Improper toy waste handling can harm human health via seafood consumption: A comprehensive risk assessment of heavy metals.

Toy production has been increasing over the last few decades to meet the growing demands for toys across the globe, which has inevitably worsened the problem of toy waste. Given the lack of modern waste disposal facilities, rural villagers in developing countries often discard and incinerate toy waste in backyards or riverbanks, which may release the pollutants from toys (e.g., heavy metals), contaminate the surrounding areas, and eventually threaten the health of residents. As such, this study assessed the impact of improper toy waste handling on the nearby aquaculture site by measuring the contamination level of heavy metals (As, Cd, Cu, Pb, and Zn) in the sediment and seafood (crabs, shrimps, and fish). The health risk of heavy metals via seafood consumption was assessed in different groups of people (males, females, teenagers, and seniors). Results showed that the sediment and seafood at the aquaculture site were generally not contaminated with heavy metals (i.e., contamination factor and bioaccumulation factor < 1). However, consuming the seafood cultured at this site, especially for crabs, could pose health risks to humans due to As and Cd (hazard quotient > 1), irrespective of their age and gender. This risk could not be lowered by cooking, except As by boiling. Overall, we revealed that improper toy waste handling did not cause severe heavy metal pollution in the surrounding environment. However, the consumption of contaminated seafood could still threaten human health. To safeguard public health, we propose that toy waste be appropriately treated by the authorities concerned. At the same time, consuming seafood with long culture periods (e.g., crabs) should be reduced to minimize the dietary intake of heavy metals and their associated health risk.

Harmonizing florbetapir and PiB PET measurements of cortical Aß plaque burden using multiple regions-of-interest and machine learning techniques: An alternative to the Centiloid approach.

INTRODUCTION: Machine learning (ML) can optimize amyloid (Aß) comparability among positron emission tomography (PET) radiotracers. Using multi-regional florbetapir (FBP) measures and ML, we report better Pittsburgh compound-B (PiB)/FBP harmonization of mean-cortical Aß (mcAß) than Centiloid. METHODS: PiB-FBP pairs from 92 subjects in www.oasis-brains.org and 46 in www.gaain.org/centiloid-project were used as the training/testing sets. FreeSurfer-extracted FBP multi-regional Aß and actual PiB mcAß in the training set were used to train ML models generating synthetic PiB mcAß. The correlation coefficient (R) between the synthetic/actual PiB mcAß in the testing set was assessed. RESULTS: In the testing set, the synthetic/actual PiB mcAß correlation R = 0.985 (R2  = 0.970) using artificial neural network was significantly higher (p ≤ 6.6e-4) than the FBP/PiB correlation R = 0.927 (R2  = 0.860), improving total variance percentage (R2 ) from 86% to 97%. Other ML models such as partial least square, ensemble, and relevance vector regressions also improved R (p = 9.677e-05 /0.045/0.0017). DISCUSSION: ML improved mcAß comparability. Additional studies are needed for the generalizability to other amyloid tracers, and to tau PET. Highlights Centiloid is a calibration of the amyloid scale, not harmonization. Centiloid unifies the amyloid scale without improving inter-tracer association (R2 ). Machine learning (ML) can harmonize the amyloid scale by improving R2 . ML harmonization maps multi-regional florbetapir SUVRs to PiB mean-cortical SUVR. Artificial neural network ML increases Centiloid R2 from 86% to 97%.

Dentin matrix protein 1 and HUVEC-ECM scaffold promote the differentiation of human dental pulp stem cells into endothelial lineage: implications in regenerative medicine.

