Polystyrene nanoplastics cause reproductive toxicity in zebrafish: PPAR mediated lipid metabolism disorder.

The ubiquitous presence of micro-and nanoplastics (MNPs) in the environment and everyday products has attracted attention due to their hazardous risks. However, the effects of MNPs on reproduction and the underlying mechanisms remain unclear. The present study investigated the impact of polystyrene (PS) nanoplastics of 80, 200 and 500 nm diameters on zebrafish reproduction at an environmentally relevant concentration of 0.5 mg/L. Exposure to PS delayed spermatogenesis and caused aberrant follicular growth, resulting in dysgenesis in F0 adults and impacting F1 embryo development. Notably, the reproductive toxicity exhibited size-dependency, with the 500 nm PS being the most detrimental. Combined analyses of transcriptomics and metabolomics in ovary tissue revealed that treatment with 500 nm PS affected the peroxisome proliferator-activated receptor (PPAR) signaling pathway, dysregulated lipid transport, binding and activity processes, and led to dysgenesis in zebrafish. Specifically, the ovulatory dysfunction induced by PS exposure resembled clinical manifestations of polycystic ovary syndrome (PCOS) and can be attributed to lipid metabolism disorder involving glycerophospholipid, sphingolipid, arachidonic acid, and alpha-linolenic acid. Collectively, our results provide new evidence revealing the molecular mechanisms of PS-induced reproductive toxicity, highlighting that MNPs may pose a risk to female reproductive health.

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy.

The induction of cuproptosis, a recently identified form of copper-dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu2+) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis-inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis-mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor-infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death-1 (PD-1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis-mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy.

DDT exposure induces tremor-like behavior and neurotoxicity in developmental stages of embryonic zebrafish.

Dichlorodiphenyltrichloroethane (DDT) is a broad-spectrum insecticide, widely detected in environments due to its high stability characteristic and long natural half-life period. The adverse impact of DDT exposure on organisms and humans has attracted great concern worldwide. The current study explored the developmental and neurobehavioral toxicity response of DDT in embryonic zebrafish. The embryos were treated with DDT (0, 0.1, 1, 2.5 and 5 µM) during 6 h post fertilization (hpf) to 144 hpf. Our result indicated that DDT exposures increased the embryo hatching rate at 48 and 60 hpf, the larval malformation rate at 120 hpf and mortality rate at 144 hpf. The manifested malformations included uninflated swim bladder, bent spine and tail, deformed liver, and pericardial edema. The 120 hpf larval organs size of the gut and swim bladder was decreased in higher exposed concentration groups. Besides, DDT exposure resulted in hyperactivity for the embryo spontaneous movement at 24 hpf and tremor like movement measured by the free larval activity at 72 hpf, as well as the larval activity at 96 hpf under light-dark transition stimulus. Mechanistic examinations at 120 hpf revealed DDT exposure elevated oxidative stress through MDA formation increase, ATP level decrease as well as antioxidant enzyme genes (sod1 and gpx1a) expression decrease. DDT exposure induced abnormal neurotransmitters expression with DA level increase, 5-HT and NOS level decrease. DDT exposure suppressed the gene expressions involved in axon development (rab33a and nrxn2a) and potassium channel (kcnq2 and kcnq3). Our results suggest that the hyperactivity and tremor like movement in DDT-exposed embryos/larvae may result from oxidative stress involved with neuronal damage.

Primary microcephaly gene CENPE is a novel biomarker and potential therapeutic target for non-WNT/non-SHH medulloblastoma.

Background: Non-WNT/non-SHH medulloblastoma (MB) is one of the subtypes with the highest genetic heterogeneity in MB, and its current treatment strategies have unsatisfactory results and significant side effects. As a member of the centromere protein (CENP) family, centromeric protein E (CENPE) is a microtubule plus-end-directed kinetochore protein. Heterozygous mutations in CENPE can leads to primary microcephaly syndrome. It has been reported that CENPE is upregulated in MB, but its role in MB development is still unknown. Methods: We downloaded the relevant RNA seq data and matched clinical information from the GEO database. Bioinformatics analysis includes differential gene expression analysis, Kaplan-Meier survival analysis, nomogram analysis, ROC curve analysis, immune cell infiltration analysis, and gene function enrichment analysis. Moreover, the effects of CENPE expression on cell proliferation, cell cycle, and p53 signaling pathway of non-WNT/non-SHH MB were validated using CENPE specific siRNA in vitro experiments. Results: Compared with normal tissues, CENPE was highly expressed in MB tissues and served as an independent prognostic factor for survival in non-WNT/non-SHH MB patients. The nomogram analysis and ROC curve further confirmed these findings. At the same time, immune cell infiltration analysis showed that CENPE may participate in the immune response and tumor microenvironment (TME) of non-WNT/non-SHH MB. In addition, gene enrichment analysis showed that CENPE was closely related to the cell cycle and p53 pathway in non-WNT/non-SHH MB. In vitro experimental validation showed that knockdown of CENPE inhibited cell proliferation by activating the p53 signaling pathway and blocking the cell cycle. Conclusion: The expression of CENPE in non-WNT/non-SHH MB was positively correlated with poor prognosis. CENPE may affect tumor progression by regulating cell cycle, p53 pathway, and immune infiltration. Hence, CENPE is highly likely a novel biomarker and potential therapeutic target for non-WNT/non-SHH MB.

