The Correlation Between Peripheral Blood Micro-Ribonucleic Acid Expression Level and Personality Disorder in Patients with Schizophrenia.

Objective: Schizophrenia patients often have personality disorders; schizophrenia patients with personality disorders are more difficult to treat and have a worse prognosis. Early identification of this group of patients and early intervention can achieve better prognosis. Therefore, it is very important to explore effective biomarkers and early diagnosis for the prognosis of schizophrenia. The primary purpose of this paper is to explore the relationship between plasma miRNA expression level and personality disorder with schizophrenia. Methods: Gene microarrays in miRNA files were employed, and the plasma of peripheral blood of 82 schizophrenic patients and 43 healthy control subjects were examined. Real-time reverse transcription polymerase chain reaction detection were performed to explore the results. Spearman correlation analysis was used to analyze the correlation between expression level of miRNAs and Personality Diagnosis Questionnaire-4 score. Results: The results showed that miR-1273d, miR-1303, miR-3064-5p, miR-3131, miR-3687, miR-4428, miR-4725-3p, and miR-5096 were up-regulated in schizophrenic patients. Compared to healthy control subjects, the difference was statistically significant (P < .05). Schizophrenic patients with schizoid, paranoid, schizotypal, and obsessive compulsive traits had negative correlation with miR-1303, miR-3131, miR-4428, and miR-5096 expression level (r = -0.40 to -0.62, P < .05); there were no significant differences in the other miRNAs. Correlation with other personality traits was not significant (P > .05). The stepwise regression analysis indicated that miR-5096, miR-3131, and miR-1273d have a significant predictive effect on the schizoid trait (P < .01). MiR-4428 and miR-1303 had a significant predictive effect on the schizotypal trait (P < .01). MiR-5096, miR-4428, and miR-4725-3P had a significant predictive effect on the paranoid trait (P < .05). MiR-4428, miR-1303, and miR-5096 had a significant predictive effect on the obsessive compulsive trait (P < .05). Conclusion: The expression levels of miR-1273d, miR-1303, miR-3064-5p, miR-3131, miR-3687, miR-4428, miR-4725-3p, and miR-5096 were up-regulated in the peripheral blood of patients with schizophrenia, and these miRNAs are expected to be diagnostic biomarkers for accurate diagnosis of schizophrenia. The expression levels of miR-1303, miR-3131, miR-1273d, miR-4428, miR-4725-3p, and miR-5096 have significant predictive effects on personality disorder in schizophrenia.

Developing a Machine-Learning Predictive Model for Retention of Posterior Cruciate Ligament in Patients Undergoing Total Knee Arthroplasty.

OBJECTIVE: Predicting whether the posterior cruciate ligament (PCL) should be preserved during total knee arthroplasty (TKA) procedures is a complex task in the preoperative phase. The choice to either retain or excise the PCL has a substantial effect on the surgical outcomes and biomechanical integrity of the knee joint after the operation. To enhance surgeons' ability to predict the removal and retention of the PCL in patients before TKA, we developed machine learning models. We also identified significant feature factors that contribute to accurate predictions during this process. METHODS: Patients' data on TKA continuously performed by a single surgeon who had intended initially to undergo implantation of cruciate-retaining (CR) prostheses was collected. During the sacrifice of PCL, we utilized anterior-stabilized (AS) tibial bearings. The dataset was split into CR and AS categories to form distinct groups. Relevant information regarding age, gender, body mass index (BMI), the affected side, and preoperative diagnosis was extracted by reviewing the medical records of the patients. To ensure the authenticity of the research, an initial step involved capturing X-ray images before the surgery. These images were then analyzed to determine the height of the medial condyle (MMH) and lateral condyle (LMH), as well as the ratios between MLW and MMH and MLW and LMH. Additionally, the insall-salvati index (ISI) was calculated, and the severity of any varus or valgus deformities was assessed. Eight machine-learning methods were developed to predict the retention of PCL in TKA. Risk factor analysis was performed using the SHApley Additive exPlanations method. RESULTS: A total of 307 knee joints from 266 patients were included, among which there were 254 females and 53 males. A stratified random sampling technique was used to split patients in a 70:30 ratio into a training dataset and a testing dataset. Eight machine-learning models were trained using data feeding. Except for the AUC of the LGBM Classifier, which is 0.70, the AUCs of other machine learning models are all lower than 0.70. In importance-based analysis, ISI, MMH, LMH, deformity, and age were confirmed as important predictive factors for PCL retention in operations. CONCLUSION: The LGBM Classifier model achieved the best performance in predicting PCL retention in TKA. Among the potential risk factors, ISI, MMH, LMH, and deformity played essential roles in the prediction of PCL retention.