Reprograming of the dental pulp somatic cells to endothelial cells is an attractive strategy for generation of new blood vessels. For tissue regeneration, vascularization of engineered constructs is crucial to improve repair mechanisms. In this study, we show that dentin matrix protein 1 (DMP1) and HUVEC-ECM scaffold enhances the differentiation potential of dental pulp stem cells (DPSCs) to an endothelial phenotype. Our results show that the differentiated DPSCs expressed endothelial markers CD31 and VE-Cadherin (CD144) at 7 and 14 days. Expression of CD31 and VE-Cadherin (CD144) were also confirmed by immunofluorescence. Furthermore, flow cytometry analysis revealed a steady increase in CD31 and VE-Cadherin (CD144) positive cells with DMP1 treatment when compared with control. In addition, integrins specific for endothelial cells were highly expressed during the differentiation process. The endothelial cell signature of differentiated DPSCs were additionally characterized for key endothelial cell markers using gene expression by RT-PCR, Western blotting, immunostaining, and RNA-seq analysis. Furthermore, the angiogenic phenotype was confirmed by tubule and capillary sprout formation. Overall, stimulation of DPSCs by DMP1 and use of HUVEC-ECM scaffold promoted their differentiation into phenotypically, transcriptionally, and functionally differentiated bonafide endothelial cells. This study is novel, physiologically relevant and different from conventional strategies.

Combination of TrxR1 inhibitor and lenvatinib triggers ROS-dependent cell death in human lung cancer cells.

Lung cancer is one of the most lethal diseases in the world. Although there has been significant progress in the treatment of lung cancer, there is still a lack of effective strategies for advanced cases. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has achieved much attention due to its antitumor properties. Nevertheless, the use of lenvatinib is restricted by the characteristics of poor efficacy and drug resistance. In this study, we assessed the effectiveness of lenvatinib combined with thioredoxin reductase 1 (TrxR1) inhibitors in human lung cancer cells. Our results indicate that the combination therapy involving TrxR1 inhibitors and lenvatinib exhibited significant synergistic antitumor effects in human lung cancer cells. Moreover, siTrxR1 also showed significant synergy with lenvatinib in lung cancer cells. Mechanically, we demonstrated that ROS accumulation significantly contributes to the synergism between lenvatinib and TrxR1 inhibitor auranofin. Furthermore, the combination of lenvatinib and auranofin can activate endoplasmic reticulum stress and JNK signaling pathways to achieve the goal of killing lung cancer cells. Importantly, combination therapy with lenvatinib and auranofin exerted a synergistic antitumor effect in vivo. To sum up, the combination therapy involving lenvatinib and auranofin may be a potential strategy for treating lung cancer.

[Mechanism of electroacupuncture for vascular dementia based on proteomics].

OBJECTIVE: To explore the potential mechanism of electroacupuncture (EA) for vascular dementia (VD) using tandem mass tag (TMT) quantitative proteomics technology. METHODS: Among 80 male SPF SD rats, 78 rats which met the selection criteria through the Morris water maze test were selected and randomly divided into a sham surgery group (18 rats) and a surgery group (60 rats). VD model was established by four-vessel occlusion (4-VO) method in the surgery group, and 36 rats with successful modeling were randomly assigned to a model group (18 rats) and an EA group (18 rats). Each group was further divided into three subgroups based on intervention duration, with each subgroup containing 6 rats. Seven days after model establishment, the EA group received EA intervention at left and right "Sishencong" (EX-HN 1) and bilateral "Fengchi" (GB 20), with continuous wave at a frequency of 2 Hz and current intensity of 1 mA, daily for 30 min, with subgroups receiving EA for 7, 14, or 21 d respectively. Cognitive function before and after interventions was assessed using Morris water maze. Proteomic analysis was conducted on the optimal EA subgroup and corresponding sham surgery and model subgroups, identifying differentially expressed proteins and analyzing them through bioinformatics. Differentially expressed target proteins was performed using parallel reaction monitoring (PRM) and Western blot techniques. RESULTS: Compared to the sham surgery group, the model group exhibited prolonged escape latency and reduced number of platform crossings (P<0.01); compared with model group, the EA group showed reductions in escape latency and increased platform crossings after 7, 14, and 21 days of intervention (P<0.01, P<0.05). Compared to the 7 and 14-day intervention, the rats in the EA group of 21-day intervention showed the most significant improvements in reductions of escape latency and increased platform crossings (P<0.01, P<0.05), and was selected for further proteomic, PRM analyses, and Western blot validation. Compared to the sham surgery group, the model group displayed 71 differentially expressed proteins, with 50 up-regulated and 21 down-regulated proteins; compared to the model group, the EA group had 54 differentially expressed proteins, with 30 up-regulated and 24 down-regulated proteins. Functional enrichment and clustering analyses indicated that these proteins were primarily associated with cellular processes, metabolic processes, phagocytosis recognition, immune response, and regulation of extracellular matrix, etc. Enrichment was observed in the mammalian target of rapamycin (mTOR) signaling pathway and neurotrophic factors signaling pathways, involving glycogen synthase kinase 3ß (GSK3ß) and mitogen-activated protein kinase kinase 2 (Map2k2), with PRM and Western blot findings consistent with the proteomic results. Which meant that compared with the model group, the protein expression of GSK3ß and Map2k2 of hippocampus was increased in the EA group (P<0.01, P<0.05). CONCLUSION: EA at "Sishencong" (EX-HN 1) and "Fengchi" (GB 20) could improve cognitive function in VD rats, with the mechanism involving multiple targets and pathways, potentially related to GSK3ß, Map2k2 proteins, and the mTOR and neurotrophic factor signaling pathways.

