Label-Free Detection of Programmed Death-Ligand 1 for Prognosis Using a Truncated Aptamer and SYBR Green I.

The rapid and accurate detection of programmed death-ligand 1 (PD-L1) expression is of great value in the diagnosis and treatment of tumors. ELISA-based traditional method is the gold standard for protein detection, but there are still some shortcomings, especially the antigen-antibody dependence, greatly increased the detection time and cost. This work constructed a label-free fluorescent probe for rapid and sensitive detection of PD-L1 using a truncated aptamer as recognition molecules and double-stranded DNA specific dyes (SYBR Green I) as signal units. After a series of optimization conditions, this probe has good detection capability for PD-L1 in buffer solution with the detection limit as low as 0.68 ng/mL. Due to the specific recognition ability of aptamer and target, this method also has good selectivity for PD-L1 detection. The recovery of PD-L1 in human serum samples ranges from 86.20 to 96.36%. Compared with other methods, this strategy does not need to be marked, and does not need other complex design and purification process, but simple operation process and strong anti-interference ability. The whole detection process can be completed within 20 min and has good application prospect. This work will provide reference for drug dosage and prognosis evaluation of specific tumor therapy.

Novel insights into the role of immunomodulatory extracellular vesicles in the pathogenesis of liver fibrosis.

Liver fibrosis, a chronic and long-term disease, can develop into hepatocellular carcinoma (HCC) and ultimately lead to liver failure. Early diagnosis and effective treatment still face significant challenges. Liver inflammation leads to liver fibrosis through continuous activation of hepatic stellate cells (HSCs) and the accumulation of immune cells. Intracellular communication among various immune cells is important for mediating the inflammatory response during fibrogenesis. Extracellular vesicles (EVs), which are lipid bilayer membrane-enclosed particles naturally secreted by cells, make great contributions to cell-cell communication and the transport of bioactive molecules. Nearly all the cells that participate in liver fibrosis release EVs loaded with lipids, proteins, and nucleic acids. EVs from hepatocytes, immune cells and stem cells are involved in mediating the inflammatory microenvironment of liver fibrosis. Recently, an increasing number of extracellular vesicle-based clinical applications have emerged, providing promising cell-free diagnostic and therapeutic tools for liver fibrosis because of their crucial role in immunomodulation during pathogenesis. The advantages of extracellular vesicle-based therapies include stability, biocompatibility, low cytotoxicity, and minimal immunogenicity, which highlight their great potential for drug delivery and specific treatments for liver fibrosis. In this review, we summarize the complex biological functions of EVs in the inflammatory response in the pathogenesis of liver fibrosis and evaluate the potential of EVs in the diagnosis and treatment of liver fibrosis.

Spatiotemporal variations of farmland crop residue burning in China from 2013 to 2022.

Farmland crop residue burning (FCRB) significantly impacts air quality, necessitating understanding its spatiotemporal variations to evaluate control measures and guide future policies. This study analyzes FCRB across China from 2013 to 2022 using remote sensing technology and spatiotemporal analysis. Results indicate that the first phase (2013-2017) of the "Clean Air Action" control measures has been proven ineffective, with a 30.9 % increase in FCRB. Effective measures implemented in the second phase (2018-2020) resulted in a reduction of 41.4 % and led to a decrease of 34.3 % in 2022 compared to 2013. FCRB exhibits significant seasonal and regional variations, with a 69 % decrease in autumn and a 23 % increase in spring. While the variations in FCRB across regions are found to be significantly negatively correlated with the stringency of control measures, there is a 61.2 % reduction in the central region, 42.4 % in the western region, 29.7 % in the eastern region with the highest intra-regional disparities, and only 4.5 % in the northeastern region, which is attributed to the high FCRB in Heilongjiang province. FCRB demonstrates the "club convergence" phenomenon and the spillover effects of adjacent provinces, leading to high-high clusters in the northeastern region, emphasizing the need for region-specific control measures (e.g., Heilongjiang province in the northeastern) and the implementation of similar control measures in adjacent areas. Additionally, it is necessary to avoid the rebound phenomenon determined by the analysis of the kernel density estimation curve. Our findings underscore the importance of tailored strategies in managing FCRB and improving air quality in critical areas.