Prenatal organophosphate esters exposure and neurodevelopment trajectory in infancy: Evidence from the Shanghai Maternal-Child Pairs Cohort.

BACKGROUND: Concerns remain about the neurotoxic properties of the ubiquitous organophosphate esters (OPEs), the replacement of the toxicant polybrominated diphenyl ethers. OBJECTIVES: We examined the associations of prenatal exposure to OPEs and their mixtures with early-life neurodevelopment trajectories. METHODS: Totally 1276 mother-child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure the levels of 7 OPEs in cord serum. Ages and Stages Questionnaires was used to examine children's neuropsychological development at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Multiple linear regression and logistic regression model were performed to assess the relationships between OPEs exposure and neurodevelopment and trajectories. Mixtures for widely detected OPEs (n = 4) were investigated using quantile-based g-computation. RESULTS: Tributyl phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and 2-ethylhexyl diphenyl phosphate (EHDPP), had detection rates >50 %. TDCPP had the highest median concentration (1.02 µg/L) in cord serum. EHDPP concentrations were negatively associated with scores in most domains at 12 months of age, with effect values (ß) ranging from -1.89 to -0.57. EHDPP could negatively affect the total ASQ (OR = 1.07, 95 % CI: 1, 1.15) and gross-motor (OR = 1.09, 95 % CI: 1.02, 1.17) trajectory in infancy. Joint exposure to OPEs was associated with decreased scores in the total ASQ, gross-motor, fine-motor and problem-solving domain of 12-month-old infants, with ß ranging from -5.93 to -1.25. In addition, the qgcomp models indicated significant positive associations between the concentrations of OPEs mixtures and risks of the persistently low group of the total ASQ, gross-motor and fine-motor development in early childhood. The impact of OPEs was more pronounced in boys. DISCUSSION: Our findings suggested OPEs, especially EHDPP, had a persistently negative effect on neurodevelopment during the first 2 years.

A handheld isothermal fluorescence detector for duplex visualization of aquatic pathogens via enhanced one-pot LAMP-PfAgo assay.

The expansion of large-scale aquaculture has exacerbated the challenge of aquatic diseases, resulting in substantial economic losses annually. Currently, traditional laboratory-based diagnostic methods are time-consuming and costly, hindering on-site testing for individual farmers. We address this issue by developing a state-of-the-art handheld isothermal nucleic acid amplification device (WeD-1) capable of fluorescence tracking of reactions and integrating it with an enhanced one-pot Prokaryotic Argonaute based nucleic acid detection method, enabling duplex visual detection of aquatic pathogens. WeD-1 is portable, reusable, user-friendly, and cost-effective, offering real-time smartphone interaction and enabling real-time fluorescence observation during the reaction. The enhanced one-pot Loop-Mediated Isothermal Amplification (LAMP)-PfAgo method, incorporating paraffin-encapsulated lyophilized PfAgo protein, achieves precise target-specific cleavage, significantly enhancing multiplex nucleic acid detection. This innovation streamlines on-site testing, negating the need for specialized laboratory conditions while ensuring an aerosol-free system. With newly developed and highly sensitive LAMP primer sets, our compact WeD-1/LAMP-PfAgo nucleic acid rapid testing system exhibits remarkable sensitivity, readily detecting aquatic pathogens with naked eyes from rapidly prepared fish and shrimp samples within 40 min, even when the Ct values are as high as 34.

High-throughput metabolomics identifies new biomarkers for cervical cancer.