Link between mutations in ACVRL1 and PLA2G4A genes and chronic intestinal ulcers: A case report and review of literature.

BACKGROUND: Genetic factors of chronic intestinal ulcers are increasingly garnering attention. We present a case of chronic intestinal ulcers and bleeding associated with mutations of the activin A receptor type II-like 1 (ACVRL1) and phospholipase A2 group IVA (PLA2G4A) genes and review the available relevant literature. CASE SUMMARY: A 20-year-old man was admitted to our center with a 6-year history of recurrent abdominal pain, diarrhea, and dark stools. At the onset 6 years ago, the patient had received treatment at a local hospital for abdominal pain persisting for 7 d, under the diagnosis of diffuse peritonitis, acute gangrenous appendicitis with perforation, adhesive intestinal obstruction, and pelvic abscess. The surgical treatment included exploratory laparotomy, appendectomy, intestinal adhesiolysis, and pelvic abscess removal. The patient's condition improved and he was discharged. However, the recurrent episodes of abdominal pain and passage of black stools started again one year after discharge. On the basis of these features and results of subsequent colonoscopy, the clinical diagnosis was established as inflammatory bowel disease (IBD). Accordingly, aminosalicylic acid, immunotherapy, and related symptomatic treatment were administered, but the symptoms of the patient did not improve significantly. Further investigations revealed mutations in the ACVRL1 and PLA2G4A genes. ACVRL1 and PLA2G4A are involved in angiogenesis and coagulation, respectively. This suggests that the chronic intestinal ulcers and bleeding in this case may be linked to mutations in the ACVRL1 and PLA2G4A genes. Oral Kangfuxin liquid was administered to promote healing of the intestinal mucosa and effectively manage clinical symptoms. CONCLUSION: Mutations in the ACVRL1 and PLA2G4A genes may be one of the causes of chronic intestinal ulcers and bleeding in IBD. Orally administered Kangfuxin liquid may have therapeutic potential.

Synergistic targeting of TrxR1 and ATM/AKT pathway in human colon cancer cells.

Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer.

Deep learning model to predict lupus nephritis renal flare based on dynamic multivariable time-series data.

