2, 5-dichloro-1, 4-benuinone exposure to zebrafish embryos/larvae causes neurodevelopmental toxicity.

2, 5-dichloro-1, 4-benuinone (2, 5-DCBQ) is an emerging disinfection by-product belonging to the class of halobenzoquinones (HBQs). However, there is limited evidence regarding the neurotoxic effects of 2, 5-DCBQ. To better understand the toxicological mechanisms of aquatic organisms, zebrafish embryos were exposed to 0.2 mg/L, 0.4 mg/L, and 0.6 mg/L of 2, 5-DCBQ from 4 h post-fertilization (hpf) to 120 hpf. Developmental defects, such as reduced body length, decreased heart rate, decreased pigmentation, and abnormal motor axon structure was observed. In particular, the locomotor activity of zebrafish larvae reduced with exposure to increasing 2, 5-DCBQ concentrations, and this effect was more pronounced under dark stimulation. The results indicated that the genes associated with neuronal development (gfap, mbp, syn2a, elavl3, ache, and a1-tubulin) were significantly downregulated after treatment with 2, 5-DCBQ. Furthermore, the KEGG result showed the neuroactive ligand-receptor interaction and apoptosis pathways were visibly disrupted, and we found acetylcholinesterase activity was also affected. In summary, the disinfection by-product, 2, 5-DCBQ, exhibits neurodevelopmental toxicity in zebrafish embryos, providing novel evidence for comprehensive analyses of its toxicity.

Identification of the miRNA signature and key genes in colorectal cancer lymph node metastasis.

BACKGROUND: Because its metastasis to the lymph nodes are closely related to poor prognosis, miRNAs and mRNAs can serve as biomarkers for the diagnosis, prognosis, and therapy of colorectal cancer (CRC). This study aimed to identify novel gene signatures in the lymph node metastasis of CRC. METHODS: GSE56350, GSE70574, and GSE95109 datasets were downloaded from the Gene Expression Omnibus (GEO) database, while data from 569 colorectal cancer cases were also downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed miRNAs (DE-miRNAs) were calculated using R programming language (Version 3.6.3), while gene ontology and enrichment analysis of target mRNAs were performed using FunRich ( http://www.funrich.org ). Furthermore, the mRNA-miRNA network was constructed using Cytoscape software (Version 3.8.0). Gene expression levels were verified using the GEO datasets. Similarly, quantitative real-time PCR (qPCR) was used to examine expression profiles from 20 paired non-metastatic and metastatic lymph node tissue samples obtained from patients with CRC. RESULTS: In total, five DE-miRNAs were selected, and 34 mRNAs were identified after filtering the results. Moreover, two key miRNAs (hsa-miR-99a, hsa-miR-100) and one gene (heparan sulfate-glucosamine 3-sulfotransferase 2 [HS3ST2]) were identified. The GEO datasets analysis and qPCR results showed that the expression of key miRNA and genes were consistent with that obtained from the bioinformatic analysis. A novel miRNA-mRNA network capable of predicting the prognosis and confirmed experimentally, hsa-miR-99a-HS3ST2-hsa-miR-100, was found after expression analysis in metastasized lymph node tissue from CRC samples. CONCLUSION: In summary, miRNAs and genes with potential as biomarkers were found and a novel miRNA-mRNA network was established for CRC lymph node metastasis by systematic bioinformatic analysis and experimental validation. This network may be used as a potential biomarker in the development of lymph node metastatic CRC.

High Expression of N-Acetylgalactosaminyl-transferase 1 (GALNT1) Associated with Invasion, Metastasis, and Proliferation in Osteosarcoma.

BACKGROUND Osteosarcoma (OS) is very common worldwide, and the mechanisms underlying its development remain unclear. This study aims to identify key genes promoting the reproduction, invasion, and transfer of osteosarcoma cells. MATERIAL AND METHODS Gene expression profile data (GSE42352 and GSE42572) were downloaded from the Gene Expression Omnibus database. Differentially expressed genes were calculated using R software. Gene ontology and enriched pathway analysis of mRNAs were analyzed by using FunRich. Verification of the genes was conducted by using quantitative real-time polymerase chain reaction and western blot analyses to measure gene expression. Transwell and wound-healing assays were performed on osteosarcoma cells after knockdown to detect whether the genes enhanced the aggressiveness of osteosarcoma. RESULTS In total, 34 genes were selected after filtering. Kyoto Encyclopedia of Genes and Genomes enrichment analysis demonstrated that the genes were enriched in multiple tumor pathways. N-acetylgalactosaminyltransferase 1 (GALNT1) was identified for further study, and its expression was higher in osteosarcoma cells than in human osteoblasts. The invasion ability of cells was significantly decreased after gene knockdown. CONCLUSIONS Through the use of microarray and bioinformatics analysis, differentially expressed genes were selected and a complete gene network was constructed. Our findings provide new biomarkers for the treatment and prognosis of osteosarcoma. These biomarkers may contribute to the discovery of new therapeutic targets for clinical application.

