Integration of physiology, microbiota and metabolomics reveals toxic response of zebrafish gut to co-exposure to polystyrene nanoplastics and arsenic.

Both nanoplastic (NP) particles and arsenic (As) are widespread in aquatic environments and pose a combined risk of exposure to aquatic organisms. How the gut of aquatic organisms responds to combined risk of exposure is still unclear. In this study, zebrafish (Danio rerio) were subjected to three distinct As stress environments: only As group (10 μg/L), and As combined with different concentrations of polystyrene (PS) NPs (1 mg/L and 10 mg/L) groups for 21 days via semi-static waterborne exposure. The physiological responses to combined stress, the diversity of gut microorganisms, and the metabolomic response of the gut were investigated. The findings indicated that PSNPs were prevalent in the intestines of zebrafish in the co-exposed group. Furthermore, the administration of 1 mg/L and 10 mg/L of PSNPs in the co-exposed group was observed to elevate As levels in the intestines by 24.88% and 76.95%, respectively, in comparison to As treatment alone. Simultaneous exposure of the gut to PSNPs and As resulted in increased contents/activities of MDA, SOD, CAT, and GST, and a decrease in contents/activities of GSH and GPx, when compared to As exposure alone. Additionally, the combined exposure led to an elevated expression of the Cu/Zn-sod, Mn-sod, gpx, and cat genes. The combined treatment with NPs and As resulted in an increase in the abundance of Proteobacteria and Fusobacteriota at the phylum level, as well as a significant increase in the abundance of Cetobacterium, Rhodococcus, and Bacteroides at the genus level. Non-targeted metabolomics analyses suggest that metabolic pathways affected by co-exposure include glycerophospholipid metabolism, glycerolipid metabolism, ABC transporters and autophagy. The findings of this study are of considerable significance for the evaluation of the toxicological impact of co-existing pollutants.

Li G ，Lv M ，Yu H ，Zhang H ，Zhang D ，Li Q ，Wang L ，Wu Y ... -  《-》

Trophic transfer induced gut inflammation, dysbiosis, and inflammatory pathways in zebrafish via Artemia franciscana: A differential analysis of nanoplastic toxicity.

Rising glbal population and plastic consumption have caused a dramatic increase in plastic waste, leading to micro- and nanoplastic ingestion by aquatic organisms and subsequent bioaccumulation in their tissues. This transfer to higher trophic levels raises nanoplastic concentrations and bioavailability, potentially harming organisms' health and development. This poses a risk to human health via seafood. To address these issues, this study assesses the toxicological impacts of nanoplastics (NPs) on brine shrimp (Artemia franciscana) and their trophic transfer to zebrafish. The research unveiled concentration-dependent bioaccumulation of NPs in zebrafish and Artemia franciscana (A. franciscana). Polystyrene nanoplastics (PS-NPs) exhibited higher accumulation in A. franciscana whereas PP-NPs showed greater accumulation in zebrafish gut. Histopathological analysis under PS-NPs exposure revealed significant tissue alterations, indicative of inflammatory responses and impaired mucosal barrier integrity. Gene expression analyses confirmed these findings, showing activation of the P38-MAPK pathway by PS-NPs, which correlated with increased inflammatory cytokines. Additionally, PE-NPs activated the JNK-MAPK pathway, while PP-NPs exposure triggered the NOD-like receptor signaling pathway. Moreover, the composition of gut microbiota shifted to a dysbiotic state, characterized by an increase in pathogenic bacteria in the PS-NPs and PP-NPs groups, elevating the risk of developing Inflammatory Bowel Disease (IBD). PS-NPs were regarded as the most toxic due to their lower stability and higher aggregation tendencies, followed by PP-NPs and PE-NPs. Taken together, the overall study highlighted the complex interactions between NPs, gut microbiota, and host health, emphasizing the importance of thoroughly assessing the ecological and physiological impacts of nanoplastic pollution.

Sultan M ，Cai ZX ，Bao L ，Duan JJ ，Liu YY ，Yang G ，Pei DS ... -  《-》

Effects of diuron and two of its metabolites in biochemical markers and behavior of zebrafish larvae.