OBJECTIVES: To develop an interpretable deep learning model of lupus nephritis (LN) relapse prediction based on dynamic multivariable time-series data. DESIGN: A single-centre, retrospective cohort study in China. SETTING: A Chinese central tertiary hospital. PARTICIPANTS: The cohort study consisted of 1694 LN patients who had been registered in the Nanjing Glomerulonephritis Registry at the National Clinical Research Center of Kidney Diseases, Jinling Hospital from January 1985 to December 2010. METHODS: We developed a deep learning algorithm to predict LN relapse that consists of 59 features, including demographic, clinical, immunological, pathological and therapeutic characteristics that were collected for baseline analysis. A total of 32 227 data points were collected by the sliding window method and randomly divided into training (80%), validation (10%) and testing sets (10%). We developed a deep learning algorithm-based interpretable multivariable long short-term memory model for LN relapse risk prediction considering censored time-series data based on a cohort of 1694 LN patients. A mixture attention mechanism was deployed to capture variable interactions at different time points for estimating the temporal importance of the variables. Model performance was assessed according to C-index (concordance index). RESULTS: The median follow-up time since remission was 4.1 (IQR, 1.7-6.7) years. The interpretable deep learning model based on dynamic multivariable time-series data achieved the best performance, with a C-index of 0.897, among models using only variables at the point of remission or time-variant variables. The importance of urinary protein, serum albumin and serum C3 showed time dependency in the model, that is, their contributions to the risk prediction increased over time. CONCLUSIONS: Deep learning algorithms can effectively learn through time-series data to develop a predictive model for LN relapse. The model provides accurate predictions of LN relapse for different renal disease stages, which could be used in clinical practice to guide physicians on the management of LN patients.

Aggregation-Induced Emission-Active Photosensitizer-Mediated Photodynamic Therapy for Anti-Psoriasis.

Hyperproliferative keratinocytes and subcutaneous inflammation contribute to the characteristic symptoms of psoriasis, including erythema, scales, or scaly plaques on the skin. These symptoms significantly affect patients' quality of life and cause severe physical and psychological distress. However, current treatment strategies have limited therapeutic effect and may lead to adverse side effects. In this study, we present the novel organic photosensitizer TBTDC [5-(((5-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)methylene)amino)-3-methylthiophene-2,4-dicarbonitrile] nanoparticles (NPs) with aggregation-induced emission (AIE) characteristics to mediate photodynamic therapy (TBTDC NP-PDT) for psoriasis treatment. We demonstrate that TBTDC NPs effectively generate reactive oxygen species upon light irradiation and lead to significant apoptosis of psoriatic keratinocytes. Furthermore, TBTDC NPs exhibit high cellular uptake in diseased keratinocytes and induce endoplasmic reticulum stress (ERS)-mediated autophagy, which can also enhance apoptosis. Importantly, TBTDC NPs show no cytotoxicity toward keratinocytes. These unique properties of TBTDC NPs enable remarkable therapeutic effects against psoriasis-like skin lesions and related inflammation in vivo. Overall, our AIE-active TBTDC NP-PDT represents a promising strategy for treating psoriasis in clinical settings.

Substantial decline of organ preservation fluid contamination following adoption of ischemia-free liver transplantation: a post-hoc analysis.

INTRODUCTION: Preservation fluid (PF) contaminations are common in conventional liver transplantation (CLT) and presumably originate from organ or PF exposures to the external environment in a non-strict sterile manner. Such exposures and PF contamination may be avoided in ischaemia-free liver transplantation (IFLT) because of the strict sterile surgical procedures. In this study, the authors evaluated the impact of IFLT on organ PF contamination. METHODS: A post-hoc analysis using data from the first randomized controlled trial of IFLT was performed to compare the incidence, pathogenic spectrum of PF contamination, and incidence of early recipient infection between IFLT and CLT. Multivariable logistic regression was used to explore risk factors for PF contamination. RESULTS: Of the 68 cases recruited in the trial, 64 were included in this post-hoc analysis. The incidence of culture-positive PF was 9.4% (3/32) in the IFLT group versus 78.1% (25/32) in the CLT group ( P <0.001). Three microorganisms were isolated from PF in the IFLT group, while 43 were isolated in the CLT group. The recipient infection rate within postoperative day 14 was 3.1% (1/32) in the IFLT group vs 15.6% (5/32) in the CLT group, although this difference did not reach statistical significance ( P =0.196). Multivariate analysis revealed that adopting IFLT is an independent protective factor for culture-positive PF. CONCLUSION: PF contamination is substantially decreased in IFLT, and IFLT application is an independent protective factor for PF contamination. Using rigorous sterile measures and effective antibiotic therapy during IFLT may decrease PF contamination.