Altered leptin level in autism spectrum disorder and meta-analysis of adipokines.

BACKGROUND: Increasing evidence suggests that leptin is involved in the pathology of autism spectrum disorder (ASD). In this study, our objective was to investigate the levels of leptin in the blood of children with ASD and to examine the overall profile of adipokine markers in ASD through meta-analysis. METHODS: Leptin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) kit, while adipokine profiling, including leptin, was performed via meta-analysis. Original reports that included measurements of peripheral adipokines in ASD patients and healthy controls (HCs) were collected from databases such as Web of Science, PubMed, and Cochrane Library. These studies were collected from September 2022 to September 2023 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Standardized mean differences were calculated using a random effects model for the meta-analysis. Additionally, we performed meta-regression and explored heterogeneity among studies. RESULTS: Our findings revealed a significant increase in leptin levels in children with ASD compared to HCs (p = 0.0319). This result was consistent with the findings obtained from the meta-analysis (p < 0.001). Furthermore, progranulin concentrations were significantly reduced in children with ASD. However, for the other five adipokines analyzed, there were no significant differences observed between the children with ASD and HCs children. Heterogeneity was found among the studies, and the meta-regression analysis indicated that publication year and latitude might influence the results of the meta-analysis. CONCLUSIONS: These findings provide compelling evidence that leptin levels are increased in children with ASD compared to healthy controls, suggesting a potential mechanism involving adipokines, particularly leptin, in the pathogenesis of ASD. These results contribute to a better understanding of the pathology of ASD and provide new insights for future investigations.

Prognostic analysis of systemic antitumor therapy in young patients with advanced liver cancer: A cohort study.

Advanced liver cancer is the most common malignant tumor in the elderly, but it also occurs in young people in areas where hepatitis B virus is prevalent. The aim of the present study was to assess the efficacy of systemic antitumor therapy in young patients with advanced liver cancer and investigate the influencing factors. The baseline demographic and clinical data of 38 young patients (≤35 years old) with liver cancer were collected as group A and that of 79 elderly patients (≥55 years old) with liver cancer were collected as group B. There were no significant between-group differences regarding the proportion of patients with increased serum aspartate aminotransferase, low serum albumin, increased α-fetoprotein (AFP) and high Child-Pugh score. The median (m)PFS time in groups A and B was 3.9 and 8.3 months, respectively [hazard ratio (HR), 1.702; P=0.009]. The mOS in group A (17.6 months) was 12.4 months shorter than that in group B (HR, 1.799; P=0.010). In the subgroup analysis, male sex [HR, 1.73; 95% confidence interval (CI), 1.07-2.79], pathological diagnosis (HR, 1.79; 95% CI, 1.10-2.91), previous surgical treatment (HR, 2.16; 95% CI, 1.18-3.95), no tumor thrombus (HR, 2.45; 95% CI, 1.22-4.93), increased alanine aminotransferase (HR, 2.23; 95% CI, 1.07-4.65), increased aspartate aminotransferase (HR, 3.22; 95% CI, 1.62-6.39), normal total bilirubin (HR, 1.77; 95% CI, 1.09-2.87) and increased AFP (HR, 2.02; 95% CI, 1.19-3.41) were associated with shorter survival time in group A compared with those in group B (P<0.05). Group A also had a higher incidence of hyper-progressive disease (HPD) (31.6 vs. 3.8%; P<0.001). HPD was a risk factor for advanced liver cancer (HR, 4.530; 95% CI, 2.251-9.115; P<0.001]. In conclusion, the efficacy of systemic antitumor therapy in young patients was poorer compared with that in elderly patients. Young patients with liver cancer had a high HBV infection rate and were prone to HPD.

Downregulation of enhancer RNA AC003092.1 is associated with poor prognosis in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is the most common histological type of renal cancer, enhancer RNA plays a significant role in tumor growth, however, it has been less studied in renal cancer. The aim of this study was to investigate the role of eRNA AC003092.1 in KIRC. Clinical and RNA expression data were downloaded from a TCGA database, and performed bioinformatics analysis, including expression level analysis, survival analysis, clinical correlation analysis, immune correlation analysis. We further confirmed the expression level of AC003092.1 between normal and tumor cell, predicted the biological role of AC003092.1 in KIRC, and performed cell proliferation and wound healing assays, followed by GSEA enrichment analysis and western blot to detect the proteins of the enriched pathway. Bioinformatics results showed that AC003092.1 expression was elevated in tumor tissues, and knockdown of AC003092.1 expression inhibited cell proliferation and migration. GSEA and western blot results showed that knockdown AC003092.1 expression alleviated the extracellular matrix (ECM) process in KIRC cell lines. Our study provides evidence that AC003092.1 play an important role in KIRC, and AC003092.1 may promote tumor cell progression by affecting the ECM process during tumor development.