BACKGROUND: Cervical cancer (CC) is a danger to women's health, especially in many developing countries. Metabolomics can make the connection between genotypes and phenotypes. It provides a wide spectrum profile of biological processes under pathological or physiological conditions. METHOD: In this study, we conducted plasma metabolomics of healthy volunteers and CC patients and integratively analyzed them with public CC tissue transcriptomics from Gene Expression Omnibus (GEO). RESULT: Here, we screened out a panel of 5 metabolites to precisely distinguish CC patients from healthy volunteers. Furthermore, we utilized multi-omics approaches to explore patients with stage I-IIA1 and IIA2-IV4 CC and comprehensively analyzed the dysregulation of genes and metabolites in CC progression. We identified that plasma levels of trimethylamine N-oxide (TMAO) were associated with tumor size and regarded as a risk factor for CC. Moreover, we demonstrated that TMAO could promote HeLa cell proliferation in vitro. In this study, we delineated metabolic profiling in healthy volunteers and CC patients and revealed that TMAO was a potential biomarker to discriminate between I-IIA1 and IIA2-IV patients to indicate CC deterioration. CONCLUSION: Our study identified a diagnostic model consisting of five metabolites in plasma that can effectively distinguish CC from healthy volunteers. Furthermore, we proposed that TMAO was associated with CC progression and might serve as a potential non-invasive biomarker to predict CC substage. IMPACT: These findings provided evidence of the important role of metabolic molecules in the progression of cervical cancer disease, as well as their ability as potential biomarkers.

Prenatal PFAS exposure, gut microbiota dysbiosis, and neurobehavioral development in childhood.

Studies on the role of the gut microbiota in the associations between per- and polyfluoroalkyl substance (PFAS) exposure and adverse neurodevelopment are limited. Umbilical cord serum and faeces samples were collected from children, and the Strengths and Difficulties Questionnaire (SDQ) was conducted. Generalized linear models, linear mixed-effects models, multivariate analysis by linear models and microbiome regression-based kernel association tests were used to evaluate the associations among PFAS exposure, the gut microbiota, and neurobehavioural development. Perfluorohexane sulfonic acid (PFHxS) exposure was associated with increased scores for conduct problems and externalizing problems, as well as altered gut microbiota alpha and beta diversity. PFHxS concentrations were associated with higher relative abundances of Enterococcus spp. but lower relative abundances of several short-chain fatty acid-producing genera (e.g., Ruminococcus gauvreauii group spp.). PFHxS exposure was also associated with increased oxidative phosphorylation. Alpha and beta diversity were found significantly associated with conduct problems and externalizing problems. Ruminococcus gauvreauii group spp. abundance was positively correlated with prosocial behavior scores. Increased alpha diversity played a mediating role in the associations of PFHxS exposure with conduct problems. Our results suggest that the gut microbiota might play an important role in PFAS neurotoxicity, which may have implications for PFAS control.

Screening and staging of chronic obstructive pulmonary disease with deep learning based on chest X-ray images and clinical parameters.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is underdiagnosed with the current gold standard measure pulmonary function test (PFT). A more sensitive and simple option for early detection and severity evaluation of COPD could benefit practitioners and patients. METHODS: In this multicenter retrospective study, frontal chest X-ray (CXR) images and related clinical information of 1055 participants were collected and processed. Different deep learning algorithms and transfer learning models were trained to classify COPD based on clinical data and CXR images from 666 subjects, and validated in internal test set based on 284 participants. External test including 105 participants was also performed to verify the generalization ability of the learning algorithms in diagnosing COPD. Meanwhile, the model was further used to evaluate disease severity of COPD by predicting different grads. RESULTS: The Ensemble model showed an AUC of 0.969 in distinguishing COPD by simultaneously extracting fusion features of clinical parameters and CXR images in internal test, better than models that used clinical parameters (AUC = 0.963) or images (AUC = 0.946) only. For the external test set, the AUC slightly declined to 0.934 in predicting COPD based on clinical parameters and CXR images. When applying the Ensemble model to determine disease severity of COPD, the AUC reached 0.894 for three-classification and 0.852 for five-classification respectively. CONCLUSION: The present study used DL algorithms to screen COPD and predict disease severity based on CXR imaging and clinical parameters. The models showed good performance and the approach might be an effective case-finding tool with low radiation dose for COPD diagnosis and staging.

Somatic mutations in a multigene panel and impact on prognosis based on TP53 status in Chinese HER2-positive patients undergoing neoadjuvant therapy: A single-institution retrospective cohort.