Characteristics and health risks assessment of PM2.5-bound heavy metals during winter in urban areas of northern China: A case study in Kaifeng.

The health impact of heavy metals in atmospheric PM2.5 has garnered increasingly widespread attention. We have collected PM2.5 samples in a typical city (Kaifeng) within the Central Plains Urban Agglomeration in China during winter and measured the mass concentration of PM2.5-bound heavy metals. The pollution of As and Cr in the urban atmosphere requires significant attention. As PM2.5 concentrations increased, the enrichment factors (EFs) of Mn, Cu, Zn, As, and Pb also rose, suggesting a growing contribution from anthropogenic emissions. The analysis showed that the hazard quotient (HQ) for the non-heating and heating periods (HQ < 1) did not result in a cumulative non-carcinogenic health risk to humans. Regarding carcinogenic effects, As and Cr exhibit significant carcinogenic impacts on both children and adults (ELCR>1 × 10-6), indicating that the carcinogenic risks posed by As and Cr under PM2.5 exposure in Kaifeng could not be overlooked. It was found that industrial and biomass combustion are the primary sources of carcinogenic risk in Kaifeng city. From the non-heating to the heating period, the industrial carcinogenic risk increased from 37.12 % to 43.39 %, while the contribution of biomass burning remained at 25 %. This result was strongly correlated with the high proportions of heavy metal elements such as As, Mn, Pb, and Ni from the metal refinery industry. The results of this study revealed the equally important source of heavy metals, compared to coal combustion in North China Plain. In addition to residential coal combustion, industrial emissions are a major source of PM2.5-bound heavy metals in Kaifeng, contributing significantly to overall air pollution and providing a useful reference to mitigating human health risks in the area.

Enhancement of Apple Stress Resistance via Proline Elevation by Sugar Substitutes.

Plants encounter numerous adversities during growth, necessitating the identification of common stress activators to bolster their resistance. However, the current understanding of these activators' mechanisms remains limited. This study identified three anti-stress activators applicable to apple trees, all of which elevate plant proline content to enhance resistance against various adversities. The results showed that the application of these sugar substitutes increased apple proline content by two to three times compared to the untreated group. Even at a lower concentration, these activators triggered plant stress resistance without compromising apple fruit quality. Therefore, these three sugar substitutes can be exogenously sprayed on apple trees to augment proline content and fortify stress resistance. Given their effectiveness and low production cost, these activators possess significant application value. Since they have been widely used in the food industry, they hold potential for broader application in plants, fostering apple industry development.

Increased circulating LOX-1+ neutrophils activate T cells and demonstrate a pro-inflammatory role in allergic rhinitis.

Background: Low-density neutrophils are heterogeneous immune cells with immunosuppressive (such as polymorphonuclear myeloid-derived suppressor cells [PMN-MDSC]) or pro-inflammatory (such as low-density granulocytes [LDG]) properties that have been well described in multiple cancers and immune diseases. However, its role in allergic rhinitis (AR) is still unclear. Methods: In the present study, we defined low-density neutrophils as CD14-CD11B+CD15+LOX-1+ (LOX-1+ neutrophils), and their levels in the peripheral blood (PB) were evaluated and compared between patients with AR and healthy donors using flow cytometric analysis. LOX-1 expression on polymorphonuclear neutrophils was identified. Carboxyfluorescein succinimidyl ester (CFSE)-stained CD3+ T cells were cultured alone or with LOX-1+ neutrophils, T cell proliferation was assessed using flow cytometry, and pro-inflammatory cytokines in the supernatants were detected using enzyme-linked immunosorbent assay (ELISA). Clinicopathological analyses were performed to gain a thorough understanding of LOX-1+ neutrophils. Results: We determined that LOX-1+ neutrophils were significantly increased in the PB of patients with AR, and LOX-1 expression in neutrophils from patients with AR was elevated. Interestingly, LOX-1+ neutrophils derived from patients with AR, unlike PMN-MDSC, promoted T cell proliferation and pro-inflammatory cytokine production. Moreover, clinicopathological analysis revealed that there was no any relation between circulating LOX-1+ neutrophil levels and the levels of IgE, age and sex. Conclusion: These findings indicate that elevated circulating LOX-1+ neutrophils play a pro-inflammatory role in AR.