Efficient dose-volume histogram-based pretreatment patient-specific quality assurance methodology with combined deep learning and machine learning models for volumetric modulated arc radiotherapy.

BACKGROUND: Weak correlation between gamma passing rates and dose differences in target volumes and organs at risk (OARs) has been reported in several studies. Evaluation on the differences between planned dose-volume histogram (DVH) and reconstructed DVH from measurement was adopted and incorporated into patient-specific quality assurance (PSQA). However, it is difficult to develop a methodology allowing the evaluation of errors on DVHs accurately and quickly. PURPOSE: To develop a DVH-based pretreatment PSQA for volumetric modulated arc therapy (VMAT) with combined deep learning (DL) and machine learning models to overcome the limitation of conventional gamma index (GI) and improve the efficiency of DVH-based PSQA. METHODS: A DL model with a three-dimensional squeeze-and-excitation residual blocks incorporated into a modified U-net was developed to predict the measured PSQA DVHs of 208 head-and-neck (H&N) cancer patients underwent VMAT between 2018 and 2021 from two hospitals, in which 162 cases was randomly selected for training, 18 for validation, and 28 for testing. After evaluating the differences between treatment planning system (TPS) and PSQA DVHs predicted by DL model with multiple metrics, a pass or fail (PoF) classification model was developed using XGBoost algorithm. Evaluation of domain experts on dose errors between TPS and reconstructed PSQA DVHs was taken as ground truth for PoF classification model training. RESULTS: The prediction model was able to achieve a good agreement between predicted, measured, and TPS doses. Quantitative evaluation demonstrated no significant difference between predicted PSQA dose and measured dose for target and OARs, except for Dmean of PTV6900 (p = 0.001), D50 of PTV6000 (p = 0.014), D2 of PTV5400 (p = 0.009), D50 of left parotid (p = 0.015), and Dmax of left inner ear (p = 0.007). The XGBoost model achieved an area under curves, accuracy, sensitivity, and specificity of 0.89 versus 0.88, 0.89 versus 0.86, 0. 71 versus 0.71, and 0.95 versus 0.91 with measured and predicted PSQA doses, respectively. The agreement between domain experts and the classification model was 86% for 28 test cases. CONCLUSIONS: The successful prediction of PSQA doses and classification of PoF for H&N VMAT PSQA indicating that this DVH-based PSQA method is promising to overcome the limitations of GI and to improve the efficiency and accuracy of VMAT delivery.

[Acupuncture treatment of insomnia based on the spleen and stomach theory].

OBJECTIVE: To observe the impact of acupuncture on the subjective symptom, sleep quality and sleep efficiency in the patients of insomnia differentiated as spleen deficiency or non-spleen deficiency in terms of the spleen and stomach theory. METHODS: Sixty patients with insomnia were divided into a spleen deficiency group and a non-spleen deficiency group, 30 cases in each one. In the two groups, acupuncture was applied at Sishencong (EX-HN1), Shenmen (HT 7), Sanyinjiao (SP 6), Zusanli (ST 36) and Tianshu (ST 25). The treatment was given once every other day, five times as one course, and two courses were required. The Athens Insomnia Scale (AIS) was used to observe the changes in the patients' subjective symptoms. The Pittsburgh sleep quality index (PSQI) was adopted to observe the changes of patients' sleep quality. The sleep efficiency was applied to observe the changes in sleep time. The clinical efficacy was determined. RESULTS: The total effective rate was both 80. 0% (24/30) after 5 and 10 treatments in the spleen deficiency group and was 76. 7% (23/30) and 80. 0% (24/30) respectively in the non-spleen deficiency group. The differences were not significant between the two groups (both P >0. 05). The AIS total scores and PSQI total scores were reduced apparently after 5 and 10 treatments as compared with those before treatment (all P<0. 01). The difference at each time point was not significant between the two groups (all P>0. 05). The sleep efficiency after 5 and 10 treatments was all improved as compared with that before the treatment in the two groups (all P<0. 01). CONCLUSION: Acupuncture based on the spleen and stomach theory achieves possibly the same clinical efficacy in the patients of insomnia differentiated as those with spleen deficiency and non-spleen deficiency. It relieves the subjective symptoms and improves the sleep quality and sleep efficiency in the patients.