BACKGROUND: Gene mutations play a crucial role in the occurrence and development of tumors, particularly in breast cancer (BC). Neoadjuvant therapy (NAT) has shown greater clinical benefit in HER2-positive breast cancer. However, further clinical investigation is needed to fully understand the correlation between genetic mutations and NAT efficacy and the long-term prognosis in HER2-positive BC. METHODS: This was a retrospective cohort study of 222 patients receiving NAT between 2017 and 2021 in the Department of Breast Surgery of Fudan University Shanghai Cancer Center. Tumor samples from these patients were subjected to Next Generation Sequencing (NGS) to analyze mutations in 513 cancer-related genes. This study aimed to investigate the association between these genetic mutations and postoperative pathological complete response (pCR), as well as their impact on disease-free survival (DFS). RESULTS: In total, 48.65% patients reached pCR, ER-negative status (p < 0.001), PR-negative status (p < 0.001), Ki67 ≥ 20 (p = 0.011), and dual-targeted therapy (p < 0.001) were all associated with enhanced pCR rates. The frequency of somatic alterations in TP53 (60%), PIK3CA (15%), and ERBB2 (11%) was highest. In the HER2+/HR- cohort, patients who achieved pCR had a significant benefit in prognosis (HR = 3.049, p = 0.0498). KMT2C (p = 0.036) and TP53 (p = 0.037) mutations were significantly increased in patients with DFS events. Moreover, TP53 mutations had prognostic significance in HER2-positive BC patients with HR-negative (HR = 3.712, p = 0.027) and pCR (HR = 6.253, p = 0.027) status and who received herceptin-only targeted therapy (HR = 4.145, p = 0.011). CONCLUSIONS: The genetic mutation profiles of Chinese HER2+ patients who received NAT were discrepant with respect to HR status or DFS events. TP53 mutations have significant prognostic value in patients with NAT for HER2-positive BC and patients benefit differently depending on HR status, the neoadjuvant regimen and response, which highlights the significance of genetic factors in treatment customization based on individual genetic and clinical characteristics.

CRTAM promotes antitumor immune response in triple negative breast cancer by enhancing CD8+ T cell infiltration.

The immunomodulatory (IM) subtype of triple negative breast cancer (TNBC) exhibits high expression of immune cell signaling genes and is more responsive to immunotherapy. However, the specific mechanism underlying this phenomenon remains unclear. One of the potential key genes appears to be the cytotoxic and regulatory T cell molecule (CRTAM). A cohort of 360 previously untreated TNBC patients from Fudan University Shanghai Cancer Center (FUSCC) underwent RNA sequencing analysis of their primary tumor tissue. Combined with three RNA-seq datasets obtained from the GEO database, a LASSO regression analysis was conducted to identify genes specific to the IM type of TNBC. Our findings revealed elevated CRTAM expression in the IM-type TNBC, which correlated with a favorable overall survival and recurrence-free survival in TNBC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated a strong association between CRTAM and immune responses as well as immune system processes. Notably, CRTAM overexpression induced STAT1 phosphorylation and upregulation of interferon-stimulated genes. We also found that CRTAM enhanced tumor-associated immune cell infiltration, especially CD8+ T cells, which may be related to the increased expression of MHC class I molecules caused by CRTAM overexpression. These results suggest that CRTAM may serve as a potential biomarker for predicting the efficacy of immunotherapy in TNBC.

Elucidating the relationship between breast cancer and brain cortical structure: a Mendelian randomization study.

Cancer-associated cognitive impairment is a significant challenge for individuals who have survived breast cancer, affecting their quality of life. In this study, we conducted an inaugural comprehensive Mendelian randomization analysis discerning the causal relationship between breast cancer, including its two subtypes, and the cerebral cortical structure. Our analysis indicated that estrogen receptor-negative breast cancer significantly decreased surface area (ß = -593.01 mm2, 95% CI: -1134.9 to -51.1 mm2, P = 0.032). At the regional level, estrogen receptor-negative breast cancer showed a significant association with surface area and thickness in 17 cortical regions. These regions included the insula, posterior cingulate, superior frontal, precuneus, fusiform, lateral occipital, and rostral middle frontal. Specifically, estrogen receptor-negative breast cancer had a significant impact on decreasing the surface area of the insula without considering global weight (ß = -14.09 mm2, 95% CI: -22.91 to -5.27 mm2, P = 0.0017). The results from meta-analysis and LD Score Regression provide support for our findings. This investigation unveils the correlations between breast cancer, its various subcategories, and the cerebral cortical structure. Notably, breast cancer of the estrogen receptor-negative variety may elicit more widespread cerebral atrophy.

Sex-specific effects of organophosphate ester exposure on child growth trajectories in the first two years.