Epidermodysplasia Verruciformis and Vδ2 γδ T-cell Expansion in STK4 Deficiency.

The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects. This variability is influenced by pathogen exposure, healthcare access and host-environment interactions. We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia. The patient was born to consanguineous parents living in the United States. Exome sequencing identified a previously unknown biallelic STK4 stop-gain mutation (p.Trp425X). The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties. Despite his low CD4+ T-cell count, the patient had normal counts of CD3+ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2+ γδ T cells. γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency. The Vδ2 γδ T cells of this STK4-deficient patient are mostly CD45RA-CD27+CCR7+ central memory γδT cells, and their ability to proliferate in response to T-cell activation was impaired, as was that of CD4+ T cells. In conclusion, γδ T-cell expansion may act as a compensatory mechanism to combat viral infection, providing immune protection in immunocompromised individuals.

Anti-oxidant activity of 1-(1H-imidazo[4,5-c]pyridin-4-yl)ethenone, a Maillard reaction product derived from fructose and histidine.

BACKGROUND: The Maillard reaction involves the interaction of various amino acids and reducing sugars, resulting in food browning. It often produces appealing aromas and flavors. The complexities of the reaction are such that it can be challenging to identify the often numerous and frequently volatile products formed by it. In the present study, we sought to identify and evaluate an unusual product with anti-oxidant activity arising from a fructose-histidine Maillard reaction model. The anti-oxidant profile of this product was assessed by computational means. RESULTS: The fructose-histidine Maillard reaction products (FH-MRPs) were generated by heating a 2:1 mixture of the sugar and the amino acid at 140 °C for 2 h. Chromatographically separable fractions, labelled DM-1 to DM-8, were obtained using silica gel as the stationary phase and dichloromethane/methanol (DCM/MeOH) mixtures as the mobile one. Fraction DM-5 exhibited the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, and further bio-assay guided fractionation led to isolation and identification of 1-(1H-imidazo[4,5-c]pyridin-4-yl)ethenone (IMPE) as the active principal, the structure of which was established by nuclear magnetic resonance (NMR) spectroscopic and mass spectral techniques. A mechanism for the formation of IMPE from its precursors is proposed. Density functional theory (DFT) calculations suggest this novel heterocyclic compound exerts its anti-oxidant effects by interacting with DPPH and 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals. Essentially, IMPE was non-toxic below 300 ug mL-1, showing a concentration-dependent free radical clearance capacity and reducing power within the 100-1000 µg mL-1 range, and moreover, exhibiting significant Fe2+ chelating abilities wihin the 50-200 µg mL-1 range. CONCLUSION: This study identified the unique FH-MRP, IMPE, and found that it acts as food antioxidant through the chelation of metal ions. © 2024 Society of Chemical Industry.

Distinct dynamics of parental 5-hydroxymethylcytosine during human preimplantation development regulate early lineage gene expression.

The conversion of DNA 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by TET enzymes represents a significant epigenetic modification, yet its role in early human embryos remains largely unknown. Here we showed that the early human embryo inherited a significant amount of 5hmCs from an oocyte, which unexpectedly underwent de novo hydroxymethylation during its growth. Furthermore, the generation of 5hmC in the paternal genome after fertilization roughly followed the maternal pattern, which was linked to DNA methylation dynamics and regions of sustained methylation. The 5hmCs persisted until the eight-cell stage and exhibited high enrichment at OTX2 binding sites, whereas knockdown of OTX2 in human embryos compromised the expression of early lineage genes. Specifically, the depletion of 5hmC affected the activation of embryonic genes, which was further evaluated by ectopically expressing mouse Tet3 in human early embryos. These findings revealed distinct dynamics of 5hmC and unravelled its multifaceted functions in early human embryonic development.