HyGloadAttack: Hard-label black-box textual adversarial attacks via hybrid optimization.

Hard-label black-box textual adversarial attacks present a highly challenging task due to the discrete and non-differentiable nature of text data and the lack of direct access to the model's predictions. Research in this issue is still in its early stages, and the performance and efficiency of existing methods has potential for improvement. For instance, exchange-based and gradient-based attacks may become trapped in local optima and require excessive queries, hindering the generation of adversarial examples with high semantic similarity and low perturbation under limited query conditions. To address these issues, we propose a novel framework called HyGloadAttack (adversarial Attacks via Hybrid optimization and Global random initialization) for crafting high-quality adversarial examples. HyGloadAttack utilizes a perturbation matrix in the word embedding space to find nearby adversarial examples after global initialization and selects synonyms that maximize similarity while maintaining adversarial properties. Furthermore, we introduce a gradient-based quick search method to accelerate the search process of optimization. Extensive experiments on five datasets of text classification and natural language inference, as well as two real APIs, demonstrate the significant superiority of our proposed HyGloadAttack method over state-of-the-art baseline methods.

Obeticholic Acid Inhibit Mitochondria Dysfunction Via Regulating ERK1/2-DRP Pathway to Exert Protective Effect on Lipopolysaccharide-Induced Myocardial Injury.

Farnesoid X receptor (FXR) plays critical regulatory roles in cardiovascular physiology/pathology. However, the role of FXR agonist obeticholic acid (OCA) in sepsis-associated myocardial injury and underlying mechanisms remain unclear. C57BL/6J mice are treated with OCA before lipopolysaccharide (LPS) administration. The histopathology of the heart and assessment of FXR expression and mitochondria function are performed. To explore the underlying mechanisms, H9c2 cells, and primary cardiomyocytes are pre-treated with OCA before LPS treatment, and extracellular signal-regulated protein kinase (ERK) inhibitor PD98059 is used. LPS-induced myocardial injury in mice is significantly improved by OCA pretreatment. Mechanistically, OCA pretreatment decreased reactive oxygen species (ROS) levels and blocked the loss of mitochondrial membrane potential (ΔΨm) in cardiomyocytes. The expression of glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF-2) increased in the case of OCA pretreatment. In addition, OCA improved mitochondria respiratory chain with increasing Complex I expression and decreasing cytochrome C (Cyt-C) diffusion. Moreover, OCA pretreatment inhibited LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway. FXR agonist OCA inhibits LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway to protect mice against LPS-induced myocardial injury.

[Effect of Low-Dose Recombinant Interleukin-2 Therapy on Immunocyte Subsets in Children with Solid Tumor].

OBJECTIVE: To evaluate the effect of low-dose recombinant interleukin-2 (rIL-2) therapy on immunocyte subsets and its side effects in children with solid tumor. METHODS: A total of 22 children (11 males and 11 females) with solid tumor in our department from December 2012 to November 2017 were selected, with a median age of 9 (3-16) years old when starting IL-2 therapy. ALL surgeries and chemotherapy of children had been completed before low-dose rIL-2 therapy, and 17 cases achieved complete remission (CR) and 5 cases achieved partial remission (PR). A low-dose rIL-2 therapy was given 1 month after chemotherapy for 1 year: 4×105 IU/(m2·d), s.c. for every other day, 3 times per week. The immunocyte subsets were detected every 3 months until the end of treatment, meanwhile, disease condition and therapy-related side effects were followed up. RESULTS: After low-dose rIL-2 therapy in 22 children, the absolute values of CD3+ T cells, CD3-CD56+ natural killer cells, CD3+CD4+ helper T cells (Th) and CD3+CD8+ cytotoxic T cells were up-regulated remarkably, as well as Th/suppressor T cells (all P < 0.05). While, there were no significant differences in absolute value and proportion of CD4+CD25+CD127- Treg cells during therapy. Among the 17 children who achieved CR before rIL-2 therapy, 14 cases continued to maintain CR after therapy, while 3 cases relapsed, and with 2 died after treatment abandonment. The 5 children who achieved PR before low-dose rIL-2 therapy were evaluated CR by PET/CT scan after treatment. In the early stage of low-dose rIL-2 therapy, 1 child developed skin rashes at the injection sites, and 2 children ran a slight to mild transient fever. Their symptoms disappeared without any organ damage after symptomatic treatment. CONCLUSION: Low-dose rIL-2 therapy has good drug tolerance, and changes the distribution of anti-tumor immune-cell subgroup in peripheral blood of children with solid tumor remarkably without up-regulation of absolute value and ratio of Treg cells.