Thermo-Sensitive Liposome co-Loaded of Vincristine and Doxorubicin Based on Their Similar Physicochemical Properties had Synergism on Tumor Treatment.

PURPOSE: To develop vincristine (VCR) and doxorubicin (DOX) co-encapsulated thermo-sensitive liposomes (VD-TSL) against drug resistance, with increased tumor inhibition rate and decreased system toxicity, improving drug targeting efficiency upon mild hyperthermia (HT) in solid tumor. METHODS: Based on similar physicochemical properties, VCR and DOX were co-loaded in TSL with pH gradient active loading method and characterized. The time-dependent drug release profiles at 37 and 42°C were assessed by HPLC. Then we analysed the phospholipids in filtrate after ultrafiltration and studied VD-TSL stability in mimic in vivo conditions and long-time storage conditions (4°C and -20°C). Cytotoxic effect was studied on PANC and sw-620 using MTT. Intracellular drug delivery was studied by confocal microscopy on HT-1080. In vivo imaging of TSL pharmacokinetic and biodistribution was performed on MCF-7 tumor-bearing nude mice. And therapeutic efficacy on these xenograft models were followed under HT. RESULTS: VD-TSL had excellent particle distribution (about 90 nm), high entrapment efficiency (>95%), obvious thermo-sensitive property, and good stability. MTT proved VD-TSL had strongest cell lethality compared with other formulations. Confocal microscopy demonstrated specific accumulation of drugs in tumor cells. In vivo imaging proved the targeting efficiency of TSL under hyperthermia. Then therapeutic efficacy revealed synergism of VCR and DOX co-loaded in TSL, together with HT. CONCLUSION: VD-TSL could increase drug efficacy and decrease system toxicity, by making good use of synergism of VCR and DOX, as well as high targeting efficiency of TSL.

[Current status and prospect of translational medicine in nanotechnology].

Nowadays, nanotechnologies have shown wide application foreground in the biomedical field of medicine laboratory tests, drug delivery, gene therapy and bioremediation. However, in recent years, nanomaterials have been labeled poisonous, because of the disputes and misunderstandings of mainstream views on their safety. Besides, for the barriers of technical issues in preparation like: (1) low efficacy (poor PK & PD and low drug loading), (2) high cost (irreproducibility and difficulty in scale up), little of that research has been successfully translated into commercial products. Currently, along with the new theory of "physical damage is the origin of nanotoxicity", biodegradability and biocompatibility of nanomaterials are listed as the basic principle of safe application of nanomaterials. Combining scientific design based on molecular level with precision control of process engineering will provide a new strategy to overcome the core technical challenges. New turning point of translational medicine in nanotechnology may emerge.

Keratin 6A (KRT6A) promotes radioresistance, invasion, and metastasis in lung cancer via p53 signaling pathway.

BACKGROUND: It is reported that the incidence rate and mortality of lung cancer are very high. Therefore, early diagnosis and identification of specific biomarkers are crucial for the clinical treatment of lung cancer. This study aims to comprehensively investigate the prognostic significance of KRT6A in human lung cancer. METHODS: The GEO2R online tool was utilized to analyze the differential expression of mRNA between lung carcinoma tissues and radioresistant tissues in the GSE73095 and GSE197236 datasets. DAVID database was used to perform GO and KEGG enrichment analyses on target genes. The Kaplan-Meier plotter tool was used to analyze the impact of key messenger ribonucleic acid on the survival status of lung cancer. In addition, quantitative real-time polymerase chain reaction (qPCR) was used to investigate the impact of key genes on the phenotype of lung cancer cells. After the knockout, we conducted cell migration and CCK-8 experiments to detect their effects on cell proliferation and invasion. RESULTS: 40 differentially expressed genes (DEGs) were chosen from GSE73095 and 118 DEGs were chosen from GSE197236. Kaplan-Meier map analysis showed that the overall cancer survival rate of the high-expression KRT6A group was higher than that of the low-expression group (P < 0.05). Besides, cell experiments have shown that when the KRT6A gene is downregulated, the proliferation and invasion ability of lung cancer cells is weakened. CONCLUSIONS: Our research concluded that KRT6A may take part in the radioresistance and progression of lung cancer and can be a potential biomarker for lung cancer patients.

Emerging insights into cuproptosis and copper metabolism: implications for age-related diseases and potential therapeutic strategies.

The expanding geriatric population, whose predisposition toward disabling morbidities and age-related diseases (ARD) is well-documented, has become a paramount social issue, exerting an onerous burden on both the healthcare industry and wider society. ARD manifest as the progressive deterioration of bodily tissues and organs, eventually resulting in the failure of these vital components. At present, no efficacious measures exist to hinder the onset of ARD. Copper, an essential trace element, is involved in a wide range of physiological processes across different cell types. In recent research, a novel variant of copper-dependent cell death, termed cuproptosis, has been identified. This mode of cellular demise stands apart from previously recognized types of cell death. Cuproptosis occurs when copper binds with acyl-CoA synthetase in the tricarboxylic acid (TCA) cycle, resulting in protein aggregation and protein toxicity stress, ultimately leading to cell death. In this paper, we provide a concise overview of the current understanding concerning the metabolism of copper, copper-related diseases, the hallmarks of copper toxicity, and the mechanisms that regulate copper toxicity. Additionally, we discuss the implications of cuproptosis mutations in the development of ARD, as well as the potential for targeting cuproptosis as a treatment for ARD.