Quercetin alleviates inflammation induced by porcine reproductive and respiratory syndrome virus in MARC-145 cells through the regulation of arachidonic acid and glutamine metabolism.

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes severe inflammatory response, respiratory disease and sow reproductive failure. Quercetin is among the widely occurring polypheno found abundantly in nature. Quercetin has anti-inflammatory, anti-oxidative and anti-viral properties. OBJECTIVES: This study aimed to explore the effect and mechanism of quercetin on PRRSV-induced inflammation in MARC-145 cells. METHODS: Observing the cytopathic effect and measurements of inflammatory markers in MARC-145 cells collectively demonstrate that quercetin elicits a curative effect on PRRSV-induced inflammation. Liquid chromatography-mass spectrometry was further used for a non-targeted metabolic analysis of the role of quercetin in the metabolic regulation of PRRSV inflammation in MARC-145 cells. RESULTS: It was shown that quercetin attenuated PRRSV-induced cytopathy in MARC-145 cells. Quercetin treatment inhibited PRRSV replication in MARC-145 cells in a dose-dependent manner. We also found that quercetin inhibited PRRSV-induced mRNA expression and secretion levels of tumour necrosis factor-α, interleukin 1ß and interleukin 6. Metabolomics analysis revealed that quercetin ameliorated PRRSV-induced inflammation. Pathway analysis results revealed that PRRSV-induced pathways including arachidonic acid metabolism, linoleic acid, glycerophospholipid and alanine, aspartate and glutamate metabolism were suppressed by quercetin. Moreover, we confirmed that quercetin inhibited the activation of NF-κB/p65 pathway, probably by attenuating PLA2, ALOX and COX mRNA expression. CONCLUSIONS: These results provide a crucial insight into the molecular mechanism of quercetin in alleviating PRRSV-induced inflammation.

Trametinib boosts palbociclib's efficacy in breast cancer via autophagy inhibition.

Breast cancer, a predominant global health issue, requires ongoing exploration of new therapeutic strategies. Palbociclib (PAL), a well-known cyclin-dependent kinase (CDK) inhibitor, plays a critical role in breast cancer treatment. While its efficacy is recognized, the interplay between PAL and cellular autophagy, particularly in the context of the RAF/MEK/ERK signaling pathway, remains insufficiently explored. This study investigates PAL's inhibitory effects on breast cancer using both in vitro (MCF7 and MDA-MB-468 cells) and in vivo (tumor-bearing nude mice) models. Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib (TRA), an MEK inhibitor, our research seeks to address the challenge of PAL-induced drug resistance. Our findings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells. However, PAL also induces protective autophagy, potentially leading to drug resistance via the RAF/MEK/ERK pathway activation. Introducing TRA effectively neutralized this autophagy, enhancing PAL's anti-tumor efficacy. A combination of PAL and TRA synergistically reduced cell viability and proliferation, and in vivo studies showed notable tumor size reduction. In conclusion, the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance, offering a new horizon in breast cancer treatment.

Disease types and pathogenic mechanisms induced by PM2.5 in five human systems: An analysis using omics and human disease databases.

