activating MEK/ERK Pathway Through a LIN28/let-7d Positive Feedback Loop.

The invasion of glioblastoma usually results in the recurrence and poor prognosis in patients with glioma. However, the underlying mechanisms involved in glioma invasion remains undefined. In this study, immunohistochemistry analyses of glioma specimens demonstrated that high expression of Par6 was positively correlated with malignancy and poor prognosis of patients with glioma. Par6-overexpressing glioma cells showed much more fibroblast-like morphology, suggesting that regulation of Par6 expression might be associated with tumor invasion in glioma cells. Further study indicated that Par6 overexpression subsequently increased CD44 and N-cadherin expression to enhance glioma invasion through activating MEK/ERK/STAT3 pathway, in vivo and in vitro. Moreover, we found that LIN28/let-7d axis was involved in this process via a positive feedback loop, suggesting that MEK/ERK/LIN28/let-7d/STAT3 cascade might be essential for Par6-mediated glioma invasion. Therefore, these data highlight the roles of Par6 in glioma invasion, and Par6 may serve as a potential therapeutic target for patients with glioma.

Systemic Chemotherapy With or Without Hepatic Arterial Infusion Chemotherapy for Liver Metastases From Pancreatic Cancer: A Propensity Score Matching Analysis.

BACKGROUND: The significance of systemic chemotherapy (SCT) combined with hepatic arterial infusion (HAI) chemotherapy in the treatment of pancreatic ductal adenocarcinoma with liver metastases (PACLM) remains unclear. Based on previous studies, this single-center propensity score matching (PSM) study aimed to explore the efficacy of SCT with or without HAI for PACLM. PATIENT AND METHODS: The PSM method was used to screen 661 cases of PACLM who received SCT at Tianjin Medical University Cancer Institute and Hospital from 2001 to 2020. According to the 1:6 ratio with PSM, 385 patients were divided into the SCT+HAI group (n = 55) and the SCT group (n = 330). After a median follow-up of 49 (range 7-153) months, overall survival (OS) and survival-related prognostic factors were analyzed. RESULTS: The main baseline characteristics of the SCT+HAI group and the SCT alone group were matched appropriately (P > .05). After PSM, the median OS for patients in the 2 groups was 10.6 and 7.6 months, respectively (P = .02). Multivariate analysis revealed that peritoneal metastases (P = .03), CA199 ≥ 500U/mL (P = .03), and lactate dehydrogenase (LDH) ≥ 250U/L (P = .03) were prognostic factors of poor survival, modern SCT plus HAI (P = .04) was a protective factor. CONCLUSION: Our findings indicated that adequate cycles of SCT+HAI result in better survival than SCT alone in patients with PACLM. Patients with peritoneal metastases, markedly elevated CA19-9 and LDH have a poorer prognosis. The conclusion has yet to be validated in randomized controlled clinical trials.

Nanoplastics exposure induces vascular malformation by interfering with the VEGFA/VEGFR pathway in zebrafish (Danio rerio).

The widespread accumulation and adverse effects of nanoplastics (NPs) are a growing concern for environmental and human health. However, the potential toxicological effects of nanoplastics, especially on vascular development, have not been well studied. In this study, the zebrafish model was utilized to systematically study the developmental toxicity of nanoplastics exposure at different concentrations with morphological, histological, and molecular levels. The results revealed developmental defects in zebrafish embryos after exposure to different concentrations of nanoplastics. Specifically, the morphological deformities, including pericardial oedema and spine curvature, as well as the abnormal body length and the rates of survival and hatching were induced after nanoplastics exposure in zebrafish embryos. In addition, we found that nanoplastics exposure could induce vascular malformation, including the ectopic sprouting of intersegmental vessels (ISVs), malformation of superficial ocular vessels (SOVs), and overgrowth of the common cardinal vein (CCV), as well as the disorganized vasculature of the subintestinal venous plexus (SIVP). Moreover, further study indicated that SU5416, a specific vascular endothelial growth factor receptor (VEGFR) inhibitor, partially rescued the nanoplastics exposure-impaired vasculature, suggesting that the VEGFA/VEGFR pathway might be associated with nanoplastics-induced vascular malformation in zebrafish embryos. Further quantitative polymerase chain reaction assays revealed that the mRNA levels of VEGFA/VEGFR pathway-related genes, including vegfa, nrp1, klf6a, flt1, fih-1, flk1, cldn5a, and rspo3, were altered in different groups, indicating that nanoplastics exposure interferes with the VEGFA/VEGFR pathway, thereby inducing vascular malformation during the early developmental stage in zebrafish embryos. Therefore, our findings illustrated that nanoplastics might induce vascular malformation by regulating VEGFA/VEGFR pathway-related genes at the early developmental stage in zebrafish.

