TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia.

Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2V617F mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.

Nuclear matrix protein 22 in bladder cancer.

Bladder cancer (BC) is ranked as the ninth most common malignancy worldwide, with approximately 570,000 new cases reported annually and over 200,000 deaths. Cystoscopy remains the gold standard for the diagnosis of BC, however, its invasiveness, cost, and discomfort have driven the demand for the development of non-invasive, cost-effective alternatives. Nuclear matrix protein 22 (NMP22) is a promising non-invasive diagnostic tool, having received FDA approval. Traditional methods for detecting NMP22 require a laboratory environment equipped with specialized equipment and trained personnel, thus, the development of NMP22 detection devices holds substantial potential for application. In this review, we evaluate the NMP22 sensors developed over the past decade, including electrochemical, colorimetric, and fluorescence biosensors. These sensors have enhanced detection sensitivity and overcome the limitations of existing diagnostic methods. However, many emerging devices exhibit deficiencies that limit their potential clinical use, therefore, we propose how sensor design can be optimized to enhance the likelihood of clinical translation and discuss the future applications of NMP22 as a legacy biomarker, providing insights for the design of new sensors.

Heterogeneity of myeloid cells in common cancers: Single cell insights and targeting strategies.

Tumor microenvironment (TME), is characterized by a complex and heterogenous composition involving a substantial population of immune cells. Myeloid cells comprising over half of the solid tumor mass, are undoubtedly one of the most prominent cell populations associated with tumors. Studies have unambiguously established that myeloid cells play a key role in tumor development, including immune suppression, pro-inflammation, promote tumor metastasis and angiogenesis, for example, tumor-associated macrophages promote tumor progression in a variety of common tumors, including lung cancer, through direct or indirect interactions with the TME. However, due to previous technological constraints, research on myeloid cells often tended to be conducted as studies with low throughput and limited resolution. For example, the conventional categorization of macrophages into M1-like and M2-like subsets based solely on their anti-tumor and pro-tumor roles has disregarded their continuum of states, resulting in an inadequate analysis of the high heterogeneity characterizing myeloid cells. The widespread adoption of single-cell RNA sequencing (scRNA-seq) in tumor immunology has propelled researchers into a new realm of understanding, leading to the establishment of novel subsets and targets. In this review, the origin of myeloid cells in high-incidence cancers, the functions of myeloid cell subsets examined through traditional and single-cell perspectives, as well as specific targeting strategies, are comprehensively outlined. As a result of this endeavor, we will gain a better understanding of myeloid cell heterogeneity, as well as contribute to the development of new therapeutic approaches.

Risk Factors for Occupational Blood Exposure, Compliance with Policies of Infection Prevention and Control, and Costs Associated with Post Exposure Management Among Nursing Staff.

Objective: To examine the risk factors linked with occupational blood exposure (OBE) among nursing staff (NS), we pinpoint deficiencies in the compliance with policies of infection prevention and control, and assess the expenditures associated with infection prevention and control. Methods: Healthcare workers that completed an "Occupational Blood Exposure Report Form" were divided into NS (observation) group and non-NS (control) group. Univariate and multivariable analyses were conducted to compare both groups in various aspects. We also explored design patents intended to minimize occupational exposure. Results: The highest incidence of OBE was observed in the department of neurosurgery. Among NS, OBE incidence was found to be influenced by independent risk factors, such as gender, age, occupational title, work location, and incidence of sharps injuries. Protective factors against OBEs included the use of arterial blood gas needles and suture needles. Personal protective equipment (PPE) usage rates were low in both groups prior to OBEs (0.74% vs 0.00%, P > 0.05). Correct emergency management could be improved promptly by both groups following an OBE (P > 0.05). However, the observation group exhibited a higher proportion of blood expression after a sharps injury and a higher re-evaluation rate at 6 months post-exposure compared to the control group (P < 0.05). In 2018, the per capita costs of infection prevention and control for NS were the Chinese Yuan (RMB) 339.43 per individual. In response to these findings, two utility model patents have been authorized. Conclusion: The risk and protective factors related to the occurrence of OBEs were investigated in this study, suggesting that there is a need for improvement in the rate of PPE usage and the re-evaluation rate of OBEs among NS. Additionally, focused training on emergency blood expression and compliance with policies among non-NS personnel is deemed necessary.

