Circulating Tumor Cell Phenotype Detection and Epithelial-Mesenchymal Transition Tracking Based on Dual Biomarker Co-Recognition in an Integrated PDMS Chip.

Circulating tumor cells (CTCs) are widely considered as a reliable and promising class of markers in the field of liquid biopsy. As CTCs undergo epithelial-mesenchymal transition (EMT), phenotype detection of heterogeneous CTCs based on EMT markers is of great significance. In this report, an integrated analytical strategy that can simultaneously capture and differentially detect epithelial- and mesenchymal-expressed CTCs in bloods of non-small cell lung cancer (NSCLS) patients is proposed. First, a commercial biomimetic polycarbonate (PCTE) microfiltration membrane is employed as the capture interface for heterogenous CTCs. Meanwhile, differential detection of the captured CTCs is realized by preparing two distinct CdTe quantum dots (QDs) with red and green emissions, attached with EpCAM and Vimentin aptamers, respectively. For combined analysis, a polydimethylsiloxane (PDMS) chip with simple structure is designed, which integrates the membrane capture and QDs-based phenotype detection of CTCs. This chip not only implements the analysis of the number of CTCs down to 2 cells mL-1, but enables EMT process tracking according to the specific signals of the two QDs. Finally, this method is successfully applied to inspect the correlations of numbers or proportions of heterogenous CTCs in 94 NSCLS patients with disease stage and whether there is distant metastasis.

A real-world study was conducted to develop a nomogram that predicts the occurrence of anastomotic leakage in patients with esophageal cancer following esophagectomy.

BACKGROUND: The incidence of anastomotic leakage (AL) following esophagectomy is regarded as a noteworthy complication. There is a need for biomarkers to facilitate early diagnosis of AL in high-risk esophageal cancer (EC) patients, thereby minimizing its morbidity and mortality. We assessed the predictive abilities of inflammatory biomarkers for AL in patients after esophagectomy. METHODS: In order to ascertain the predictive efficacy of biomarkers for AL, Receiver Operating Characteristic (ROC) curves were generated. Furthermore, univariate, LASSO, and multivariate logistic regression analyses were conducted to discern the risk factors associated with AL. Based on these identified risk factors, a diagnostic nomogram model was formulated and subsequently assessed for its predictive performance. RESULTS: Among the 438 patients diagnosed with EC, a total of 25 patients encountered AL. Notably, elevated levels of interleukin-6 (IL-6), IL-10, C-reactive protein (CRP), and procalcitonin (PCT) were observed in the AL group as compared to the non-AL group, demonstrating statistical significance. Particularly, IL-6 exhibited the highest predictive capacity for early postoperative AL, exhibiting a sensitivity of 92.00% and specificity of 61.02% at a cut-off value of 132.13 pg/ml. Univariate, LASSO, and multivariate logistic regression analyses revealed that fasting blood glucose ≥7.0mmol/L and heightened levels of IL-10, IL-6, CRP, and PCT were associated with an augmented risk of AL. Consequently, a nomogram model was formulated based on the results of multivariate logistic analyses. The diagnostic nomogram model displayed a robust discriminatory ability in predicting AL, as indicated by a C-Index value of 0.940. Moreover, the decision curve analysis provided further evidence supporting the clinical utility of this diagnostic nomogram model. CONCLUSIONS: This predictive instrument can serve as a valuable resource for clinicians, empowering them to make informed clinical judgments aimed at averting the onset of AL.

Investigating the neural effects of typicality and predictability for face and object stimuli.

The brain calibrates itself based on the past stimulus diet, which makes frequently observed stimuli appear as typical (as opposed to uncommon stimuli, which appear as distinctive). Based on predictive processing theory, the brain should be more "prepared" for typical exemplars, because these contain information that has been encountered frequently, allowing it to economically represent items of that category. Thus, one could ask whether predictability and typicality of visual stimuli interact, or rather act in an additive manner. We adapted the design by Egner and colleagues (2010), who used cues to induce expectations about stimulus category (face vs. chair) occurrence during an orthogonal inversion detection task. We measured BOLD responses with fMRI in 35 participants. First, distinctive stimuli always elicited stronger responses than typical ones in all ROIs, and our whole-brain directional contrasts for the effects of typicality and distinctiveness converge with previous findings. Second and importantly, we could not replicate the interaction between category and predictability reported by Egner et al. (2010), which casts doubt on whether cueing designs are ideal to elicit reliable predictability effects. Third, likely as a consequence of the lack of predictability effects, we found no interaction between predictability and typicality in any of the four tested regions (bilateral fusiform face areas, lateral occipital complexes) when considering both categories, nor in the whole brain. We discuss the issue of replicability in neuroscience and sketch an agenda for how future studies might address the same question.

Electroacupuncture stimulation modulates functional brain connectivity in the treatment of pediatric cerebral palsy: a case report.