Effects of SARS-CoV-2 infection on incidence and treatment strategies of hepatocellular carcinoma in people with chronic liver disease.

BACKGROUND: Chronic liver disease (CLD) was associated with adverse clinical outcomes among people with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. AIM: To determine the effects of SARS-CoV-2 infection on the incidence and treatment strategy of hepatocellular carcinoma (HCC) among patients with CLD. METHODS: A retrospective, territory-wide cohort of CLD patients was identified from an electronic health database in Hong Kong. Patients with confirmed SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)+CLD] between January 1, 2020 and October 25, 2022 were identified and matched 1:1 by propensity-score with those without (COVID-19-CLD). Each patient was followed up until death, outcome event, or November 15, 2022. Primary outcome was incidence of HCC. Secondary outcomes included all-cause mortality, adverse hepatic outcomes, and different treatment strategies to HCC (curative, non-curative treatment, and palliative care). Analyses were further stratified by acute (within 20 d) and post-acute (21 d or beyond) phases of SARS-CoV-2 infection. Incidence rate ratios (IRRs) were estimated by Poisson regression models. RESULTS: Of 193589 CLD patients (> 95% non-cirrhotic) in the cohort, 55163 patients with COVID-19+CLD and 55163 patients with COVID-19-CLD were included after 1:1 propensity-score matching. Upon 249-d median follow-up, COVID-19+CLD was not associated with increased risk of incident HCC (IRR: 1.19, 95%CI: 0.99-1.42, P = 0.06), but higher risks of receiving palliative care for HCC (IRR: 1.60, 95%CI: 1.46-1.75, P < 0.001), compared to COVID-19-CLD. In both acute and post-acute phases of infection, COVID-19+CLD were associated with increased risks of all-cause mortality (acute: IRR: 7.06, 95%CI: 5.78-8.63, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.14-1.36, P < 0.001) and adverse hepatic outcomes (acute: IRR: 1.98, 95%CI: 1.79-2.18, P < 0.001; post-acute: IRR: 1.24, 95%CI: 1.13-1.35, P < 0.001), compared to COVID-19-CLD. CONCLUSION: Although CLD patients with SARS-CoV-2 infection were not associated with increased risk of HCC, they were more likely to receive palliative treatment than those without. The detrimental effects of SARS-CoV-2 infection persisted in post-acute phase.

PvGeneExpDB: An integrative gene expression database for in-depth understanding on the Pacific white shrimp (Litopenaeus vannamei).

The Pacific white shrimp (Litopenaeus vannamei) is a high-valued economic farming species. With the development of high-throughput sequencing technology, cumulative large-scale transcriptomic studies have been revealing molecular landscape of various biological conditions including genetic selection, breeding, evolution, disease landscape, etc. However, no single experiment or databases allow thorough investigations of transcriptomic dynamics for these progressions. Meanwhile, the available datasets are often scattered and lack management. Here, we have established PvGeneExpDB, the first gene expression database for L. vannamei (www.bio-marine-scau.com/pv_ex/), which encompasses gene expression profiles, differential expression, and co-expression analyses under various biological conditions. Based on the analyses of 7 datasets, which include 53 samples with accurate and detailed records, PvGeneExpDB identifies 20,599 novel transcripts, shows expression profiles of a total of 20,817 genes, and implements Gene Ontology (GO) reconstruction of 76.7 % of these genes. Besides, 26 co-expressed groups were first identified by large-scale, cross-sample Weighted Gene Co-expression Network Analysis (WGCNA). By integrating the gene expression data in the database, our goal is to deepen the biological understanding of L. vannamei.

Risks of incident major osteoporotic fractures following SARS-CoV-2 infection among older individuals: a population-based cohort study in Hong Kong.