Tumors Established in a Defective Immune Environment Reprogram the Oncogenic Signaling Pathways to Escalate Tumor Antigenicity.

Tumors developed in immunocompromised hosts are more immunogenic. However, few studies have addressed the potential mechanisms underlying the high immunogenicity of tumors found in a suppressed immune system. Therefore, we aimed to elucidate the impacts of the immune system on tumor behaviors and immunogenicity sculpting. A murine colorectal adenocarcinoma cell line, CT26wt, was administrated into immunocompetent (BALB/c) and immunocompromised (NOD.SCID) mice, respectively. On day 11, the CT26 cells slowly progressed in the NOD.SCID mice compared to the BALB/c mice. We then performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed the differentially expressed proteins (DEPs). The DEPs participated in numerous oncogenic pathways, PI3K/AKT/mTOR cell signaling, and the silencing of several tumor suppressors, such as PTEN and RBL1, during tumorigenesis. On day 34, the CT26/SCID tumors inversely became malignant counterparts; then the CT26/SCID tumors were harvested and re-inoculated into immunocompetent mice (CT26/SCID-Re tumors) to determine the immunogenicity. The CT26/SCID-Re tumor growth rate significantly decreased. Furthermore, increased infiltrations of dendritic cells and tumor-infiltrating T lymphocytes were found in the CT26/SCID-Re tumors. These findings suggest that immunogenic tumors might express multiple tumor rejection antigens, unlike wild-type tumors, and attract more immune cells, therefore decreasing the growth rate. Collectively, our study first revealed that in immunodeficient hosts, tumor suppressors were silenced and oncogenic signaling pathways were changed during the initial phase of tumor development. With tumor progression, the tumor antigens were overexpressed, exhibiting elevated immunogenicity. This study offers a hint on the mechanisms of tumorigenesis and provides a niche for investigating the interaction between host immunity and cancer development.

Health Benefits of Different Sports: a Systematic Review and Meta-Analysis of Longitudinal and Intervention Studies Including 2.6 Million Adult Participants.

BACKGROUND: Several reviews have examined the health benefits of participation in specific sports, such as baseball, cricket, cross-country skiing, cycling, downhill skiing, football, golf, judo, rugby, running and swimming. However, new primary studies on the topic have recently been published, and the respective meta-analytic evidence needs to be updated. OBJECTIVES: To systematically review, summarise and appraise evidence on physical health benefits of participation in different recreational sports. METHODS: Searches for journal articles were conducted in PubMed/MEDLINE, Scopus, SpoLit, SPORTDiscus, Sports Medicine & Education Index and Web of Science. We included longitudinal and intervention studies investigating physical health outcomes associated with participation in a given sport among generally healthy adults without disability. RESULTS: A total of 136 papers from 76 studies conducted among 2.6 million participants were included in the review. Our meta-analyses of available evidence found that: (1) cycling reduces the risk of coronary heart disease by 16% (pooled hazard ratio [HR] = 0.84; 95% confidence interval [CI]: 0.80, 0.89), all-cause mortality by 21% (HR = 0.79; 95% CI: 0.73, 0.84), cancer mortality by 10% (HR = 0.90; 95% CI: 0.85, 0.96) and cardiovascular mortality by 20% (HR = 0.80; 95% CI: 0.74, 0.86); (2) football has favourable effects on body composition, blood lipids, fasting blood glucose, blood pressure, cardiovascular function at rest, cardiorespiratory fitness and bone strength (p < 0.050); (3) handball has favourable effects on body composition and cardiorespiratory fitness (p < 0.050); (4) running reduces the risk of all-cause mortality by 23% (HR = 0.77; 95% CI: 0.70, 0.85), cancer mortality by 20% (HR = 0.80; 95% CI: 0.72, 0.89) and cardiovascular mortality by 27% (HR = 0.73; 95% CI: 0.57, 0.94) and improves body composition, cardiovascular function at rest and cardiorespiratory fitness (p < 0.010); and (5) swimming reduces the risk of all-cause mortality by 24% (HR = 0.76; 95% CI: 0.63, 0.92) and improves body composition and blood lipids (p < 0.010). CONCLUSIONS: A range of physical health benefits are associated with participation in recreational cycling, football, handball, running and swimming. More studies are needed to enable meta-analyses of health benefits of participation in other sports. PROSPERO registration number CRD42021234839.