Background: Pediatric cerebral palsy (CP) is a non-progressive brain injury syndrome characterized by central motor dysfunction and insufficient brain coordination ability. The etiology of CP is complex and often accompanied by diverse complications such as intellectual disability and language disorders, making clinical treatment difficult. Despite the availability of pharmacological interventions, rehabilitation programs, and spasticity relief surgery as treatment options for CP, their effectiveness is still constrained. Electroacupuncture (EA) stimulation has demonstrated great improvements in motor function, but its comprehensive, objective therapeutic effects on pediatric CP remain to be clarified. Methods: We present a case of a 5-year-old Chinese female child who was diagnosed with CP at the age of 4. The patient exhibited severe impairments in motor, language, social, and cognitive functions. We performed a 3-month period of EA rehabilitation, obtaining resting state functional magnetic resonance imaging (rs-fMRI) of the patient at 0 month, 3 months and 5 months since treatment started, then characterized brain functional connectivity patterns in each phase for comparison. Results: After a 12-month follow-up, notable advancements were observed in the patient's language and social symptoms. Changes of functional connectivity patterns confirmed this therapeutic effect and showed specific benefits for different recovery phase: starting from language functions then modulating social participation and other developmental behaviors. Conclusion: This is a pioneering report demonstrating the longitudinal effect of EA stimulation on functional brain connectivity in CP patients, suggesting EA an effective intervention for developmental disabilities (especially language and social dysfunctions) associated with pediatric CP.

Gel microspheres enhance the stemness of ADSCs by regulating cell-ECM interaction.

The gel microsphere culture system (GMCS) showed various advantages for mesenchymal stem cell (MSC) expansion and delivery, such as high specific surface area, small and regular shape, extensive adjustability, and biomimetic properties. Although various technologies and materials have been developed to promote the development of gel microspheres, the differences in the biological status of MSCs between the GMCS and the traditional Petri dish culture system (PDCS) are still unknown, hindering gel microspheres from becoming a culture system as widely used as petri dishes. In the previous study, an excellent "all-in-one" GMCS has been established for the expansion of human adipose-derived MSCs (hADSCs), which showed convenient cell culture operation. Here, we performed transcriptome and proteome sequencing on hADSCs cultured on the "all-in-one" GMCS and the PDCS. We found that hADSCs cultured in the GMCS kept in an undifferentiation status with a high stemness index, whose transcriptome profile is closer to the adipose progenitor cells (APCs) in vivo than those cultured in the PDCS. Further, the high stemness status of hADSCs in the GMCS was maintained through regulating cell-ECM interaction. For application, bilayer scaffolds were constructed by osteo- and chondro-differentiation of hADSCs cultured in the GMCS and the PDCS. The effect of osteochondral regeneration of the bilayer scaffolds in the GMCS group was better than that in the PDCS group. This study revealed the high stemness and excellent functionality of MSCs cultured in the GMCS, which promoted the application of gel microspheres in cell culture and tissue regeneration.

Interferon-induced transmembrane protein-1 competitively blocks Ephrin receptor A2-mediated Epstein-Barr virus entry into epithelial cells.

Epstein-Barr virus (EBV) can infect both B cells and epithelial cells (ECs), causing diseases such as mononucleosis and cancer. It enters ECs via Ephrin receptor A2 (EphA2). The function of interferon-induced transmembrane protein-1 (IFITM1) in EBV infection of ECs remains elusive. Here we report that IFITM1 inhibits EphA2-mediated EBV entry into ECs. RNA-sequencing and clinical sample analysis show reduced IFITM1 in EBV-positive ECs and a negative correlation between IFITM1 level and EBV copy number. IFITM1 depletion increases EBV infection and vice versa. Exogenous soluble IFITM1 effectively prevents EBV infection in vitro and in vivo. Furthermore, three-dimensional structure prediction and site-directed mutagenesis demonstrate that IFITM1 interacts with EphA2 via its two specific residues, competitively blocking EphA2 binding to EBV glycoproteins. Finally, YTHDF3, an m6A reader, suppresses IFITM1 via degradation-related DEAD-box protein 5 (DDX5). Thus, this study underscores IFITM1's crucial role in blocking EphA2-mediated EBV entry into ECs, indicating its potential in preventing EBV infection.

A mini review of reinfection with the SARS-CoV-2 Omicron variant.

Background: COVID-19 has caused severe morbidity and mortality worldwide. After the end of the dynamic zero-COVID policy in China in December, 2022, concerns regarding reinfection were raised while little was known due to the lack of surveillance data in this country. Aims: This study reviews the probability, risk factors, and severity of severe acute respiratory syndrome coronavirus 2 Omicron variant reinfection, as well as the interval between infections, risk of onward transmission by reinfected cases, and the role of booster vaccination against reinfection. Sources: References for this review were identified through searches of PubMed and Web of Science up to September 24, 2023. Results: The rate of reinfection ranges from 3.1% to 13.0%. Factors associated with a higher risk of reinfection include being female, having comorbidities, and being unvaccinated. Reinfection with the BA.4 or BA.5 variant occurs approximately 180 days after the initial infection. Reinfections are less clinically severe than primary infections, and there is evidence of lower transmissibility. The debate surrounding the effectiveness and feasibility of booster vaccinations in preventing reinfection continues. Conclusions: The reinfection rate during the Omicron epidemic is significantly higher than in previous epidemic periods. However, the symptoms and infectivity of reinfection were weaker than those of the prior infection. Medical staff and individuals at high risk of reinfection should be vigilant. The efficacy of booster vaccinations in reducing reinfection is currently under debate.