The combination of body mass index and fasting plasma glucose is associated with type 2 diabetes mellitus in Japan: a secondary retrospective analysis.

Background: Body mass index (BMI) and fasting plasma glucose (FPG) are known risk factors for type 2 diabetes mellitus (T2DM), but data on the prospective association of the combination of BMI and FPG with T2DM are limited. This study sought to characterize the association of the combination of BMI and FPG (ByG) with T2DM. Methods: The current study used the NAGALA database. We categorized participants by tertiles of ByG. The association of ByG with T2DM was expressed with hazard ratios (HRs) with 95% confidence intervals (CIs) after adjustment for potential risk factors. Results: During a median follow-up of 6.19 years in the normoglycemia cohort and 5.58 years in the prediabetes cohort, the incidence of T2DM was 0.75% and 7.79%, respectively. Following multivariable adjustments, there were stepwise increases in T2DM with increasing tertiles of ByG. After a similar multivariable adjustment, the risk of T2DM was 2.57 (95% CI 2.26 - 2.92), 1.97 (95% CI 1.53 - 2.54) and 1.50 (95% CI 1.30 - 1.74) for a per-SD change in ByG in all populations, the normoglycemia cohort and the prediabetes cohort, respectively. Conclusion: ByG was associated with an increased risk of T2DM in Japan. The result reinforced the importance of the combination of BMI and FPG in assessing T2DM risk.

Waist circumference glucose, a novel and effective predictor of type 2 diabetes: a prospective cohort study.

Introduction: Waist circumference (WC) and fasting plasma glucose (FPG) have been demonstrated as risk factors for type 2 diabetes mellitus (T2DM). Evidence is limited regarding the association of the combination of WC and FPG (WyG) with the risk of T2DM. The primary aim of the study was to investigate the relationship between WyG and T2DM. Research design and methods: The current study was a population-based cohort study using data from the NAGALA database. Participants were divided into tertiles based on WyG. Cox proportional hazard regression model was applied to identify the association of WyG with T2DM. Results: During a median follow-up of 6.19 years in the normoglycemia group and 5.58 years in the prediabetes group, respectively, 88 and 285 individuals in the two groups received a diagnosis of T2DM. After full adjustment, risk of T2DM increased in step-wise fashion with increasing tertiles of WyG. For a per-SD increase in WyG, the hazard ratios for T2DM were 3.05 (95% CI 2.64 - 3.51) in all populations, 1.94 (95% CI 1.46 - 2.58) in the normoglycemia group and 1.63 (95% CI 1.40 - 1.90) in the prediabetes group. The interaction between WyG and fatty liver on T2DM was statistically significant in the prediabetes group (P for interaction = 0.034). Conclusions: Elevated WyG was independently associated with incident T2DM in Japan. Baseline WyG help identify individuals at high risk of T2DM and implement effective preventive measures.

DANet: Semi-supervised differentiated auxiliaries guided network for video action recognition.

Video Action Recognition (ViAR) aims to identify the category of the human action observed in a given video. With the advent of Deep Learning (DL) techniques, noticeable performance breakthroughs have been achieved in this study. However, the success of most existing DL-based ViAR methods heavily relies on the existence of a large amount of annotated data, i.e., videos with corresponding action categories. In practice, obtaining such a desired number of annotations is often difficult due to expensive labeling costs, which may lead to significant performance degradation for these methods. To address this issue, we propose an end-to-end semi-supervised Differentiated Auxiliary guided Network (DANet) to best use a few annotated videos. Except for the common supervised learning on a few annotated videos, the DANet also involves the knowledge of multiple pre-trained auxiliary networks to optimize the ViAR network in a self-supervised way on the unannotated data by removing the annotations. Considering the tight connection between video action recognition and classical static image-based visual tasks, the abundant knowledge from the pre-trained static image-based models can be used for training the ViAR model. Specifically, the DANet is a two-branch architecture, which includes a target branch of the ViAR network, and an auxiliary branch of multiple auxiliary networks (i.e., referring to diverse off-the-shelf models of relevant image tasks). Given a limited number of annotated videos, we train the target ViAR network end-to-end in a semi-supervised way, namely, with both the supervised cross-entropy loss on annotated videos, and the per-auxiliary weighted self-supervised contrastive losses on the same videos but without using annotations. Besides, we further explore different weighted guidance of the auxiliary networks to the ViAR network to better reflect different relationships between the image-based models and the ViAR model. Finally, we conduct extensive experiments on several popular action recognition benchmarks in comparison with existing state-of-the-art methods, and the experimental results demonstrate the superiority of DANet over most of the compared methods. In particular, the DANet obviously suppresses state-of-the-art ViAR methods even with very fewer annotated videos.