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is an herbicide used in many crops, including sugar cane cultivation. It is commonly found in aquatic ecosystem and is of high concern due to its ability to persist in the environment. Diuron metabolites include DCA (3,4-dichloroaniline) and DCPMU (3-(3,4-dichlorophenyl-1-methylurea). The objective of this study was to evaluate the effects of diuron and two of its metabolites in zebrafish (Danio rerio) developing embryos, from biochemical to individual level. Activities of the enzymes acetylcholinesterase (AChE), catalase (CAT), glutathione-S-transferase (GST), and lactate dehydrogenase (LDH) and the levels of lipid peroxidation (LPO), swimming activity, and body length were investigated after an exposure of 120 h, and the heart rate was determined after 48 h of exposure. The range of concentrations tested was 0.003-3.000 mg/L diuron, 0.020-1.500 mg/L DCA, and 0.020-2.100 mg/L DCPMU. Results showed that AChE activity was inhibited by diuron (3.000 mg/L) and DCPMU (0.326, 0.828 mg/L). However, the swimming activity of fish larvae exposed to diuron or its metabolites was not affected. The CAT was induced by DCPMU, and GST was induced by diuron. This suggests that CAT is acting to cope with oxidative stress induced by DCPMU and GST might have a role in the detoxification of diuron. In addition, larvae exposed to DCA (0.633 and 1.500 mg/L) had a reduction in their length, and larvae exposed to diuron (0.754 and 3.000 mg/L) and DCA (0.267, 0.633, and 1.500 mg/L) presented bradycardia, suggesting cardiotoxicity. Overall, results indicate that diuron, DCA, or DCPMU induces adverse effects during the early phases of zebrafish development, such as the impairment of neurotransmission and cardiovascular function and alterations in antioxidant enzymes and growth. Diuron appeared as more toxic than its metabolites since the lowest LOEC (0.012 mg/L) and higher integrated biomarker response (IBR) values were obtained with exposure to this herbicide. Furthermore, as it is fast degraded into DCA and DCPMU, which also affected the zebrafish developing embryos at environmentally relevant concentrations, its use might be of concern in ecosystems that receive agriculture runoff due to their potential adverse effects to aquatic biota.

Sales BCP ，Pereira LC ，Quintaneiro C ，da Maia Soares AMV ，Monteiro MS ... -  《-》

Abrocitinib, tralokinumab and upadacitinib for treating moderate-to-severe atopic dermatitis.

Edwards SJ ，Karner C ，Jhita T ，Barton S ，Marceniuk G ，Yiu ZZN ，Wittmann M ... -  《-》

Comparison of Two Modern Survival Prediction Tools, SORG-MLA and METSSS, in Patients With Symptomatic Long-bone Metastases Who Underwent Local Treatment With Surgery Followed by Radiotherapy and With Radiotherapy Alone.