The connections between urinary organophosphate ester (OPE) metabolites and child growth have been identified in prior research, but there is currently a dearth of epidemiological evidence regarding the sex-specific impact of OPEs on child growth trajectories. This study enrolled 804 maternal-child pairs, and five OPE congeners were quantified in maternal serum during pregnancy. In this study, the impact of prenatal OPE exposure on child growth trajectories was assessed using linear mixed-effect models and a group-based trajectory model (GBTM), with consideration given to sex-specific effects. Fetuses were frequently exposed to OPEs in utero, and tris(2-butoxyethel) phosphate (TBEP) exhibited the highest concentration levels in maternal serum. Among male children, an increase of 2.72 ng/g lipid in TBEP concentration was associated with a 0.11-unit increase in head circumference-for-age z-score (HCAZ), and the effect was mainly concentrated at 1 and 2 months of age. Among female children, an increase of 2.72 ng/g lipid in tris(2-chloro-1-(chloromethyl) ethyl) phosphate (TDCPP) concentration was associated with a 0.15-unit increase in length-for-age z-score (LAZ) and a 0.14-unit increase in weight-for-age z-score (WAZ), and the effects were mainly concentrated at 9 months of age. For HCAZ trajectories, higher prenatal TBEP exposure was associated with higher odds for the fast growth group in male children. For the LAZ and WAZ trajectories, higher prenatal TDCPP exposure was associated with higher odds for the fast growth group in female children. The trajectory analysis approach provided insight into the complex associations between OPE exposure and child growth.

[miR-23b-3p regulates the differentiation of goat intramuscular preadipocytes by targeting the PDE4B gene].

This study aimed to explore the effect of miR-23b-3p on the differentiation of goat intramuscular preadipocytes, and to confirm whether miR-23b-3p plays its roles via targeting the PDE4B gene. Based on the pre-transcriptome sequencing data obtained previously, the miR-23b-3p, which was differentially expressed in goat intramuscular adipocytes before and after differentiation, was used as an entry point. real-time quantitative-polymerase chain reaction (qPCR) was used to detect the expression pattern of miR-23b-3p during the differentiation of goat intramuscular preadipocytes. The effects of miR-23b-3p on adipose differentiation and adipose differentiation marker genes were determined at the morphological and molecular levels. The downstream target genes of miR-23b-3p were determined using bioinformatics prediction as well as dual luciferase reporter assay to clarify the targeting relationship between miR-23b-3p and the predicted target genes. The results indicated that overexpression of miR-23b-3p reduced lipid droplet accumulation in goat intramuscular adipocytes, significantly down-regulated the expression levels of adipogenic marker genes AP2, C/EBPα, FASN, and LPL (P < 0.01). In addition, the expressions of C/EBPß, DGAT2, GLUT4 and PPARγ were significantly downregulated (P < 0.05). After interfering with the expression of miR-23b-3p, lipid droplet accumulation was increased in goat intramuscular adipocytes. The expression levels of ACC, ATGL, AP2, DGAT2, GLUT4, FASN and SREBP1 were extremely significantly up-regulated (P < 0.01), and the expression levels of C/EBPß, LPL and PPARγ were significantly up-regulated (P < 0.05). It was predicted that PDE4B might be a target gene of miR-23b-3p. The mRNA expression level of PDE4B was significantly decreased after overexpression of miR-23b-3p (P < 0.01), and the interference with miR-23b-3p significantly increased the mRNA level of PDE4B (P < 0.05). The dual luciferase reporter assay indicated that miR-23b-3p had a targeting relationship with PDE4B gene. MiR-23b-3p regulates the differentiation of goat intramuscular preadipocytes by targeting the PDE4B gene.

Research on multi-strategy improved sparrow search optimization algorithm.

To address the issues with inadequate search space, sluggish convergence and easy fall into local optimality during iteration of the sparrow search algorithm (SSA), a multi-strategy improved sparrow search algorithm (ISSA), is developed. First, the population dynamic adjustment strategy is carried out to restrict the amount of sparrow population discoverers and joiners. Second, the update strategy in the mining phase of the honeypot optimization algorithm (HBA) is combined to change the update formula of the joiner's position to enhance the global exploration ability of the algorithm. Finally, the optimal position of population discoverers is perturbed using the perturbation operator and levy flight strategy to improve the ability of the algorithm to jump out of local optimum. The experimental simulations are put up against the basic sparrow search algorithm and the other four swarm intelligence (SI) algorithms in 13 benchmark test functions, and the Wilcoxon rank sum test is used to determine whether the algorithm is significantly different from the other algorithms. The results show that the improved sparrow search algorithm has better convergence and solution accuracy, and the global optimization ability is greatly improved. When the proposed algorithm is used in pilot optimization in channel estimation, the bit error rate is greatly improved, which shows the superiority of the proposed algorithm in engineering application.