Atmospheric fine particulate matter (PM2.5) can harm various systems in the human body. Due to limitations in the current understanding of epidemiology and toxicology, the disease types and pathogenic mechanisms induced by PM2.5 in various human systems remain unclear. In this study, the disease types induced by PM2.5 in the respiratory, circulatory, endocrine, and female and male urogenital systems have been investigated and the pathogenic mechanisms identified at molecular level. The results reveal that PM2.5 is highly likely to induce pulmonary emphysema, reperfusion injury, malignant thyroid neoplasm, ovarian endometriosis, and nephritis in each of the above systems respectively. The most important co-existing gene, cellular component, biological process, molecular function, and pathway in the five systems targeted by PM2.5 are Fos proto-oncogene (FOS), extracellular matrix, urogenital system development, extracellular matrix structural constituent conferring tensile strength, and ferroptosis respectively. Differentially expressed genes that are significantly and uniquely targeted by PM2.5 in each system are BTG2 (respiratory), BIRC5 (circulatory), NFE2L2 (endocrine), TBK1 (female urogenital) and STAT1 (male urogenital). Important disease-related cellular components, biological processes, and molecular functions are specifically induced by PM2.5. For example, response to wounding, blood vessel morphogenesis, body morphogenesis, negative regulation of response to endoplasmic reticulum stress, and response to type I interferon are the top uniquely existing biological processes in each system respectively. PM2.5 mainly acts on key disease-related pathways such as the PD-L1 expression and PD-1 checkpoint pathway in cancer (respiratory), cell cycle (circulatory), apoptosis (endocrine), antigen processing and presentation (female urogenital), and neuroactive ligand-receptor interaction (male urogenital). This study provides a novel analysis strategy for elucidating PM2.5-related disease types and is an important supplement to epidemiological investigation. It clarifies the risks of PM2.5 exposure, elucidates the pathogenic mechanisms, and provides scientific support for promoting the precise prevention and treatment of PM2.5-related diseases.

A systematic review of biochar aging and the potential eco-environmental risk in heavy metal contaminated soil.

Biochar is widely accepted as a green and effective amendment for remediating heavy metals (HMs) contaminated soil, but its long-term efficiency and safety changes with biochar aging in fields. Currently, some reviews have qualitatively summarized biochar aging methods and mechanisms, aging-induced changes in biochar properties, and often ignored the potential eco-environmental risk during biochar aging process. Therefore, this review systematically summarizes the study methods of biochar aging, quantitatively compares the effects of different biochar aging process on its properties, and discusses the potential eco-environmental risk due to biochar aging in HMs contaminated soil. At present, various artificial aging methods (physical aging, chemical aging and biological aging) rather than natural field aging have been applied to study the changes of biochar's properties. Generally, biochar aging increases specific surface area (SSA), pore volume (PV), surface oxygen-containing functional group (OFGs) and O content, while decreases pH, ash, H, C and N content. Chemical aging method has a greater effect on the properties of biochar than other aging methods. In addition, biochar aging may lead to HMs remobilization and produce new types of pollutants, such as polycyclic aromatic hydrocarbons (PAHs), environmentally persistent free radicals (EPFRs) and colloidal/nano biochar particles, which consequently bring secondary eco-environmental risk. Finally, future research directions are suggested to establish a more accurate assessment method and model on biochar aging behavior and evaluate the environmental safety of aged biochar, in order to promote its wider application for remediating HMs contaminated soil.

Autophagy in hepatic progenitor cells modulates exosomal miRNAs to inhibit liver fibrosis in schistosomiasis.

Schistosoma infection is one of the major causes of liver fibrosis. Emerging roles of hepatic progenitor cells (HPCs) in the pathogenesis of liver fibrosis have been identified. Nevertheless, the precise mechanism underlying the role of HPCs in liver fibrosis in schistosomiasis remains unclear. This study examined how autophagy in HPCs affects schistosomiasis-induced liver fibrosis by modulating exosomal miRNAs. The activation of HPCs was verified by immunohistochemistry (IHC) and immunofluorescence (IF) staining in fibrotic liver from patients and mice with Schistosoma japonicum infection. By coculturing HPCs with hepatic stellate cells (HSCs) and assessing the autophagy level in HPCs by proteomic analysis and in vitro phenotypic assays, we found that impaired autophagy degradation in these activated HPCs was mediated by lysosomal dysfunction. Blocking autophagy by the autophagy inhibitor chloroquine (CQ) significantly diminished liver fibrosis and granuloma formation in S. japonicum-infected mice. HPC-secreted extracellular vehicles (EVs) were further isolated and studied by miRNA sequencing. miR-1306-3p, miR-493-3p, and miR-34a-5p were identified, and their distribution into EVs was inhibited due to impaired autophagy in HPCs, which contributed to suppressing HSC activation. In conclusion, we showed that the altered autophagy process upon HPC activation may prevent liver fibrosis by modulating exosomal miRNA release and inhibiting HSC activation in schistosomiasis. Targeting the autophagy degradation process may be a therapeutic strategy for liver fibrosis during Schistosoma infection.