Population-based epidemiological studies on post-acute phase coronavirus 2019 (COVID-19)-related fractures in older adults are lacking. This study aims to examine the risk of incident major osteoporotic fractures following SARS-CoV-2 infection among individuals aged ≥50, compared to individuals without COVID-19. It was a retrospective, propensity-score matched, population-based cohort study of COVID-19 patients and non-COVID individuals identified from the electronic database of the Hong Kong Hospital Authority from January 2020 to March 2022. The primary outcome was a composite of major osteoporotic fractures (hip, clinical vertebral, and upper limb). COVID-19 patients were 1:1 matched to controls using propensity-score according to age, sex, vaccination status, medical comorbidities and baseline medications. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. A total of 429 459 COVID-19 patients were included, 1:1 matched to non-COVID individuals. Upon median follow-up of 11 months, COVID-19 patients had higher risks of major osteoporotic fractures (5.08 vs 3.95 per 1000 persons; HR 1.22 95%CI [1.15-1.31]), hip fractures (2.71 vs 1.94; 1.33 [1.22-1.46]), clinical vertebral fractures (0.42 vs 0.31; 1.29 [1.03-1.62]), and falls (13.83 vs 10.36; 1.28 [1.23-1.33]). Subgroup analyses revealed no significant interaction. In acute (within 30 days) and post-acute phases (beyond 30 days) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we consistently observed a significant increase in fractures and falls risks. Our study demonstrated increased risk of major osteoporotic fractures after SARS-CoV-2 infection in both acute and post-acute phases in older adults, partly due to increased fall risk. Clinicians should be aware of musculoskeletal health of COVID-19 survivors.

Our study showed that older individuals with coronavirus 2019 (COVID-19) infection are at a higher risk of suffering from major osteoporotic fractures, ie serious bone fractures related to osteoporosis, compared to those not infected. The study analyzed the health records of 429 459 patients aged 50 and older in Hong Kong who had been diagnosed with COVID-19 between January 2020 and March 2022. These patients were compared with a matched group without COVID-19, considering age, sex, vaccination status, medical comorbidities, and concomitant medications. Findings indicated that individuals who had contracted COVID-19 experienced a higher risk of major osteoporotic fractures, hip fractures, and clinical vertebral fractures. The risk of falls, a common cause of these fractures, was also higher in the COVID-19 group. This increased risk of major osteoporotic fractures and falls persists both shortly after infection and in the following months, underscoring the lasting impact of COVID-19 on the bone health of older adults. These results support the recommendations for the assessment of bone health and fall risks, and an urgent review of the requirement for interventions to reduce the risk of fragility fractures in older adult COVID-19 survivors.

Risk of Incident Thyroid Dysfunction in the Post-Acute Phase of COVID-19: A Population-Based Cohort Study in Hong Kong.

OBJECTIVE: The evidence of thyroid dysfunction in the post-acute phase of SARS-CoV-2 infection is limited. This study aimed to evaluate the risk of incident thyroid dysfunction in the post-acute phase of COVID-19. METHODS: This retrospective, propensity-score matched, population-based study included COVID-19 patients and non-COVID-19 individuals between January 2020 and March 2022, identified from the electronic medical records of the Hong Kong Hospital Authority. The cohort was followed up until the occurrence of outcomes, death, or 31 January 2023, whichever came first. Patients with COVID-19 were 1:1 matched to controls based on various variables. The primary outcome was a composite of thyroid dysfunction (hyperthyroidism, hypothyroidism, initiation of antithyroid drug or levothyroxine, and thyroiditis). Cox regression was employed to evaluate the risk of incident thyroid dysfunction during the post-acute phase. RESULTS: A total of 84 034 COVID-19 survivors and 84 034 matched controls were identified. Upon a median follow-up of 303 days, there was no significant increase in the risk of diagnosed thyroid dysfunction in the post-acute phase of COVID-19 (hazard ratio [HR] 1.058, 95% confidence interval 0.979-1.144, P = .154). Regarding the secondary outcomes, patients with COVID-19 did not have increased risk of hyperthyroidism (HR 1.061, P = .345), hypothyroidism (HR 1.062, P = .255), initiation of antithyroid drug (HR 1.302, P = .070), initiation of levothyroxine (HR 1.086, P = .426), or thyroiditis (P = .252). Subgroup and sensitivity analyses were largely consistent with the main analyses. CONCLUSION: Our population-based cohort study provided important reassuring data that COVID-19 was unlikely to be associated with persistent effects on thyroid function.