MdAIL5 overexpression promotes apple adventitious shoot regeneration by regulating hormone signaling and activating the expression of shoot development-related genes.

Adventitious shoot (AS) regeneration is a significant factor in the genetic transformation of horticultural plants. It is also a noteworthy approach to their vegetative propagation. AS regeneration remains highly dependent on the genotype or maturity of explants. We here found that the AS regeneration abilities of apple leaves were positively correlated with MdAIL5 expression. MdAIL5 overexpression dramatically increased AS regeneration efficiency. Notably, MdAIL5 overexpression could restore the AS formation ability of explants to a certain extent, which was lost with an increase in maturity. Endogenous hormone detection revealed that MdAIL5 overexpression changed the contents of auxin, cytokinin (CK), and other hormones in apple leaves. Transcriptome analysis revealed that many genes related to auxin, CK, and brassinolide signaling pathways were significantly and differentially expressed between MdAIL5-overexpressing transgenic apple and wild-type apple plants. Yeast one-hybrid assays, the electrophoretic mobility shift assay, and the dual-luciferase reporter assay revealed that MdAIL5 directly binds to MdARF9 and MdHB14 promoters and positively affects their expression. We here established a model of MdAIL5 regulating AS formation, which acts as a theoretical basis for facilitating genotype- or explant maturity-independent AS regeneration in the future.

Performance evaluation of a CRISPR Cas9-based selective exponential amplification assay for the detection of KRAS mutations in plasma of patients with advanced pancreatic cancer.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is highly malignant, with shockingly mortality rates. KRAS oncoprotein is the main molecular target for PDAC. Liquid biopsies, such as the detection of circulating tumour DNA (ctDNA), offer a promising approach for less invasive diagnosis. In this study, we aim to evaluate the precision and utility of programmable enzyme-based selective exponential amplification (PASEA) assay for rare mutant alleles identification. METHODS: PASEA uses CRISPR-Cas9 to continuously shear wild-type alleles during recombinase polymerase amplification, while mutant alleles are exponentially amplified, ultimately reaching a level detectable by Sanger sequencing. We applied PASEA to detect KRAS mutations in plasma ctDNA. A total of 153 patients with stage IV PDAC were enrolled. We investigated the relationship between ctDNA detection rates with various clinical factors. RESULTS: Our results showed 91.43% vs 44.83% detection rate in patients of prechemotherapy and undergoing chemotherapy. KRAS ctDNA was more prevalent in patients with liver metastases and patients did not undergo surgical resection. Patients with liver metastases prior to chemotherapy showed a sensitivity of 95.24% (20/21) with PASEA. Through longitudinal monitoring, we found ctDNA may be a more accurate biomarker for monitoring chemotherapy efficacy in PDAC than CA19-9. CONCLUSIONS: Our study sheds light on the potential of ctDNA as a valuable complementary biomarker for precision targeted therapy, emphasising the importance of considering chemotherapy status, metastatic sites and surgical history when evaluating its diagnostic potential in PDAC. PASEA technology provides a reliable, cost-effective and minimally invasive method for detecting ctDNA of PDAC.

Co-exposure to organic UV filters and phthalates and their associations with oxidative stress levels in children: A prospective follow-up study in China.

Children are highly vulnerable to environmental pollutants, especially endocrine-disrupting chemicals (EDCs). Previous research has linked both organic UV filters and phthalates exposure to adiposity and pubertal development in children. Nevertheless, the individual and collective effects of these chemicals on this population remain poorly understood. In this study, twelve organic UV filters and metabolites, six phthalate metabolites and two oxidative stress biomarkers were analyzed in a prospective follow-up study in Shanghai, China after a baseline study conducted 1.5 years earlier. Results revealed a positive association between exposure to individual organic UV filters or their mixture and levels of 8-OHdG (ß ranging from 0.242 to 0.588, P < 0.05), a marker of oxidative DNA damage. BP-3 and OD-PABA made a greater contribution to oxidative DNA damage than other UV filters. Levels of 8-OHdG were also positively correlated with single phthalate metabolites and their mixture, with MnBP and MMP contributing the most. Stratified analysis found that these associations were mainly observed in girls. Our mixture analysis revealed cumulative risks of oxidative DNA damage when there was co-exposure to these two kinds of EDCs. These results underscore the importance of considering the risks associated with organic UV filters and the necessity of evaluating the effects of all these pollutants, both individually and in mixtures.

SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells.

BACKGROUND: Acute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML. METHODS: The up-regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used. RESULTS: Through bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small-molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS-5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS-5584 induced apoptosis and cycle arrest of AML cells in a dose- and time-dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS-5584 treatment, with 287 proteins being down-regulated and 71 proteins being up-regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS-5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS-5584 caused a significant reduction in the half-maximal inhibitory concentration (IC50 ) of VS-5584 on AML cells. In vivo, experiments suggested that VS-5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein. CONCLUSIONS: Taken together, the PI3K/mTOR inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

Differentiation value of miR-26b for major depressive disorder, schizophrenia, generalized anxiety disorder.

Introduction: First episode and drug naive schizophrenia (SZ) patients comorbid with major depressive episode and generalized anxiety disorder (GAD) comorbid with major depressive disorder (MDD) are common in clinical practice, overlapping symptomatology during first presentation of MDD, SZ and GAD challenged the diagnostic process. Materials and Methods: This study aimed to investigate the differentiation value of peripheral microRNA-26b expression in 52 patients of MDD, SZ, and GAD, respectively, and 52 controls. Quantitative real-time reverse transcription polymerase chain reaction was used to further verify aberrant miRNAs of previous identified in MDD and investigate expression level of these peripheral miRNAs in SZ and GAD. Results: The expression levels of miR-26b and miR-4743 were significantly upregulated and of miR-4498, miR-4485, and miR-1972 had no significant difference. There were no significant differences of expression levels of miR-26b, miR-4498, miR-4485, and miR-1972 except miR-4743 between SZ patients and control group and of miR-26b, miR-1972, miR-4498, and miR-4485 between GAD group and the controls. The receiver operating characteristic (ROC) curve of miR-26b in MDD patients showed that its sensitivity and specificity for diagnosis were 0.540 and 0.830, respectively, with the area under curve (AUC) being 0.728; the ROC of miR-26b for SZ and MDD differentiation showed that its sensitivity and specificity were 0.580 and 0.710, respectively, with AUC being 0.631; the ROC of miR-26b for GAD and MDD differentiation suggested that sensitivity and specificity were 0.560 and 0.750, respectively, with AUC being 0.637. Conclusion: MiR-26b might have potential value of differentiation biomarker for MDD, SZ, and GAD.

[Human Umbilical Cord-Derived Mesenchymal Stem Cells Prevent Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation Via Exosome-Mediated MicroRNA and Its Mechanism].

OBJECTIVE: To explore molecular mechanisms by which umbilical cord-derived mesenchymal stem cells suppress the development of GVHD after bone marrow hematopoietic stem cell transplantation. METHODS: A mouse model of aGVHD was constructed after bone marrow hematopoietic stem cell transplantation, and the umbilical cord-derived mesenchymal stem cells were cultured, and then injected into the aGVHD mouse model, so as to investigate its prophylactic efficacy. Prophylactic effect of the exosomes isolated from umbilical cord-derived mesenchymal stem cells on aGVHD mice was assessed. Sequencing analysis of miRNA from exosomes was performed. RESULTS: aGVHD model was successfully constructed after hematopoietic stem cell transplantation. By injecting umbilical cord-derived mesenchymal stem cells into the GVHD mouse model, it was found that the treatment significantly prolonged survival time of mice compared to the untreated group. Injection exosomes derived from umbilical cord-derived mesenchymal stem cells into the GVHD mouse model significantly prolonged the survival time of mice compared to the untreated group. High-throughput sequencing data showed that microRNA such as miR-21 in exosomes isolated from umbilical cord-derived mesenchymal stem cells, which mainly affected the signaling pathways such as cell adhesion, RNA degradation. CONCLUSION: The umbilical cord-derived mesenchymal stem cells can prevent the occurrence of aGVHD after HSCT, which is mediate by MicroRNA in the exosomes derived from umbilical cord-derived mesenchymal stem cells.