Current understanding of gliomagenesis: from model to mechanism.

Glioma, a kind of central nervous system (CNS) tumor, is hard to cure and accounts for 32% of all CNS tumors. Establishing a stable glioma model is critically important to investigate the underlying molecular mechanisms involved in tumorigenesis and tumor progression. Various core signaling pathways have been identified in gliomagenesis, such as RTK/RAS/PI3K, TP53, and RB1. Traditional methods of establishing glioma animal models have included chemical induction, xenotransplantation, and genetic modifications (RCAS/t-va system, Cre-loxP, and TALENs). Recently, CRISPR/Cas9 has emerged as an efficient gene editing tool with high germline transmission and has extended the scope of stable and efficient glioma models that can be generated. Therefore, this review will highlight the documented evidence about the molecular characteristics, critical genetic markers, and signaling pathways responsible for gliomagenesis and progression. Moreover, methods of establishing glioma models using gene editing techniques and therapeutic aspects will be discussed. Finally, the prospect of applying gene editing in glioma by using CRISPR/Cas9 strategy and future research directions to establish a stable glioma model are also included in this review. In-depth knowledge of glioma signaling pathways and use of CRISPR/Cas9 can greatly assist in the development of a stable, efficient, and spontaneous glioma model, which can ultimately improve the effectiveness of therapeutic responses and cure glioma patients.

Extrachromosomal circular DNA in cancer drug resistance and its potential clinical implications.

Chemotherapy is widely used to treat patients with cancer. However, resistance to chemotherapeutic drugs remains a major clinical concern. The mechanisms of cancer drug resistance are extremely complex and involve such factors such as genomic instability, DNA repair, and chromothripsis. A recently emerging area of interest is extrachromosomal circular DNA (eccDNA), which forms owing to genomic instability and chromothripsis. eccDNA exists widely in physiologically healthy individuals but also arises during tumorigenesis and/or treatment as a drug resistance mechanism. In this review, we summarize the recent progress in research regarding the role of eccDNA in the development of cancer drug resistance as well as the mechanisms thereof. Furthermore, we discuss the clinical applications of eccDNA and propose some novel strategies for characterizing drug-resistant biomarkers and developing potential targeted cancer therapies.

Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish.

BACKGROUND: Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish. METHODS: We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish. RESULTS: We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish. CONCLUSION: Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.

Stepwise crosstalk between aberrant Nf1, Tp53 and Rb signalling pathways induces gliomagenesis in zebrafish.

The molecular pathogenesis of glioblastoma indicates that RTK/Ras/PI3K, RB and TP53 pathways are critical for human gliomagenesis. Here, several transgenic zebrafish lines with single or multiple deletions of nf1, tp53 and rb1 in astrocytes, were established to genetically induce gliomagenesis in zebrafish. In the mutant with a single deletion, we found only the nf1 mutation low-efficiently induced tumour incidence, suggesting that the Nf1 pathway is critical for the initiation of gliomagenesis in zebrafish. Combination of mutations, nf1;tp53 and rb1;tp53 combined knockout fish, showed much higher tumour incidences, high-grade histology, increased invasiveness, and shortened survival time. Further bioinformatics analyses demonstrated the alterations in RTK/Ras/PI3K, cell cycle, and focal adhesion pathways, induced by abrogated nf1, tp53, or rb1, were probably the critical stepwise biological events for the initiation and development of gliomagenesis in zebrafish. Gene expression profiling and histological analyses showed the tumours derived from zebrafish have significant similarities to the subgroups of human gliomas. Furthermore, temozolomide treatment effectively suppressed gliomagenesis in these glioma zebrafish models, and the histological responses in temozolomide-treated zebrafish were similar to those observed in clinically treated glioma patients. Thus, our findings will offer a potential tool for genetically investigating gliomagenesis and screening potential targeted anti-tumour compounds for glioma treatment.

Circular RNA hsa_circ_0008285 inhibits colorectal cancer cell proliferation and migration via the miR-382-5p/PTEN axis.

Abundant evidence has showed that circular RNA (circRNA) plays an important role in cancer. Nonetheless, little is known about the roles and mechanisms of specific circRNAs in different cancer types. Hsa_circ_0008285 (circ_0008285), derived from the coding gene chromodomain y-like protein (CDYL), is upregulated in hepatocellular carcinoma and mantle cell lymphoma. However, we previously found, by analyzing two independent high-throughput sequencing datasets, that it was reduced in colon cancer. In this study, we explored the function and mechanism of circ_0008285 in the progression of colorectal cancer (CRC). First, the downregulated expression of circ_0008285 in CRC tissues and cell lines was confirmed using RT-qPCR analysis. In addition, the expression level of circ_0008285 was inversely correlated with tumor size, lymphatic metastasis, and tumor-node-metastasis (TNM) stage through clinicopathological parameter analysis. Functionally, knockdown of circ_0008285 promoted CRC cell proliferation and migration in vitro. Mechanistically, by using RNA-sequencing, bioinformatics analysis, dual-luciferase reporter assay, and western blotting, we determined that circ_0008285 suppressed the PI3K/AKT pathway via the miR-382-5p/PTEN axis. In conclusion, our data demonstrate a tumor suppressor role for circ_0008285 in CRC and suggest circ_0008285 as a potential target for CRC treatment.