PS-MPs promotes the progression of inflammation and fibrosis in diabetic nephropathy through NLRP3/Caspase-1 and TGF-ß1/Smad2/3 signaling pathways.

BACKGROUND: Diabetic nephropathy (DN) is a prevalent chronic microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD). Understanding the progressive etiology of DN is critical for the development of effective health policies and interventions. Recent research indicated that polystyrene microplastics (PS-MPs) contaminate our diets and accumulate in various organs, including the liver, kidneys, and muscles. METHODS: In this study, ten-week-old db/db mice and db/m mice were fed. Besides, db/db mice were divided into two groups: PS-MPs group (oral administration of 0.5 µm PS-MPs) and an H2O group, and they were fed for three months. A type II diabetes model was established using db/db mice to investigate the effects of PS-MPs on body weight, blood glucose level, renal function, and renal fibrosis. RESULTS: The results demonstrated that PS-MPs significantly exacerbated various biochemical indicators of renal tissue damage, including fasting blood glucose, serum creatinine, blood urea nitrogen, and blood uric acid. Additionally, PS-MPs worsened the pathological alterations and degree of fibrosis in renal tissue. An increased oxidative stress state and elevated levels of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and monocyte chemoattractant protein-1 (MCP-1) were identified. Furthermore, PS-MPs significantly enhanced renal fibrosis by inhibiting the transition from epithelial cells to mesenchymal cells, specifically through the inhibition of the TGF-ß/Smad signaling pathway. The expression levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, and cleaved Caspase-1, which are inflammasome proteins, were significantly elevated in the PS-MPs group. CONCLUSION: The findings suggested that PS-MPs could aggravate kidney injury and renal fibrosis in db/db mice by promoting NLRP3/Caspase-1 and TGF-ß1/Smads signaling pathways. These findings had implications for elucidating the role of PS-MPs in DN progression, underscoring the necessity for additional research and public health interventions.

Alzheimer's disease diagnostic accuracy by fluid and neuroimaging ATN framework.

OBJECTIVES: The ATN's different modalities (fluids and neuroimaging) for each of the Aß (A), tau (T), and neurodegeneration (N) elements are used for the biological diagnosis of Alzheimer's disease (AD). We aim to identify which ATN category achieves the highest potential for diagnosis and predictive accuracy of longitudinal cognitive decline. METHODS: Based on the availability of plasma ATN biomarkers (plasma-derived Aß42/40 , p-tau181, NFL, respectively), CSF ATN biomarkers (CSF-derived Aß42 /Aß40 , p-tau181, NFL), and neuroimaging ATN biomarkers (18F-florbetapir (FBP) amyloid-PET, 18F-flortaucipir (FTP) tau-PET, and fluorodeoxyglucose (FDG)-PET), a total of 2340 participants were selected from ADNI. RESULTS: Our data analysis indicates that the area under curves (AUCs) of CSF-A, neuroimaging-T, and neuroimaging-N were ranked the top three ATN candidates for accurate diagnosis of AD. Moreover, neuroimaging ATN biomarkers display the best predictive ability for longitudinal cognitive decline among the three categories. To note, neuroimaging-T correlates well with cognitive performances in a negative correlation manner. Meanwhile, participants in the "N" element positive group, especially the CSF-N positive group, experience the fastest cognitive decline compared with other groups defined by ATN biomarkers. In addition, the voxel-wise analysis showed that CSF-A related to tau accumulation and FDG-PET indexes more strongly in subjects with MCI stage. According to our analysis of the data, the best three ATN candidates for a precise diagnosis of AD are CSF-A, neuroimaging-T, and neuroimaging-N. CONCLUSIONS: Collectively, our findings suggest that plasma, CSF, and neuroimaging biomarkers differ considerably within the ATN framework; the most accurate target biomarkers for diagnosing AD were the CSF-A, neuroimaging-T, and neuroimaging-N within each ATN modality. Moreover, neuroimaging-T and CSF-N both show excellent ability in the prediction of cognitive decline in two different dimensions.

Toxicological effects of microplastics in renal ischemia-reperfusion injury.