Survival estimation for patients with symptomatic skeletal metastases ideally should be made before a type of local treatment has already been determined. Currently available survival prediction tools, however, were generated using data from patients treated either operatively or with local radiation alone, raising concerns about whether they would generalize well to all patients presenting for assessment. The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA), trained with institution-based data of surgically treated patients, and the Metastases location, Elderly, Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy model (METSSS), trained with registry-based data of patients treated with radiotherapy alone, are two of the most recently developed survival prediction models, but they have not been tested on patients whose local treatment strategy is not yet decided. (1) Which of these two survival prediction models performed better in a mixed cohort made up both of patients who received local treatment with surgery followed by radiotherapy and who had radiation alone for symptomatic bone metastases? (2) Which model performed better among patients whose local treatment consisted of only palliative radiotherapy? (3) Are laboratory values used by SORG-MLA, which are not included in METSSS, independently associated with survival after controlling for predictions made by METSSS? Between 2010 and 2018, we provided local treatment for 2113 adult patients with skeletal metastases in the extremities at an urban tertiary referral academic medical center using one of two strategies: (1) surgery followed by postoperative radiotherapy or (2) palliative radiotherapy alone. Every patient's survivorship status was ascertained either by their medical records or the national death registry from the Taiwanese National Health Insurance Administration. After applying a priori designated exclusion criteria, 91% (1920) were analyzed here. Among them, 48% (920) of the patients were female, and the median (IQR) age was 62 years (53 to 70 years). Lung was the most common primary tumor site (41% [782]), and 59% (1128) of patients had other skeletal metastases in addition to the treated lesion(s). In general, the indications for surgery were the presence of a complete pathologic fracture or an impending pathologic fracture, defined as having a Mirels score of ≥ 9, in patients with an American Society of Anesthesiologists (ASA) classification of less than or equal to IV and who were considered fit for surgery. The indications for radiotherapy were relief of pain, local tumor control, prevention of skeletal-related events, and any combination of the above. In all, 84% (1610) of the patients received palliative radiotherapy alone as local treatment for the target lesion(s), and 16% (310) underwent surgery followed by postoperative radiotherapy. Neither METSSS nor SORG-MLA was used at the point of care to aid clinical decision-making during the treatment period. Survival was retrospectively estimated by these two models to test their potential for providing survival probabilities. We first compared SORG to METSSS in the entire population. Then, we repeated the comparison in patients who received local treatment with palliative radiation alone. We assessed model performance by area under the receiver operating characteristic curve (AUROC), calibration analysis, Brier score, and decision curve analysis (DCA). The AUROC measures discrimination, which is the ability to distinguish patients with the event of interest (such as death at a particular time point) from those without. AUROC typically ranges from 0.5 to 1.0, with 0.5 indicating random guessing and 1.0 a perfect prediction, and in general, an AUROC of ≥ 0.7 indicates adequate discrimination for clinical use. Calibration refers to the agreement between the predicted outcomes (in this case, survival probabilities) and the actual outcomes, with a perfect calibration curve having an intercept of 0 and a slope of 1. A positive intercept indicates that the actual survival is generally underestimated by the prediction model, and a negative intercept suggests the opposite (overestimation). When comparing models, an intercept closer to 0 typically indicates better calibration. Calibration can also be summarized as log(O:E), the logarithm scale of the ratio of observed (O) to expected (E) survivors. A log(O:E) > 0 signals an underestimation (the observed survival is greater than the predicted survival); and a log(O:E) < 0 indicates the opposite (the observed survival is lower than the predicted survival). A model with a log(O:E) closer to 0 is generally considered better calibrated. The Brier score is the mean squared difference between the model predictions and the observed outcomes, and it ranges from 0 (best prediction) to 1 (worst prediction). The Brier score captures both discrimination and calibration, and it is considered a measure of overall model performance. In Brier score analysis, the "null model" assigns a predicted probability equal to the prevalence of the outcome and represents a model that adds no new information. A prediction model should achieve a Brier score at least lower than the null-model Brier score to be considered as useful. The DCA was developed as a method to determine whether using a model to inform treatment decisions would do more good than harm. It plots the net benefit of making decisions based on the model's predictions across all possible risk thresholds (or cost-to-benefit ratios) in relation to the two default strategies of treating all or no patients. The care provider can decide on an acceptable risk threshold for the proposed treatment in an individual and assess the corresponding net benefit to determine whether consulting with the model is superior to adopting the default strategies. Finally, we examined whether laboratory data, which were not included in the METSSS model, would have been independently associated with survival after controlling for the METSSS model's predictions by using the multivariable logistic and Cox proportional hazards regression analyses. Between the two models, only SORG-MLA achieved adequate discrimination (an AUROC of > 0.7) in the entire cohort (of patients treated operatively or with radiation alone) and in the subgroup of patients treated with palliative radiotherapy alone. SORG-MLA outperformed METSSS by a wide margin on discrimination, calibration, and Brier score analyses in not only the entire cohort but also the subgroup of patients whose local treatment consisted of radiotherapy alone. In both the entire cohort and the subgroup, DCA demonstrated that SORG-MLA provided more net benefit compared with the two default strategies (of treating all or no patients) and compared with METSSS when risk thresholds ranged from 0.2 to 0.9 at both 90 days and 1 year, indicating that using SORG-MLA as a decision-making aid was beneficial when a patient's individualized risk threshold for opting for treatment was 0.2 to 0.9. Higher albumin, lower alkaline phosphatase, lower calcium, higher hemoglobin, lower international normalized ratio, higher lymphocytes, lower neutrophils, lower neutrophil-to-lymphocyte ratio, lower platelet-to-lymphocyte ratio, higher sodium, and lower white blood cells were independently associated with better 1-year and overall survival after adjusting for the predictions made by METSSS. Based on these discoveries, clinicians might choose to consult SORG-MLA instead of METSSS for survival estimation in patients with long-bone metastases presenting for evaluation of local treatment. Basing a treatment decision on the predictions of SORG-MLA could be beneficial when a patient's individualized risk threshold for opting to undergo a particular treatment strategy ranged from 0.2 to 0.9. Future studies might investigate relevant laboratory items when constructing or refining a survival estimation model because these data demonstrated prognostic value independent of the predictions of the METSSS model, and future studies might also seek to keep these models up to date using data from diverse, contemporary patients undergoing both modern operative and nonoperative treatments. Level III, diagnostic study.

Lee CC ，Chen CW ，Yen HK ，Lin YP ，Lai CY ，Wang JL ，Groot OQ ，Janssen SJ ，Schwab JH ，Hsu FM ，Lin WH ... -  《-》