The Risk of Adhesive Bowel Obstruction in Children With Appendicitis: A Systematic Review.

OBJECTIVE: Complicated appendicitis is associated with a higher risk of postoperative complications, including adhesive bowel obstruction. The aim of this meta-analysis is to investigate the difference in rates of postoperative bowel obstruction in paediatric patients with complicated versus simple appendicitis and whether this is influenced by the surgical approach. METHODS: A systematic literature search following PRISMA guidelines was conducted using MEDLINE, Embase and Cochrane Library for studies that analysed incidence of adhesive bowel obstruction in paediatric patients after appendicectomy. Studies from 1998 to 2022 were included in analysis. The study protocol was registered on PROSPERO (ID CRD42022309769). RESULTS: Pooled analysis of 6 studies with low risk of bias and adequate follow up periods, considering 58,962 cases of appendicectomy, revealed complex appendicitis was associated with a near two-fold increase in incidence of SBO (pooled odds ratio 2.02 (95% CI 1.35-2.69)). Interestingly, a similar pooled analysis of 10 studies, considering 62,433 cases of appendicectomy, revealed no significant difference between open and laparoscopic management of complex appendicitis (pooled odds ratio 0.93 (95% CI 0.24 to 1.62)). CONCLUSION: Complex appendicitis is associated with a two-fold increase in the rates of adhesive bowel obstruction. Whilst there are cosmetic advantages of a laparoscopic approach, surgical expertise should be favoured in decision making relating to surgical approach (laparoscopic versus open) as the evidence for a laparoscopic approach reducing risks of adhesive bowel obstruction is not convincing. LEVEL OF EVIDENCE: Level II.

Feasibility and Safety of Percutaneous Puncture Guided by a 5G-Based Telerobotic Ultrasound System: An Experimental Study.

PURPOSE: To evaluate the feasibility and safety of percutaneous puncture guided by a 5th generation mobile communication technology (5G)-based telerobotic ultrasound system in phantom and animal experiments. MATERIALS AND METHODS: In the phantom experiment, 10 simulated lesions were punctured, once at each of two angles for each lesion, under the guidance of a telerobotic ultrasound system and ultrasound-guided freehand puncture. Student's t test was used to compare the two methods in terms of puncture accuracy, total operation duration, and puncture duration. In the animal experiment, under the guidance of the telerobotic ultrasound system, an 18G puncture needle was used to puncture 3 target steel beads in the liver, right kidney, and right gluteal muscle, respectively. The animal experiment had no freehand ultrasound-guided control group. After puncture, a CT scan was performed to verify the position of the puncture needle in relation to the target, and the complications and puncture duration, etc., were recorded. RESULTS: In the phantom experiment, the mean accuracies of puncture under telerobotic ultrasound guidance and conventional ultrasound guidance were 1.8 ± 0.3 mm and 1.6 ± 0.3 mm (P = 0.09), respectively; therefore, there was no significant difference in the accuracy of the two guide methods. In the animal experiment, the first-attempt puncture success (the needle tip close to the target) rate was 93%. Polypnea occurred during one puncture. No other intraoperative or postoperative complications were observed. CONCLUSION: Puncture guided by a 5G-based telerobotic ultrasound system has shown good feasibility and safety in phantom and animal experiments.

Key role of hydrogen atoms in the preparation of sulfidated zero valent iron.