Impact of wildfire ash on skin and gut microbiomes and survival of Rana dybowskii.

Climate change and human activities escalate the frequency and intensity of wildfires, threatening amphibian habitats and survival; yet, research on these impacts remains limited. Wildfire ash alters water quality, introduces contaminants, and may disrupt microbial communities, impacting gut and skin microbiota; however, the effects on gut and skin microbiota remain unclear. Rana dybowskii were exposed to five concentrations (0 g L-1, 1.25 g L-1, 2.5 g L-1, 5 g L-1, and 10 g L-1) of aqueous extracts of wildfire ashes (AEAs) for 30 days to assess AEAs' metal content, survival, and microbiota diversity via Illumina sequencing. Our results showed that the major elements in ash were Ca > K > Mg > Al > Fe > Na > Mn, while in AEA they were K > Ca > Na > Mg > As > Al > Cu. A significant decrease in amphibian survival rates with increased AEA concentration was shown. The beta diversity analysis revealed distinct shifts in microbiota composition. Notably, bacterial genera associated with potential health risks showed increased abundance in skin microbiota, emphasising the potential for ash exposure to affect amphibian health. Functional prediction analyses revealed significant shifts in metabolic pathways related to health and disease, indicating that wildfire ash exposure may influence amphibian health through changes in microbial functions. This study highlights the urgent need for strategies to mitigate wildfire ash impacts on amphibians, as it significantly alters microbiota and affects their survival and health.

Determination of major drive of ozone formation and improvement of O3 prediction in typical North China Plain based on interpretable random forest model.

O3 pollution in China has become prominent in recent years, and it has become one of the most challenging issues in air pollution control. We used data on atmospheric pollutants and meteorology from 2019 to 2021 to build an interpretable random forest (RF) model, applying this model to predict O3 concentration in 2022 in five cities in the Southwest North China Plain. The model was also used to identify and explain the influence of various factors on O3 formation. The correlation coefficient R2 between the predicted O3 concentration and observed O3 concentration was 0.82, the MAE was 15.15 µg/m3, and the RMSE was 20.29 µg/m3, indicating that the model can effectively predict O3 concentration in the studying area. The results of correlation analysis, feature importance, and the driving factor analysis from SHapley Additive exPlanations (SHAP) model indicated that temperature (T), NO2, and relative humidity (RH) are the top three features affecting O3 prediction, while the weights of wind speed and wind direction were relatively low. Thus, O3 in the southwestern North China Plain may mainly come from the formation of local photochemical activities. The dominant factors behind O3 also varied in different seasons. In spring and autumn, O3 pollution is more likely to occur under high NO2 concentration and high-temperature conditions, while in summer, it is more likely to occur under high-temperature and precipitation-free weather. In winter, NO2 is the dominant factor in O3 formation. Finally, the interpretable RF model is used to predict future O3 concentration based on features provided by Community Multiscale Air Quality (CMAQ) and Weather Research & Forecast (WRF) model, and the simulation performance of CMAQ on O3 concentration is enhanced to a certain extent, improving the prediction of future O3 pollution situations and guiding pollution control.

Generation of rat forebrain tissues in mice.

Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite recent successes, brain tissue has not been achieved through IBC. Here, we developed an optimized IBC strategy based on C-CRISPR, which facilitated rapid screening of candidate genes and identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact. Cross-species comparative analyses revealed that rat forebrain tissues developed at the same pace as the mouse host but maintained rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late pre-natal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis.

A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells.

Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4+ T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation.