Establishment and verification of novel TNM staging system for lung mucinous adenocarcinoma.

BACKGROUND: Lung adenocarcinoma is a high-mortality rate cancer. Within this category, Lung mucinous adenocarcinoma (LMAC) is a rare and distinct subtype of lung adenocarcinoma necessitating further investigation. The study was launched to compare the difference of survival features between LMAC and lung non-mucinous adenocarcinoma (LNMAC) and to investigate the significance and demand for developing a new staging system tailored to LMAC. METHODS: This retrospective study assessed the suitableness of the current staging system for LMAC. It compared the overall survival (OS) between LMAC and LNMAC from 2004 to 2020 (LNMAC: 160,387; LMAC: 6,341) and instituted a novel classification framework for LMAC based on US population. Verification group consisting of patients from two Chinese medical centers from 2010 to 2018 (n = 392) was set to ascertain the applicability of this novel system. The primary endpoint was OS. To minimize the bias, propensity score match (PSM) was employed. Survival analysis and Log-rank test were executed to explore the survival features of LMAC. RESULTS: The results indicated that the existed staging system was not suitable for LMAC. Patients diagnosed with LMAC exhibited a superior OS compared to those with LNMAC in stage IA2 (P < 0.0001), IA3 (P < 0.0001), IB (P = 0.0062), IIA (P = 0.0090), IIB (P = 0.0005). In contrast, a worse OS in stage IVA (P = 0.0103) was found in LMAC patients. The novel classification system proposed for LMAC proved to be highly applicable and demonstrated substantial efficacy, as confirmed by the verification group. CONCLUSION: The newly established classification system was more effective for LMAC, but it necessitates large-scale verification to confirm its applicability and reliability.

Structure-activity relationships of the intramolecular disulphide bonds in LEAP2, an antimicrobial peptide from Acrossocheilus fasciatus.

BACKGROUND: The liver-expressed antimicrobial peptide 2 (LEAP2) plays a pivotal role in the host's immune response against pathogenic microorganisms. Numerous such antimicrobial peptides have recently been shown to mitigate infection risk in fish, and studying those harboured by the economically important fish Acrossocheilus fasciatus is imperative for enhancing its immune responses against pathogenic microorganisms. In this study, we cloned and sequenced LEAP2 cDNA from A. fasciatus to examine its expression in immune tissues and investigate the structure-activity relationships of its intramolecular disulphide bonds. RESULTS: The predicted amino acid sequence of A. fasciatus LEAP2 was found to include a signal peptide, pro-domain, and mature peptide. Sequence analysis indicated that A. fasciatus LEAP2 is a member of the fish LEAP2A cluster and is closely related to Cyprinus carpio LEAP2A. A. fasciatus LEAP2 transcripts were expressed in various tissues, with the head kidney exhibiting the highest mRNA levels. Upon exposure to Aeromonas hydrophila infection, LEAP2 expression was significantly upregulated in the liver, head kidney, and spleen. A mature peptide of A. fasciatus LEAP2, consisting of two disulphide bonds (Af-LEAP2-cys), and a linear form of the LEAP2 mature peptide (Af-LEAP2) were chemically synthesised. The circular dichroism spectroscopy result shows differences between the secondary structures of Af-LEAP2 and Af-LEAP2-cys, with a lower proportion of alpha helix and a higher proportion of random coil in Af-LEAP2. Af-LEAP2 exhibited potent antimicrobial activity against most tested bacteria, including Acinetobacter guillouiae, Pseudomonas aeruginosa, Staphylococcus saprophyticus, and Staphylococcus warneri. In contrast, Af-LEAP2-cys demonstrated weak or no antibacterial activity against the tested bacteria. Af-LEAP2 had a disruptive effect on bacterial cell membrane integrity, whereas Af-LEAP2-cys did not exhibit this effect. Additionally, neither Af-LEAP2 nor Af-LEAP2-cys displayed any observable ability to hydrolyse the genomic DNA of P. aeruginosa. CONCLUSIONS: Our study provides clear evidence that linear LEAP2 exhibits better antibacterial activity than oxidised LEAP2, thereby confirming, for the first time, this phenomenon in fish.

Neurotoxicity of manganese via ferroptosis induced by redox imbalance and iron overload.

Manganese (Mn) is an essential trace element for maintaining bodily functions. Excessive exposure to Mn can pose serious health risks to humans and animals, particularly to the nervous system. While Mn has been implicated as a neurotoxin, the exact mechanism of its toxicity remains unclear. Ferroptosis is a form of programmed cell death that results from iron-dependent lipid peroxidation. It plays a role in various physiological and pathological cellular processes and may be closely related to Mn-induced neurotoxicity. However, the mechanism of ferroptosis in Mn-induced neurotoxicity has not been thoroughly investigated. Therefore, this study aims to investigate the role and mechanism of ferroptosis in Mn-induced neurotoxicity. Using bioinformatics, we identified significant changes in genes associated with ferroptosis in Mn-exposed animal and cellular models. We then evaluated the role of ferroptosis in Mn-induced neurotoxicity at both the animal and cellular levels. Our findings suggest that Mn exposure causes weight loss and nervous system damage in mice. In vitro and in vivo experiments have shown that exposure to Mn increases malondialdehyde, reactive oxygen species, and ferrous iron, while decreasing glutathione and adenosine triphosphate. These findings suggest that Mn exposure leads to a significant increase in lipid peroxidation and disrupts iron metabolism, resulting in oxidative stress injury and ferroptosis. Furthermore, we assessed the expression levels of proteins and mRNAs related to ferroptosis, confirming its significant involvement in Mn-induced neurotoxicity.

A1 astrocytes contribute to murine depression-like behavior and cognitive dysfunction, which can be alleviated by IL-10 or fluorocitrate treatment.

BACKGROUND: Astrocytes are crucial regulators in the central nervous system. Abnormal activation of astrocytes contributes to some behavior deficits. However, mechanisms underlying the effects remain unclear. Here, we studied the activation of A1 astrocytes and their contribution to murine behavior deficits. METHODS: A1 astrocytes were induced by treatment with lipopolysaccharide (LPS) in vitro. The functional phenotype of astrocytes was determined by quantitative RT-PCR, ELISA, and immunohistochemistry. To assess the role of A1 astrocytes in vivo, mice were injected intraperitoneally with LPS. Then, murine behaviors were tested, and the hippocampus and cortex were analyzed by quantitative RT-PCR, ELISA, and immunohistochemistry. The function of IL-10 and fluorocitrate on A1 astrocyte activation was also examined. RESULTS: Our results show that astrocytes isolated from B6.129S6-Il10tm1Flv/J homozygotes (IL-10tm1/tm1) were prone to characteristics of A1 reactive astrocytes. Compared with their wild-type counterparts, IL-10tm1/tm1 astrocytes exhibited higher expression of glial fibrillary acidic protein (GFAP). Whether or not they were stimulated with LPS, IL-10tm1/tm1 astrocytes exhibited enhanced expression of A1-specific transcripts and proinflammatory factors IL-1ß, IL-6, and TNFα. In addition, IL-10tm1/tm1 astrocytes demonstrated hyperphosphorylation of STAT3. Moreover, astrocytes from IL-10tm1/tm1 mice showed attenuated phagocytic ability and were neurotoxic. IL-10tm1/tm1 mice demonstrated increased immobility time in the forced swim test and defective learning and memory behavior in the Morris water maze test. Moreover, enhanced neuroinflammation was found in the hippocampus and cortex of IL-10tm1/tm1 mice, accompanying with more GFAP-positive astrocytes and severe neuron loss in the hippocampus. Pretreatment IL-10tm1/tm1 mice with IL-10 or fluorocitrate decreased the expression of proinflammatory factors and A1-specific transcripts in the hippocampus and cortex, and then alleviated LPS-induced depressive-like behavior. CONCLUSION: These results demonstrate that astrocytes isolated from B6.129S6-Il10tm1Flv/J homozygotes are prone to A1 phenotype and contribute to the depression-like behavior and memory deficits. Inhibiting A1 astrocyte activation may be an attractive therapeutic strategy in some neurodegenerative diseases.

Mysm1 epigenetically regulates the immunomodulatory function of adipose-derived stem cells in part by targeting miR-150.

Adipose-derived stem cells (ASCs) are highly attractive for cell-based therapies in tissue repair and regeneration because they have multilineage differentiation capacity and are immunosuppressive. However, the detailed epigenetic mechanisms of their immunoregulatory capacity are not fully defined. In this study, we found that Mysm1 was induced in ASCs treated with inflammatory cytokines. Adipose-derived stem cells with Mysm1 knockdown exhibited attenuated immunosuppressive capacity, evidenced by less inhibition of T cell proliferation, more pro-inflammatory factor secretion and less nitric oxide (NO) production in vitro. Mysm1-deficient ASCs exacerbated inflammatory bowel diseases but inhibited tumour growth in vivo. Mysm1-deficient ASCs also showed depressed miR-150 expression. When transduced with Mysm1 overexpression lentivirus, ASCs exhibited enhanced miR-150 expression. Furthermore, Mysm1-deficient cells transduced with lentivirus containing miR-150 mimics produced less pro-inflammatory factors and more NO. Our study reveals a new role of Mysm1 in regulating the immunomodulatory activities of ASCs by targeting miR-150. These novel insights into the mechanisms through which ASCs regulate immune reactions may lead to better clinical utility of these cells.

Membrane-Binding Adhesive Particulates Enhance the Viability and Paracrine Function of Mesenchymal Cells for Cell-Based Therapy.

Understanding the fundamental cell-material interactions is essential to designing functional materials for biomedical applications. Although mesenchymal stromal cells (MSCs) are known to secrete cytokines and exosomes that are effective to treat degenerative diseases, the inherent property of biomaterials to modulate the therapeutic function of MSCs remains to be investigated. Here, a multivalent cell-membrane adhesive conjugate was generated through polyamindoamine (PAMAM) and an oligopeptide, IKVAV, and the conjugate was further complexed with hyaluronic acid (HA). The adhesive particulates were used to coat the surface of adipose-derived mesenchymal stromal cells (Ad-MSCs) and studied in the MSC spheroid culture. The analysis showed that the adhesive complexes formed via PAMAM conjugates and HA significantly promoted the proliferation and the gene expression of pro-angiogenesis cytokines in MSCs; the production of anti-inflammatory miRNAs in exosomes could also be elevated. The transplantation of the Ad-MSCs primed with PAMAM-IKVAV/HA composite particulates in a rat myocardial infarction model further demonstrated the beneficial effects of membrane-binding materials on improving the cell retention and tissue angiogenesis. The new function of membrane-binding adhesive materials potentially provides useful ways to improve cell-based therapy.

Mechanism of Cxc Chemokine Ligand 5 (CXCL5)/Cxc Chemokine Receptor 2 (CXCR2) Bio-Axis in Mice with Acute Respiratory Distress Syndrome.

BACKGROUND Acute respiratory distress syndrome (ARDS) is a common acute and severe disease in clinic. Recent studies indicated that Cxc chemokine ligand 5 (CXCL5), an inflammatory chemokine, was associated with tumorigenesis. The present study investigated the role of the CXCL5/Cxc chemokine receptor 2 (CXCR2) bio-axis in ARDS, and explored the underlying molecular mechanism. MATERIAL AND METHODS The pathological morphology of lung tissue and degree of pulmonary edema were assessed by hematoxylin-eosin staining and pulmonary edema score, respectively. Real-time PCR and Western blot analysis were performed to detect the expression levels of CXCL5, CXCR2, Matrix metalloproteinases 2 (MMP2), and Matrix metalloproteinases 9 (MMP9) in lung tissues. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the expression levels of CXCL5 and inflammatory factors (IL-1ß, IL-6, TNF-alpha, and IL-10) in serum. RESULTS The results demonstrated that diffuse alveolar damage and pulmonary edema appeared in lipopolysaccharide (LPS)-induced ARDS and were positively correlated with the severity of ARDS. In addition, CXCL5 and its receptor CXCR2 were overexpressed by upregulation of MMP2 and MMP9 in lung tissues of ARDS. In addition, CXCL5 neutralizing antibody effectively alleviated inflammatory response, diffuse alveolar damage, and pulmonary edema, and decreased the expression levels of MMP2 and MMP9 compared to LPS-induced ARDS. CONCLUSIONS We found that CXCL5/CXCR2 accelerated the progression of ARDS, partly by upregulation of MMP2 and MMP9 in lung tissues with the release of inflammatory factors.

Deubiquitinase Mysm1 regulates macrophage survival and polarization.

Macrophages play pivotal roles in innate and adaptive immune response, tissue homeostasis and cancer development. Their development and heterogeneity are tightly controlled by epigenetic program and transcription factors. Deubiquitinase Mysm1 plays crucial roles in regulating stem cell maintenance and immune cell development. Here we show that Mysm1 expression is up regulated during bone marrow macrophage development. Mysm1 deficient cells exhibit accelerating proliferation with more cells going to S phase and higher cyclin D1, cyclin D2 and c-Myc expression. However, compared to WT counterparts, more cell death is also detected in Mysm1 deficient cells no matter M-CSF deprived or not. In LPS-condition medium, Mysm1-/- macrophages show more pro-inflammatory factors IL-1ß, TNFα and iNOS production. In addition, much higher expression of surface marker CD86 is detected in Mysm1-/- macrophages. In vivo tumor model data demonstrate that in contrast to WT macrophages promoting tumor growth, Mysm1-/- macrophages inhibit tumor growth, showing the properties of M1 macrophages. Collectively, these data indicate that Mysm1 is essential for macrophage survival and plays an important role in macrophage polarization and might be a target for cell therapy.

The Effects of Acute GABA Treatment on the Functional Connectivity and Network Topology of Cortical Cultures.

γ-Aminobutyric acid (GABA) is an inhibitory transmitter, acting on receptor channels to reduce neuronal excitability in matured neural systems. However, electrophysiological responses of whole neuronal ensembles to the exposure to GABA are still unclear. We used micro-electrode arrays (MEAs) to study the effects of the increasing amount of GABA on functional network of cortical neural cultures. Then the recorded data were analyzed by the cross-covariance analysis and graph theory. Results showed that after the GABA treatment, the activity parameters of firing rate, bursting rate, bursting duration and network burst frequency in neural cultures decreased as expected. In addition, the functional connectivity also decreased in similarity, network density, and the size of the largest component. However, small-worldness was not found to be influenced by the acute GABA treatment. Our results support the position that using graph theory to evaluate the functional connectivity of neural cultures may enhance understanding of the pharmacological impact of neurotransmitters on neuronal networks.

Chelatococcus composti sp. nov., isolated from penicillin fermentation fungi residue with pig manure co-compost.

A novel Gram-stain-negative bacterium, designated strain PC-2T, was isolated from penicillin fermentation fungi residue with pig manure co-compost in China. Phylogenetic analysis, based on 16S rRNA gene sequence comparisons, revealed that strain PC-2T should be assigned to the genus Chelatococcus and that it had 98.9 % similarity with Chelatococcus daeguensis, 98.8 % with Chelatococcus sambhunathii, 98.4 %, with Chelatococcus caeni and 96.0 % with Chelatococcus asaccharovorans. The G+C content of genomic DNA was 70.9 mol%. On the basis of the phylogenetic analysis, DNA-DNA relatedness values, phenotypic characteristics and chemotaxonomic data, strain PC-2 T represents a novel species of the genus Chelatococcus, for which the name Chelatococcus composti sp. nov. is proposed. The type strain is PC-2T (=DSM 101465T=CGMCC 1.15283T).

A20 plays a critical role in the immunoregulatory function of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) possess an immunoregulatory capacity and are a therapeutic target for many inflammation-related diseases. However, the detailed mechanisms of MSC-mediated immunosuppression remain unclear. In this study, we provide new information to partly explain the molecular mechanisms of immunoregulation by MSCs. Specifically, we found that A20 expression was induced in MSCs by inflammatory cytokines. Knockdown of A20 in MSCs resulted in increased proliferation and reduced adipogenesis, and partly reversed the suppressive effect of MSCs on T cell proliferation in vitro and inhibited tumour growth in vivo. Mechanistic studies indicated that knockdown of A20 in MSCs inhibited activation of the p38 mitogen-activated protein kinase (MAPK) pathway, which potently promoted the production of tumour necrosis factor (TNF)-α and inhibited the production of interleukin (IL)-10. Collectively, these data reveal a crucial role of A20 in regulating the immunomodulatory activities of MSCs by controlling the expression of TNF-α and IL-10 in an inflammatory environment. These findings provide novel insights into the pathogenesis of various inflammatory-associated diseases, and are a new reference for the future development of treatments for such afflictions.

Redox poly(ethylene glycol)-b-poly(L-lactide) micelles containing diselenide bonds for effective drug delivery.

Bioreducible polymers have appeared as the ideal drug carriers for tumor therapy due to their properties of high stability in extracellular circulation and rapid drug release in intracellular reducing environment. Recently, the diselenide bond has emerged as a new reduction-sensitive linkage. In this work, the amphiphilic poly(ethylene glycol)-b-poly(L-lactide) containing diselenide bond has been synthesized and used to load anti-tumor drug, docetaxel (DTX), to form the redox micelles. It was found that the redox micelles showed a rapid response to glutataione (GSH), which resulted in a fast release of DTX in the presence of GSH. In contrast, <40 % of DTX was released from the micelles within 72 h under the normal condition (absence of GSH). The DTX-loaded redox micelles showed the significant inhibition effect to MCF-7 cells, and the cytotoxicity was dependent on the intracellular GSH concentrations. Moreover, considering the potentially clinical applications of the micelles through intravenous injection, the blood compatibility was also studied by the hemolysis analysis, activated partial thromboplastin time, prothrombin time and thromboelastography assays. These results confirmed that the redox micelles showed good blood safety, suggesting a potential application in tumor therapy.

The stem cell adjuvant with Exendin-4 repairs the heart after myocardial infarction via STAT3 activation.

The poor survival of cells in ischaemic myocardium is a major obstacle for stem cell therapy. Exendin-4 holds the potential of cardioprotective effect based on its pleiotropic activity. This study investigated whether Exendin-4 in conjunction with adipose-derived stem cells (ADSCs) could improve the stem cell survival and contribute to myocardial repairs after infarction. Myocardial infarction (MI) was induced by the left anterior descending artery ligation in adult male Sprague-Dawley rats. ADSCs carrying double-fusion reporter gene [firefly luciferase and monomeric red fluorescent protein (fluc-mRFP)] were quickly injected into border zone of MI in rats treated with or without Exendin-4. Exendin-4 enhanced the survival of transplanted ADSCs, as demonstrated by the longitudinal in vivo bioluminescence imaging. Moreover, ADSCs adjuvant with Exendin-4 decreased oxidative stress, apoptosis and fibrosis. They also improved myocardial viability and cardiac function and increased the differentiation rates of ADSCs into cardiomyocytes and vascular smooth muscle cells in vivo. Then, ADSCs were exposed to hydrogen peroxide/serum deprivation (H(2)O(2)/SD) to mimic the ischaemic environment in vitro. Results showed that Exendin-4 decreased the apoptosis and enhanced the paracrine effect of ADSCs. In addition, Exendin-4 activated signal transducers and activators of transcription 3 (STAT3) through the phosphorylation of Akt and ERK1/2. Furthermore, Exendin-4 increased the anti-apoptotic protein Bcl-2, but decreased the pro-apoptotic protein Bax of ADSCs. In conclusion, Exendin-4 could improve the survival and therapeutic efficacy of transplanted ADSCs through STAT3 activation via the phosphorylation of Akt and ERK1/2. This study suggests the potential application of Exendin-4 for stem cell-based heart regeneration.

Multiband task related components enhance rapid cognition decoding for both small and similar objects.

The cortically-coupled target recognition system based on rapid serial visual presentation (RSVP) has a wide range of applications in brain computer interface (BCI) fields such as medical and military. However, in the complex natural environment backgrounds, the identification of event-related potentials (ERP) of both small and similar objects that are quickly presented is a research challenge. Therefore, we designed corresponding experimental paradigms and proposed a multi-band task related components matching (MTRCM) method to improve the rapid cognitive decoding of both small and similar objects. We compared the areas under the receiver operating characteristic curve (AUC) between MTRCM and other 9 methods under different numbers of training sample using RSVP-ERP data from 50 subjects. The results showed that MTRCM maintained an overall superiority and achieved the highest average AUC (0.6562 ± 0.0091). We also optimized the frequency band and the time parameters of the method. The verification on public data sets further showed the necessity of designing MTRCM method. The MTRCM method provides a new approach for neural decoding of both small and similar RSVP objects, which is conducive to promote the further development of RSVP-BCI.

Chemically Programmed Hydrogels for Spatiotemporal Modulation of the Cardiac Pathological Microenvironment.

After myocardial infarction (MI), sustained ischemic events induce pathological microenvironments characterized by ischemia-hypoxia, oxidative stress, inflammatory responses, matrix remodeling, and fibrous scarring. Conventional clinical therapies lack spatially targeted and temporally responsive modulation of the infarct microenvironment, leading to limited myocardial repair. Engineered hydrogels have a chemically programmed toolbox for minimally invasive localization of the pathological microenvironment and personalized responsive modulation over different pathological periods. Chemically programmed strategies for crosslinking interactions, interfacial binding, and topological microstructures in hydrogels enable minimally invasive implantation and in situ integration tailored to the myocardium. This enhances substance exchange and signal interactions within the infarcted microenvironment. Programmed responsive polymer networks, intelligent micro/nanoplatforms, and biological therapeutic cues contribute to the formation of microenvironment-modulated hydrogels with precise targeting, spatiotemporal control, and on-demand feedback. Therefore, this review summarizes the features of the MI microenvironment and chemically programmed schemes for hydrogels to conform, integrate, and modulate the cardiac pathological microenvironment. Chemically programmed strategies for oxygen-generating, antioxidant, anti-inflammatory, provascular, and electrointegrated hydrogels to stimulate iterative and translational cardiac tissue engineering are discussed.

DNMT1-mediated epigenetic suppression of FBXO32 expression promoting cyclin dependent kinase 9 (CDK9) survival and esophageal cancer cell growth.