Sulfidated zero valent iron (ZVI) is a popular material for the reductive degradation of halogenated organic pollutants. Simple and economic synthesis of this material is highly demanded. In this study, sulfidated micro/nanostructured ZVI (MNZVI) particles were prepared by simply heating MNZVI particles and sulfur elements (S0) in pure water (50℃). The iron oxides on the surface of MNZVI particles were conducive to sulfidation reaction, indicating the formation of iron-sulphide minerals (FeSx) on the surface of MNZVI particles might not be from the direct reaction of Fe0 with S0 (Fe0 and S0 acted as reductant and oxidant, respectively). As an important reductant, hydrogen atom (H•) can be generated from the reduction of H+ by MNZVI particles and participate in the formation of FeSx. Quenching experiment and cyclic voltammetry analysis proved the existence of H• on the surface of MNZVI particles. DFT calculation found that the potential barrier of H•/S0 and Fe0/S0 were 1.91 and 7.24 eV, respectively, indicating that S0 would preferentially react with H• instead of Fe0. The formed H• can quickly react with S0 to generate hydrogen sulfide (H2S), which can further react with iron oxides such as α-Fe2O3 on the surface of MNZVI particles to form FeSx. In addition, the H2 partial pressure in water significantly affected the amount of H• generated, thereby affecting the sulfidation efficiency. For TCE degradation, as the sulfur loading of sulfidated MNZVI particles increased, the contribution of H• significantly decreased while the contribution of direct electron transfer increased. This study provided new insights into the synthesis mechanism of sulfidated ZVI in water.

Importance of AIM2 as a serum marker for reflecting severity and predicting a poor outcome of human severe traumatic brain injury: A prospective longitudinal cohort study.

BACKGROUND: Absent in melanoma 2 (AIM2) participates in neuroinflammation. Here, the prognostic significance of serum AIM2 was explored in severe traumatic brain injury (sTBI). METHODS: A total of 135 sTBI patients and 80 healthy controls were recruited in this prospective cohort study. Serum C-reactive protein (CRP) and AIM2 levels were measured. Glasgow Coma Scale (GCS) and Rotterdam computed tomography (CT) classification were recorded as the severity indicators. Prognostic parameters were posttraumatic six-month extended Glasgow outcome scale (GOSE) scores and poor outcome (GOSE scores of 1-4). RESULTS: As opposed to controls, there were significantly elevated serum AIM2 levels after sTBI. Serum AIM2 levels were independently correlated with serum CRP levels, GCS scores, Rotterdam CT scores, GOSE scores and poor outcome. Also, serum AIM2 levels were efficiently predictive of poor outcome under the receiver operating characteristic (ROC) curve. Under the restricted cubic spline, serum AIM2 levels were linearly correlated with risk of poor outcome. Using subgroup analysis, serum AIM2 levels did not significantly interact with other indices, such as age, gender, alcohol drinking, cigarette smoking, etc. Also, combination model, in which serum AIM2, GCS scores and Rotterdam CT scores were merged, was outlined using nomogram and performed well under calibration curve, ROC curve and decision curve. CONCLUSIONS: Raised serum AIM2 levels after sTBI, in intimate correlation with systemic inflammation and trauma severity, are independently discriminative of posttraumatic six-month neurological outcome, substantializing serum AIM2 as an inflammatory prognostic biomarker of sTBI.

Postmenopausal endometrial non-benign lesion risk classification through a clinical parameter-based machine learning model.

OBJECTIVE: This study aimed to develop and evaluate a machine learning model utilizing non-invasive clinical parameters for the classification of endometrial non-benign lesions, specifically atypical hyperplasia (AH) and endometrioid carcinoma (EC), in postmenopausal women. METHODS: Our study collected clinical parameters from a cohort of 999 patients with postmenopausal endometrial lesions and conducted preprocessing to identify 57 relevant characteristics from these irregular clinical data. To predict the presence of postmenopausal endometrial non-benign lesions, including atypical hyperplasia and endometrial cancer, we employed various models such as eXtreme Gradient Boosting (XGBoost), Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), Back Propagation Neural Network (BPNN), as well as two ensemble models. Additionally, a test set was performed on an independent dataset consisting of 152 patients. The performance evaluation of all models was based on metrics including the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, precision, and F1 score. RESULTS: The RF model demonstrated superior recognition capabilities for patients with non-benign lesions compared to other models. In the test set, it attained a sensitivity of 88.1% and an AUC of 0.93, surpassing all alternative models evaluated in this study. Furthermore, we have integrated this model into our hospital's Clinical Decision Support System (CDSS) and implemented it within the outpatient electronic medical record system to continuously validate and optimize its performance. CONCLUSIONS: We have trained a model and deployed a system with high discriminatory power that may provide a novel approach to identify patients at higher risk of postmenopausal endometrial non-benign lesions who may benefit from more tailored screening and clinical intervention.

Microbiome and Otic Quinolone Levels Following Tympanoplasty Assessed by Gelatin Sponge Analysis.

OBJECTIVE: To determine if absorbable gelatin sponge (AGS) can be used to assess the posttympanoplasty microbiome and otic antibiotic exposure. STUDY DESIGN: Prospective. SETTING: Tertiary hospital. METHODS: Patients undergoing tympanoplasty were prospectively enrolled. Intraoperatively, AGS was applied to the medial ear canal/tympanic membrane (TM) for 1 minute after canal incision, then saved for analysis. Ear canals were packed with AGS at the end of surgery. Otic ofloxacin was administered until the first postoperative visit, when AGS was collected. Microbial presence was assessed by culture. Ofloxacin levels were assessed by liquid-chromatography mass-spectrometry. RESULTS: Fifty-three patients were included. AGS was collected in 92.9% of patients seen within 21 days compared to 70.8% of those seen at 22 to 35 days. At surgery, AGS yielded bacteria and fungi in 81% and 11%, respectively, including Staphylococcus species (55%) and Pseudomonas species (25%). Postoperatively, AGS yielded bacteria in 71% and fungi in 21% at the meatus, (staphylococci 57% and pseudomonas 25%). TM samples yielded bacteria in 69%, fungi in 6%, staphylococci in 53%, and pseudomonas in 19%. Ofloxacin concentration at the meatus was 248 µg/mL (95% confidence interval [CI]: 119-377) and at the TM was 126 µg/mL (95% CI: 58-194). Ofloxacin-resistant colonies were found in 75% of patients. CONCLUSION: Analysis of AGS is a viable technique for noninvasively studying healing metrics posttympanoplasty, including the microbiome and otic antibiotic exposure. Despite exposure to a high concentration of quinolones, the tympanoplasty wound is far from sterile, which may impact healing outcomes.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis.

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

A let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility.

We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population.

Clinical Significance of Upregulation of EZH1 Expression in Hepatocellular Carcinoma Tissues.

BACKGROUND AND AIMS: The incidence and mortality of hepatocellular carcinoma (HCC) are increasing. It is urgent to develop more effective HCC biomarkers for diagnosis and treatment. This project intends to verify the expression of enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1) and its mechanism in HCC. METHODS: This study integrates global microarray and high-throughput sequencing datasets, combined with internal immunohistochemistry, to analyze the expression and prognostic value of EZH1 in HCC. Functional enrichment analysis was conducted to investigate transcriptional targets, which were achieved by intersecting HCC over-expressed genes, EZH1 co-expressed genes and putative transcriptional targets. The relationship between EZH1 and anticancer drugs was detected by drug sensitivity analysis. RESULTS: In this study, 84 datasets from 40 platforms (3,926 HCC samples and 3,428 non-cancerous liver tissues) were included to show the high expression of EZH1 in HCC. Immunohistochemistry with 159 HCC samples and 62 non-HCC samples confirmed the high expression level. HCC patients with high EZH1 expression had worse survival prognoses. Gene ontology and Reactome analysis revealed that metabolism-related pathways, including autophagy, are critical for HCC. Interestingly, as one of the EZH1 potential transcriptional targets, autophagy-related 7 (ATG7) appeared in the above pathways. ATG7 was positively correlated with EZH1, upregulated in HCC, and mediated poor prognosis. Upregulation of EZH1 was found to be in contact with HCC anti-tumor drug resistance. CONCLUSIONS: The upregulation of EZH1 expression can promote the occurrence of HCC and lead to poor clinical progression and drug resistance; these effects may be mediated by regulating ATG7.

Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders.

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

Effects of latroeggtoxin-VI on dopamine and α-synuclein in PC12 cells and the implications for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by death of dopaminergic neurons leading to dopamine deficiency, excessive α-synuclein facilitating Lewy body formation, etc. Latroeggtoxin-VI (LETX-VI), a proteinaceous neurotoxin discovered from the eggs of spider L. tredecimguttatus, was previously found to promote the synthesis and release of PC12 cells, showing a great potential as a drug candidate for PD. However, the relevant mechanisms have not been understood completely. The present study explored the mechanism underlying the effects of LETX-VI on dopamine and α-synuclein of PC12 cells and the implications for PD. RESULTS: After PC12 cells were treated with LETX-VI, the level of dopamine was significantly increased in a dose-dependent way within a certain range of concentrations. Further mechanism analysis showed that LETX-VI upregulated the expression of tyrosine hydroxylase (TH) and L-dopa decarboxylase to enhance the biosynthesis of dopamine, and downregulated that of monoamine oxidase B to reduce the degradation of dopamine. At the same time, LETX-VI promoted the transport and release of dopamine through modulating the abundance and/or posttranslational modification of vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT). While the level of dopamine was increased by LETX-VI treatment, α-synuclein content was reduced by the spider toxin. α-Synuclein overexpression significantly decreased the dopamine level and LETX-VI efficiently alleviated the inhibitory action of excessive α-synuclein on dopamine. In the MPTP-induced mouse model of PD, application of LETX-VI ameliorated parkinsonian behaviors of the mice, and reduced the magnitude of MPTP-induced α-synuclein upregulation and TH downregulation. In addition, LETX-VI displayed neuroprotective effects by inhibiting MPTP-induced decrease in the numbers of TH-positive and Nissl-stained neurons in mouse brain tissues. CONCLUSIONS: All the results demonstrate that LETX-VI promotes the synthesis and release of dopamine in PC12 cells via multiple mechanisms including preventing abnormal α-synuclein accumulation, showing implications in the prevention and treatment of PD.

Exploration of signature based on T cell-related genes in stomach adenocarcinoma by analysis of single cell sequencing data.

BACKGROUND: Gastric cancer (GC) is a leading reason for the death of cancer around the world. The immune microenvironment counts a great deal in immunotherapy of advanced tumors, in which T cells exert an indispensable function. METHODS: Single-cell RNA sequencing data were utilized to characterize the expression profile of T cells, followed by T cell-related genes (TCRGs) to construct signature and measure differences in survival time, enrichment pathways, somatic mutation status, immune status, and immunotherapy between groups. RESULTS: The complex tumor microenvironment was analyzed by scRNA-seq data of GC patients. We screened for these T cell signature expression genes and the TCRGs-based signature was successfully constructed and relied on the riskscore grouping. In gene set enrichment analysis, it was shown that pro-tumor and suppressive immune pathways were more abundant in the higher risk group. We also found different infiltration of immune cells in two groups, and that the higher risk samples had a poorer response to immunotherapy. CONCLUSION: Our study established a prognostic model, in which different groups had different prognosis, immune status, and enriched features. These results have provided additional insights into prognostic evaluation and the development of highly potent immunotherapies in GC.

Improved therapeutic consistency and efficacy of CD317+ MSCs through stabilizing TSG6 by PTX3.

BACKGROUND: Previously, we have demonstrated that the batch variations of human platelet lysate (conventional MSC expansion medium) induce MSC heterogeneity and therapeutic inconsistency. On the other hand, the MSCs expanded with chemical defined medium have improved therapeutic consistency. METHODS: In the current study, we studied the MSC subpopulation composition and variation in different types and batches of MSC expansion medium with scRNA-seq analysis. RESULTS: MSCs expanded with different batches of media have higher levels of heterogeneity from the perspective of cell subpopulation composition at transcriptome levels and therapeutic inconsistency. The CD317+ subpopulation has enhanced immune suppression activities. And the percentage of CD317+ MSCs within MSCs is tightly correlated with its immune suppression activities, and also contributes to the heterogeneity and therapeutic inconsistency of MSCs. the CD317+ MSCs have increased expression levels of PTX3, which might stabilize the TSG6 protein and improve the therapeutic effects CONCLUSIONS: Thus, purifying CD317+ MSCs is one efficient strategy to reduce MSC heterogeneity and increase the therapeutic consistency of MSCs.