Par6 regulates cell cycle progression through enhancement of Akt/PI3K/GSK-3ß signaling pathway activation in glioma.

As the key factor of the polarity protein complex, Par6 not only regulates polarization processes, but also plays important roles in tumor metastasis and progression in many epithelium malignancy tumors. Here, we showed that Par6 is an essential component in glioma tumorigenesis. Our results indicated the aberrant expression of Par6 in malignant glioma tissues and cell lines. We found that the regulation of Par6 expression induces cell proliferation and tumor growth in vivo and in vitro. Additionally, RNA-seq revealed the effects of Par6 were associated with cyclin D1-regulated cell cycle progression in glioma cells. Moreover, our results demonstrated that the regulation of Par6 can enhance the activation of Akt/PI3K signaling pathway, and subsequently upregulate the expression level of GSK-3ß protein, which then regulate cyclin D1-mediated cell cycle regulation. Furthermore, we found that TGF-ß-induced the upregulation of Par6 expression may be involved in this process. The pathological analysis confirmed the correlation between Par6 expression and the prognosis in human glioma tissues, suggesting the regulation of Par6 expression regulates glioma tumorigenesis and progression. Thus, our findings showed that Par6 might be a potential biomarker for the diagnosis and providing a therapeutic strategy for the treatment of malignant glioma.

AP endonuclease 1 (Apex1) influences brain development linking oxidative stress and DNA repair.

Brain and neurons are particularly sensitive to reactive oxygen species (ROS). Oxidative damage from ROS results in increased 8-oxoguanine in DNA followed by repair through the base excision repair (BER) pathway. We reported earlier that AP endonuclease 1 (Apex1) not only participates directly in BER but also regulates transcription factor Creb1. Here, we investigated how Apex1 affects brain to respond effectively to oxidative damage during zebrafish development. Loss of Apex1 resulted in increased ROS, 8-oxoguanine, and abasic sites as well as loss of Ogg1, which recognizes 8-oxoguanine and is required for its repair. Moreover, knock-down of Apex1 not only resulted in reduction of expression of several major proteins in the BER pathway (Polb and Ogg1), and it also resulted in maldistribution and loss of four key brain transcription factors (fezf2, otx2, egr2a, and pax2a), leading to abnormal brain development. These results were independent of p53 protein level. In contrast, exposure to exogenous H2O2 resulted in increased transcription and protein of Apex1 along with other BER components, as well as Creb1. Taken together, these results indicate that oxidative stress increased when the level of Apex1 was reduced, revealing a novel pathway of how Apex1 manages oxidative stress in developing brain.

Heparanase promotes glioma progression via enhancing CD24 expression.

Heparanase is an endo-ß-d-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans. Compelling evidence tie heparanase levels with all steps of tumor formation including tumor initiation, growth, metastasis and chemo-resistance, likely involving augmentation of signaling pathways and gene transcription. In order to reveal the molecular mechanism(s) underlying the protumorigenic properties of heparanase, we established an inducible (Tet-on) system in U87 human glioma cells and applied gene array methodology in order to identify genes associated with heparanase induction. We found that CD24, a mucin-like cell adhesion protein, is consistently upregulated by heparanase and by heparanase splice variant devoid of enzymatic activity, whereas heparanase gene silencing was associated with decreased CD24 expression. This finding was further substantiated by a similar pattern of heparanase and CD24 immunostaining in glioma patients (Pearson's correlation; R = 0.66, p = 0.00001). Noteworthy, overexpression of CD24 stimulated glioma cell migration, invasion, colony formation in soft agar and tumor growth in mice suggesting that CD24 functions promote tumor growth. Likewise, anti-CD24 neutralizing monoclonal antibody attenuated glioma tumor growth, and a similar inhibition was observed in mice treated with a neutralizing mAb directed against L1 cell adhesion molecule (L1CAM), a ligand for CD24. Importantly, significant shorter patient survival was found in heparanase-high/CD24-high tumors vs. heparanase-high/CD24-low tumors for both high-grade and low-grade glioma (p = 0.02). Our results thus uncover a novel heparanase-CD24-L1CAM axis that plays a significant role in glioma tumorigenesis.

Hypersensitive assessment of aryl hydrocarbon receptor transcriptional activity using a novel truncated cyp1a promoter in zebrafish.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent organic pollutant (POP), an unintentional byproduct of various industrial processes, and a human carcinogen. The expression of the cytochrome P450 1A (cyp1a) gene is upregulated in the presence of TCDD through activating the aryl hydrocarbon receptor pathway in a dose-dependent manner. Several essential response elements, including the 8 potential xenobiotic response elements in the cyp1a promoter region, have been identified to be the main functional parts for the response to TCDD. Thus, we aimed to develop a convenient and sensitive biomonitoring tool to examine the level of POPs in the environment and evaluate its potential human health risks by TCDD. Here, we established a transgenic zebrafish model with a red fluorescent reporter gene ( mCherry) using the truncated cyp1a promoter. Under exposure to TCDD, the expression pattern of mCherry in the reporter zebrafish mirrored that of endogenous cyp1a mRNA, and the primary target tissues for TCDD were the brain vessels, liver, gut, cloaca, and skin. Our results indicated that exposure of the embryos to TCDD at concentrations as low as 0.005 nM for 48 h, which did not elicit morphologic abnormalities in the embryos, markedly increased mCherry expression. In addition, the reporter embryos responded to other POPs, and primary liver cell culture of zebrafish revealed that Cyp1a protein was mainly expressed in the cytoplasm of liver cells. Furthermore, our transgenic fish embryos demonstrated that TCDD exposure can regulate the expression levels of several tumor-related factors, including epidermal growth factor, TNF-α, C-myc, proliferating cell nuclear antigen, TGF-ß, serine/threonine kinase (Akt), and phosphorylated Akt, suggesting that our transgenic fish can be used as a sensitive model to evaluate the carcinogenicity induced by TCDD exposure.-Luo, J.-J., Su, D.-S., Xie, S.-L., Liu, Y., Liu, P., Yang, X.-J., Pei D.-S. Hypersensitive assessment of aryl hydrocarbon receptor transcriptional activity using a novel truncated cyp1a promoter in zebrafish.

Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Epigenetic alterations have been shown to be involved in NSCLC oncogenesis; however, their function in EGFR-TKI resistance remains uncharacterized. Here, we found that an EHMT2 inhibitor, UNC0638, can significantly inhibit cell growth and induce apoptosis in EGFR-TKI-resistant NSCLC cells. Additionally, we also found that EHMT2 expression and enzymatic activity levels were elevated in EGFR-TKI-resistant NSCLC cells. Moreover, we determined that genetic or pharmacological inhibition of EHMT2 expression enhanced TKI sensitivity and suppressed migration and tumor sphere formation in EGFR-TKI-resistant NSCLC cells. Further investigation revealed that EHMT2 contributed to PTEN transcriptional repression and thus facilitated AKT pathway activation. The negative relationship between EHMT2 and PTEN was confirmed by our clinical study. Furthermore, we determined that combination treatment with the EHMT2 inhibitor and Erlotinib resulted in enhanced antitumor effects in a preclinical EGFR-TKI-resistance model. We also found that high EHMT2 expression along with low PTEN expression can predict poor overall survival in patients with NSCLC. In summary, our findings showed that EHMT2 facilitated EGFR-TKI resistance by regulating the PTEN/AKT pathway in NSCLC cells, suggesting that EHMT2 may be a target in the clinical treatment of EGFR-TKI-resistant NSCLC.

Generation and application of a novel transgenic zebrafish line Tg(cyp1a:mCherry) as an in vivo assay to sensitively monitor PAHs and TCDD in the environment.

The polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) are classified as human carcinogens, and can also cause serious health problems. To develop a convenient bio-monitoring tool for the detection of PAHs and TCDD in the environment, we generated a transgenic zebrafish line Tg(cyp1a:mCherry) with cyp1a promoter driving mCherry expression. Here, Tg(cyp1a:mCherry) embryos were treated with different concentrations of TCDD and five US EPA priority PAHs congeners. The results showed that the expressions of mCherry and endogenous cyp1a were consistent with the PAHs exposure concentrations and were largely induced by TCDD and ≥4-ring PAHs. Moreover, the sensitivity of Tg(cyp1a:mCherry) embryos was also evaluated through monitoring of the PAHs contamination in the water and soil samples. The elevated red fluorescent signals and cyp1a expression levels were observed in Tg(cyp1a:mCherry) zebrafish after exposure to water samples and soil organic extracts with higher concentrations of ≥4-ring PAHs. These results further strengthen our findings of concentration- and congener-dependent response of the newly established zebrafish. Taken together, the newly established zebrafish line will prove as a sensitive, efficient and convenient tool for monitoring PAHs and TCDD contamination in the environment.