Esophageal cancer (EC) is a common and serious form of cancer, and while DNA methyltransferase-1 (DNMT1) promotes DNA methylation and carcinogenesis, the role of F-box protein 32 (FBXO32) in EC and its regulation by DNMT1-mediated methylation is still unclear. FBXO32 expression was examined in EC cells with high DNMT1 expression using GSE163735 dataset. RT-qPCR assessed FBXO32 expression in normal and EC cells, and impact of higher FBXO32 expression on cell proliferation, migration, and invasion was evaluated, along with EMT-related proteins. The xenograft model established by injecting EC cells transfected with FBXO32 was used to evaluate tumor growth, apoptosis, and tumor cells proliferation and metastasis. Chromatin immunoprecipitation (ChIP) assay was employed to study the interaction between DNMT1 and FBXO32. HitPredict, co-immunoprecipitation (Co-IP), and Glutathione-S-transferase (GST) pulldown assay analyzed the interaction between FBXO32 and cyclin dependent kinase 9 (CDK9). Finally, the ubiquitination assay identified CDK9 ubiquitination, and its half-life was measured using cycloheximide and confirmed through western blotting. DNMT1 negatively correlated with FBXO32 expression in esophageal cells. High FBXO32 expression was associated with better overall survival in patients. Knockdown of DNMT1 in EC cells increased FBXO32 expression and suppressed malignant phenotypes. FBXO32 repressed EC tumor growth and metastasis in mice. Enrichment of DNMT1 in FBXO32 promoter region led to increased DNA methylation and reduced transcription. Mechanistically, FBXO32 degraded CDK9 through promoting its ubiquitination.

Ferroptosis at the crossroads of manganese-induced neurotoxicity: A retrospective study.

Manganese is an essential trace element, but overexposure can cause neurotoxicity and subsequent neurodegenerative diseases. Ferroptosis is a form of cell death characterized by lipid peroxidation and iron overload inside cells, which is closely related to manganese neurotoxicity. Manganese can induce ferroptosis through multiple pathways: causing oxidative stress and increased cellular reactive oxygen species (ROS), resulting in lipid peroxidation; depleting glutathione (GSH) and weakening the antioxidant capacity of cells; disrupting iron metabolism and increasing iron-dependent lipid peroxidation; damaging mitochondrial function and disrupting the electron transport chain, leading to increased ROS production. Oxidative stress, iron metabolism disorders, lipid peroxidation, GSH depletion, and mitochondrial dysfunction, typical features of ferroptosis, have been observed in animal and cell models after manganese exposure. In summary, manganese can participate in the pathogenesis of neurodegenerative diseases by inducing events related to ferroptosis. This provides new insights into studying the mechanism of manganese neurotoxicity and developing therapeutic drugs.

Single-cell transcriptomics reveals neural stem cell trans-differentiation and cell subpopulations in whole heart decellularized extracellular matrix.

The whole heart decellularized extracellular matrix (ECM) has become a promising scaffold material for cardiac tissue engineering. Our previous research has shown that the whole heart acellular matrix possesses the memory function regulating neural stem cells (NSCs) trans-differentiating to cardiac lineage cells. However, the cell subpopulations and phenotypes in the trans-differentiation of NSCs have not been clearly identified. Here, we performed single-cell RNA sequencing and identified 2,765 cells in the recellularized heart with NSCs revealing the cellular diversity of cardiac and neural lineage, confirming NSCs were capable of trans-differentiating into the cardiac lineage while maintaining the original ability to differentiate into the neural lineage. Notably, the trans-differentiated heart-like cells have dual signatures of neuroectoderm and cardiac mesoderm. This study unveils an in-depth mechanism underlying the trans-differentiation of NSCs and provides a new opportunity and theoretical basis for cardiac regeneration.

Predictive Value of Multiple Scoring Systems in the Prognosis of Septic Patients with Different Infection Sites: Analysis of the Medical Information Mart for the Intensive Care IV Database.

The heterogeneity nature of sepsis is significantly impacted by the site of infection. This study aims to explore the predictive value of multiple scoring systems in assessing the prognosis of septic patients across different infection sites. Data for this retrospective cohort study were extracted from the Medical Information Mart for Intensive Care IV database (MIMIC-IV) (v2.2). Adult patients meeting the criteria for sepsis 3.0 and admitted to the intensive care unit (ICU) were enrolled. Infection sites included were pneumonia, urinary tract infection (UTI), cellulitis, abdominal infection, and bacteremia. The primary outcome assessed was 28-day mortality. The sequential Organ Failure Assessment (SOFA) score, Oxford Acute Severity of Illness Score (OASIS), and Logistic Organ Dysfunction System (LODS) score were compared. Binomial logistic regression analysis was conducted to evaluate the association between these variables and mortality. Additionally, differences in the area under the curve (AUC) of receiver operating characteristic (ROC) among the scoring systems were analyzed. A total of 4721 patients were included in the analysis. The average 28-day mortality rate was 9.4%. Significant differences were observed in LODS, OASIS, and SOFA scores between the 28-day survival and non-survival groups across different infection sites (p < 0.01). In the pneumonia group and abdominal infection group, both the LODS and OASIS scoring systems emerged as independent risk factors for mortality in septic patients (odds ratio [OR]: 1.165, 95% confidence interval [CI]: 1.109-1.224, p < 0.001; OR: 1.047, 95% CI: 1.028-1.065, p < 0.001) (OR: 1.200, 95% CI: 1.091-1.319, p < 0.001; OR: 1.060, 95% CI: 1.025-1.095, p < 0.001). For patients with UTI, the LODS, OASIS, and SOFA scoring systems were identified as independent risk factors for mortality (OR: 1.142, 95% CI: 1.068-1.220, p < 0.001; OR: 1.062, 95% CI: 1.037-1.087, p < 0.001; OR: 1.146, 95% CI: 1.046-1.255, p = 0.004), with the AUC of LODS score and OASIS significantly higher than that of the SOFA score (p = 0.006). Among patients with cellulitis, the OASIS and SOFA scoring systems were identified as independent risk factors for mortality (OR: 1.055, 95% CI: 1.007-1.106, p = 0.025; OR: 1.187, 95% CI: 1.005-1.403, p = 0.044), with no significant difference in prognosis prediction observed (p = 0.243). In the bacteremia group, the LODS scoring system was identified as an independent risk factor for mortality (OR: 1.165, 95% CI: 1.109-1.224, p < 0.001). The findings suggest that LODS scores offer better prognostic accuracy for predicting the mortality risk in septic patients with pneumonia, abdominal infections, bacteremia, and UTI compared to SOFA scores.

Effect of nutrition-based prehabilitation on the postoperative outcomes of patients with esophagogastric cancer undergoing surgery: A systematic review and meta-analysis.

BACKGROUND: Meta-analyses have primarily focused on the effects of exercise-based prehabilitation on postoperative outcomes and ignored the role of nutritional intervention. In this study, we filled this gap by investigating the effect of nutrition-based prehabilitation on the postoperative outcomes of patients who underwent esophagectomy and gastrectomy. METHODS: Five electronic databases, namely, PubMed, the Web of Science, Embase, Cochrane Library, and CINAHL, were searched. Adults diagnosed with esophagogastric cancer who were scheduled to undergo surgery and had undergone uni- or multimodal prehabilitation, with at least a week of mandatory nutritional intervention, were included. Forest plots were used to extract and visualize the data from the included studies. The occurrence of any postoperative complication was considered the primary endpoint. RESULTS: Eight studies met the eligibility criteria, with five randomized controlled trials (RCTs) and three cohort studies. In total, 661 patients were included. Any prehabilitation, that is, unimodal (only nutrition) and multimodal prehabilitation, collectively decreased the risk of any postoperative complication by 23% (95% confidence interval [CI] = 0.66-0.90). A similar effect was exclusively observed for multimodal prehabilitation (risk ratio [RR] = 0.78, 95% CI = 0.66-0.93); however, it was not significant for unimodal prehabilitation. Any prehabilitation significantly decreased the length of hospital stay (LOS) (weighted mean difference = -0.77, 95% CI = -1.46 to -0.09). CONCLUSIONS: Nutrition-based prehabilitation, particularly multimodal prehabilitation, confers protective effects against postoperative complications after esophagectomy and gastrectomy. Our findings suggest that prehabilitation slightly decreases LOS; however, the finding is not clinically significant. Therefore, additional rigorous RCTs are warranted for further substantiation.