The widespread presence of microplastics (MPs) in the environment poses a significant threat to biological survival and human health. However, our understanding of the toxic effects of MPs on the kidneys remains limited. This study aimed to investigate the underlying mechanism of the toxic effects of MPs on the kidneys using an ischemia-reperfusion (IR) mouse model. Four-week-old ICR mice were exposed to 0.5 µm MPs for 12 weeks prior to IR injury. The results showed that MPs exposure could aggravate the IR-induced damage to renal tubules and glomeruli. Although there were no significant changes in blood urea nitrogen and serum creatinine levels 7 days after IR, MPs treatment resulted in a slight increase in both parameters. In addition, the expression levels of inflammatory factors (MCP-1 and IL-6) at the mRNA level, as well as macrophage markers (CD68 and F4/80), were significantly higher in the MPs + IR group than in the Sham group after IR. Furthermore, MPs exposure exacerbated IR-induced renal fibrosis. Importantly, the expression of pyroptosis-related genes, including NLRP3, ASC, GSDMD, cleaved caspase-1, and IL-18, was significantly upregulated by MPs, indicating that MPs exacerbate pyroptosis in the context of renal IR. In conclusion, our findings suggest that MPs exposure can aggravate renal IR-induced pyroptosis by activating NLRP3-GSDMD signaling.

The male reproductive toxicity after nanoplastics and microplastics exposure: Sperm quality and changes of different cells in testis.

Nanoplastics (NPs) and Microplastics (MPs) pollution has become a severe threat to the planet and is a growing concern. However, their effects on male reproductive toxicity remain poorly understood. In this study, a series of morphological analyses were completed to explore the influence of NPs and MPs exposure on the testis in mice. After 12-weeks exposure, although both NPs and MPs exposure can lead to reproductive toxicity, compared with NPs exposure, exposure to MPs leads to a more significant increase in reproductive toxicity dependent on some particle size. Moreover, increased reproductive toxicities, including increased spermatogenesis disorders, and sperm physiological abnormality, oxidative stress, testis inflammation was more associated with MPs group than NPs group. Ultra-pathological structure observed by transmission electron microscopy indicated that both NPs and MPs have different effects on spermatogonia, spermatocytes and Sertoli cells. Exposure to MPs resulted in decreased Sertoli cell numbers and reduced Leydig cell area, and showed no effects on differentiation of Leydig cells by the expression level of the Insulin-Like factor 3 (INSL3) in Leydig cells. Transcriptomic sequencing analysis provided valuable insights into the differential effects of NPs and MPs on cellular processes. Specifically, our findings demonstrated that NPs were predominantly involved in the regulation of steroid biosynthesis, whereas MPs primarily influenced amino acid metabolism. This study demonstrates the effect of adult-stage reproductive toxicity in mice after exposure to NPs and MPs, which will deep the understanding of the NPs and MPs induced toxicity.

Identification of mitophagy-associated proteins profile as potential plasma biomarkers of idiopathic Parkinson's disease.

BACKGROUND: Despite extensive work to identify diagnostic plasma markers for Parkinson's disease (PD), there are still no accepted and validated surrogate biomarkers. Mitophagy-associated proteins (MAPs), including PTEN-induced putative kinase 1 (PINK1), Parkin, phosphoglycerate mutase 5 (PGAM5), BCL2 interacting protein 3 (BNIP3), and phosphorylated-TBK1 (p-TBK1), are, to our best knowledge, not well studied as a panel of biomarkers of neurodegeneration in PD. METHODS: The study population comprised 116 age-matched controls (HC), 179 PD patients, alongside and 90 PD syndromes (PDs) divided between two cohorts: (i) the modeling cohort (cohort 1), including 150 PD, 97 HC, and 80 PDs; and (ii) the validated cohort (cohort 2), including 29 PD, 19 HC, and 10 PDs. RESULTS: MAPs are elevated in the plasma of PD patients. PINK1, Parkin, and PGAM5 displayed the top three measurable increase trends in amplitude compared to BNIP3 and p-TBK1. Moreover, the area under the curve (AUC) values of PINK1, PGAM5, and Parkin were ranked the top three MAP candidates in diagnosis accuracy for PD from HC, but the MAPs make it hard to differentiate PD from PDs. In addition, there are higher plasma PINK1-Parkin levels and prominent diagnostic accuracy in A-synuclein (+) subjects than in A-synuclein (-) subjects. CONCLUSIONS: These results uncover that plasma MAPs (PINK1, Parkin, and PGAM5) may be potentially useful diagnostic biomarkers for PD diagnosis. Studies on larger cohorts would be required to test whether elevated plasma MAP levels are related to PD risk or prognosis.

Expanding the applications of immune checkpoint inhibitors in advanced lung cancer beyond disease progression.

Background: Immunotherapy, particularly the utilization of immune checkpoint inhibitors (ICIs), assumes a pivotal role in the comprehensive management of advanced lung cancer. There has been substantial deliberation regarding the appropriateness of extending ICIs treatment beyond the point of disease progression. This study delves into the potential benefits of sustained utilization of ICIs subsequent to disease progression in patients. Methods: A retrospective analysis was conducted on a cohort of 248 patients diagnosed with advanced lung cancer who received treatment with ICIs. The study population comprised 99 patients in the treatment beyond progression (TBP) group and 42 patients in the non-treatment beyond progression (NTBP) group. Parameters including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were assessed. The Cox proportional hazard regression model was employed to analyze prognostic factors related to immunotherapy. Results: Patients undergoing primary treatment with PD-1/PD-L1 inhibitors exhibited a median progression-free survival (mPFS) of 5.3 months. In the context of disease progression, a comparison between the TBP and NTBP groups was performed with respect to mPFS. The results demonstrated that the TBP group manifested an mPFS of 8.6 months, contrasting with the NTBP group's mPFS of 4.0 months (p=0.028). The mean overall survival (mOS) in the TBP group exhibited a statistically significant increase in comparison to the NTBP group (14.1 months vs. 6.0 months, p=0.028). Evaluation of the objective response rate (ORR) between the TBP and NTBP groups revealed a substantial distinction. The TBP group displayed an ORR of 12.1%, while the NTBP group exhibited a lower ORR of 2.4%. The statistical analysis yielded a p-value of 0.068, signifying a notable trend towards significance. The disease control rate (DCR) was also assessed and exhibited a noteworthy variance between the two groups, with a higher DCR of 92.9% in contrast to 71.4% in the control group (p = 0.001). Conclusion: Subsequent to ICIs treatment, a subset of patients may derive continued benefits from anticancer therapy, notwithstanding the progression of their advanced lung cancer.

Blood exosome sensing via neuronal insulin-like growth factor-1 regulates autism-related phenotypes.

The development and progression of autism spectrum disorder (ASD) is characterized by multiple complex molecular events, highlighting the importance of the prefrontal brain regions in this process. Exosomes are nanovesicles that play a critical role in intercellular communication. Peripheral systems influence brain function under both physiological and pathological conditions. We investigated whether this influence was mediated by the direct sensing of peripheral blood exosomes by brain cells. Administration of serum exosomes from rats with valproic acid-induced ASD resulted in ASD-related phenotypes in mice, whereas exosomes from normal rats did not exhibit such effects. RNA sequencing and bioinformatics analysis suggested that negative regulation of medial prefrontal cortex (mPFC) insulin-like growth factor 1 (IGF-1) by exosome-derived miR-29b-3p may contribute to these ASD-associated effects. Further evidence showed that miR-29b-3p-enriched exosomes crossed the blood-brain barrier to reach the mPFC, subsequently inducing the suppression of IGF-1 expression in neurons. Optogenetic activation of excitatory neurons in the mPFC improved behavioral abnormalities in exosome-treated mice. The addition of exogenous IGF-1 or inhibition of miR-29b-3p expression in the mPFC also rescued the ASD-related phenotypes in mice. Importantly, administration of miR-29b-3p-enriched serum exosomes from human donors with ASD into the mouse medial prefrontal cortex was sufficient to induce hallmark ASD behaviors. Together, our findings indicate that blood-brain cross-talk is crucial for ASD pathophysiology and that the brain may sense peripheral system changes through exosomes, which could serve as the basis for future neurological therapies.

Comparative efficacy of endogenous stem cells recruiting hydrogels and stem cell-loaded hydrogels in knee cartilage regeneration: a meta-analysis.

Background Cartilage defects remain a challenge in diseases such as osteoarthritis (OA) and fractures. Scientists have explored the use of hydrogels in conjunction with stem cell technology as a tissue engineering method to treat cartilage defects in joints. In recent years, research into hydrogels containing stem cell technology for cartilage repair has mainly focused on two categories: stem cell-loaded hydrogels and endogenous stem cell recruiting hydrogels. The latter, utilizing cell-free products, represents a novel concept with several advantages, including easier dose standardization, wider sources, and simpler storage. This meta-analysis aims to assess and compare the therapeutic effects of endogenous stem cell recruiting hydrogels and stem cell-loaded hydrogels in promoting articular cartilage regeneration in animal models, with the goal of exploring endogenous stem cell recruiting hydrogels as a promising replacement therapy for knee cartilage regeneration in preclinical animal studies. Methods We systematically searched PubMed, Web of Science, Cochrane Library, and Embase until January 2023 using key words related to stem cells, cartilage regeneration and hydrogel. A random-effects meta-analysis was performed to evaluate the therapeutic effect on newborn cartilage formation. Stratified analyses were also carried out by independently classifying trials according to similar characteristics. The level of evidence was determined using the GRADE method. Results Twenty-eight studies satisfied the inclusion criteria. Comprehensive analyses revealed that the use of endogenous stem cell recruiting hydrogels significantly promoted the formation of new cartilage in the knee joint, as evidenced by the histological score (3.77, 95% CI 2.40, 5.15; p < 0.0001) and the International Cartilage Repair Society (ICRS) macroscopic score (3.00, 95% CI 1.83, 4.18; p = 0.04), compared with the control group. The stem cell-loaded hydrogels also increased cartilage regeneration in the knee with the histological score (3.13, 95% CI 2.22, 4.04; p = 0.02) and the ICRS macroscopic score (2.49, 95% CI 1.16, 3.82; p =0.03) in comparison to the control. Significant heterogeneity between studies was observed, and further stratified and sensitivity analyses identified the transplant site and modelling method as the sources of heterogeneity. Conclusion The current study indicates that both endogenous stem cell recruiting hydrogels and stem cell loaded hydrogels can effectively promote knee joint cartilage regeneration in animal trials.

Incidence of diabetes following COVID-19 vaccination and SARS-CoV-2 infection in Hong Kong: A population-based cohort study.

BACKGROUND: The risk of incident diabetes following Coronavirus Disease 2019 (COVID-19) vaccination remains to be elucidated. Also, it is unclear whether the risk of incident diabetes after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is modified by vaccination status or differs by SARS-CoV-2 variants. We evaluated the incidence of diabetes following mRNA (BNT162b2), inactivated (CoronaVac) COVID-19 vaccines, and after SARS-CoV-2 infection. METHODS AND FINDINGS: In this population-based cohort study, individuals without known diabetes were identified from an electronic health database in Hong Kong. The first cohort included people who received ≥1 dose of COVID-19 vaccine and those who did not receive any COVID-19 vaccines up to September 2021. The second cohort consisted of confirmed COVID-19 patients and people who were never infected up to March 2022. Both cohorts were followed until August 15, 2022. A total of 325,715 COVID-19 vaccine recipients (CoronaVac: 167,337; BNT162b2: 158,378) and 145,199 COVID-19 patients were 1:1 matched to their respective controls using propensity score for various baseline characteristics. We also adjusted for previous SARS-CoV-2 infection when estimating the conditional probability of receiving vaccinations, and vaccination status when estimating the conditional probability of contracting SARS-CoV-2 infection. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident diabetes were estimated using Cox regression models. In the first cohort, we identified 5,760 and 4,411 diabetes cases after receiving CoronaVac and BNT162b2 vaccines, respectively. Upon a median follow-up of 384 to 386 days, there was no evidence of increased risks of incident diabetes following CoronaVac or BNT162b2 vaccination (CoronaVac: 9.08 versus 9.10 per 100,000 person-days, HR = 0.998 [95% CI 0.962 to 1.035]; BNT162b2: 7.41 versus 8.58, HR = 0.862 [0.828 to 0.897]), regardless of diabetes type. In the second cohort, we observed 2,109 cases of diabetes following SARS-CoV-2 infection. Upon a median follow-up of 164 days, SARS-CoV-2 infection was associated with significantly higher risk of incident diabetes (9.04 versus 7.38, HR = 1.225 [1.150 to 1.305])-mainly type 2 diabetes-regardless of predominant circulating variants, albeit lower with Omicron variants (p for interaction = 0.009). The number needed to harm at 6 months was 406 for 1 additional diabetes case. Subgroup analysis revealed no evidence of increased risk of incident diabetes among fully vaccinated COVID-19 survivors. Main limitations of our study included possible misclassification bias as type 1 diabetes was identified through diagnostic coding and possible residual confounders due to its observational nature. CONCLUSIONS: There was no evidence of increased risks of incident diabetes following COVID-19 vaccination. The risk of incident diabetes increased following SARS-CoV-2 infection, mainly type 2 diabetes. The excess risk was lower, but still statistically significant, for Omicron variants. Fully vaccinated individuals might be protected from risks of incident diabetes following SARS-CoV-2 infection.