ETV2 regulating PHD2-HIF-1α axis controls metabolism reprogramming promotes vascularized bone regeneration.

The synchronized development of mineralized bone and blood vessels is a fundamental requirement for successful bone tissue regeneration. Adequate energy production forms the cornerstone supporting new bone formation. ETS variant 2 (ETV2) has been identified as a transcription factor that promotes energy metabolism reprogramming and facilitates the coordination between osteogenesis and angiogenesis. In vitro molecular experiments have demonstrated that ETV2 enhances osteogenic differentiation of dental pulp stem cells (DPSCs) by regulating the ETV2- prolyl hydroxylase 2 (PHD2)- hypoxia-inducible factor-1α (HIF-1α)- vascular endothelial growth factor A (VEGFA) axis. Notably, ETV2 achieves the rapid reprogramming of energy metabolism by simultaneously accelerating mitochondrial aerobic respiration and glycolysis, thus fulfilling the energy requirements essential to expedite osteogenic differentiation. Furthermore, decreased α-ketoglutarate release from ETV2-modified DPSCs contributes to microcirculation reconstruction. Additionally, we engineered hydroxyapatite/chitosan microspheres (HA/CS MS) with biomimetic nanostructures to facilitate multiple ETV2-DPSC functions and further enhanced the osteogenic differentiation. Animal experiments have validated the synergistic effect of ETV2-modified DPSCs and HA/CS MS in promoting the critical-size bone defect regeneration. In summary, this study offers a novel treatment approach for vascularized bone tissue regeneration that relies on energy metabolism activation and the maintenance of a stable local hypoxia signaling state.

Multi-modal imaging for dynamic visualization of osteogenesis and implant degradation in 3D bioprinted scaffolds.

In situ monitoring of bone regeneration enables timely diagnosis and intervention by acquiring vital biological parameters. However, an existing gap exists in the availability of effective methodologies for continuous and dynamic monitoring of the bone tissue regeneration process, encompassing the concurrent visualization of bone formation and implant degradation. Here, we present an integrated scaffold designed to facilitate real-time monitoring of both bone formation and implant degradation during the repair of bone defects. Laponite (Lap), CyP-loaded mesoporous silica (CyP@MSNs) and ultrasmall superparamagnetic iron oxide nanoparticles (USPIO@SiO2) were incorporated into a bioink containing bone marrow mesenchymal stem cells (BMSCs) to fabricate functional scaffolds denoted as C@M/GLU using 3D bioprinting technology. In both in vivo and in vitro experiments, the composite scaffold has demonstrated a significant enhancement of bone regeneration through the controlled release of silicon (Si) and magnesium (Mg) ions. Employing near-infrared fluorescence (NIR-FL) imaging, the composite scaffold facilitates the monitoring of alkaline phosphate (ALP) expression, providing an accurate reflection of the scaffold's initial osteogenic activity. Meanwhile, the degradation of scaffolds was monitored by tracking the changes in the magnetic resonance (MR) signals at various time points. These findings indicate that the designed scaffold holds potential as an in situ bone implant for combined visualization of osteogenesis and implant degradation throughout the bone repair process.

hOGG1: A novel mediator in nitrosamine-induced esophageal tumorigenesis.

BACKGROUND: The effect of human 8-Oxoguanine DNA Glycosylase (hOGG1) on exogenous chemicals in esophageal squamous cell carcinoma (ESCC) remain unclear. The study plans to determine hOGG1 expression levels in ESCC and possible interactions with known environmental risk factors in ESCC. MATERIAL AND METHODS: We analyzed levels of exposure to urinary nitrosamines in volunteers from high and low prevalence areas by GC-MS. And we performed the interaction between hOGG1 gene and nitrosamine disinfection by-products by analyzing hOGG1 gene expression in esophageal tissues. RESULTS: In ESCC, nitrosamine levels were significantly increased and hOGG1 mRNA expression levels were significantly decreased. There was a statistically significant interaction between reduced hOGG1 mRNA levels and non-tap drinking water sources in ESCC. The apparent indirect association between ESCC and NMEA indicated that 33.4% of the association between ESCC and NMEA was mediated by hOGG1. CONCLUSION: In populations which exposed to high levels of environmental pollutants NDMA, low expression of hOGG1 may promote the high incidence of esophageal cancer in Huai'an. hOGG1 may be a novel mediator in nitrosamine-induced esophageal tumorigenesis.

Baicalein alleviates cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway.

BACKGROUND: The experimental autoimmune myocarditis (EAM) model is valuable for investigating myocarditis pathogenesis. M1-type macrophages and CD4+T cells exert key pathogenic effects on EAM initiation and progression. Baicalein (5,6,7-trihydroxyflavone, C15H10O5, BAI), which is derived from the Scutellaria baicalensis root, is a primary bioactive compound with potent anti-inflammatory and antioxidant properties. BAI exerts good therapeutic effects against various autoimmune diseases; however, its effect in EAM has not been thoroughly researched. PURPOSE: This study aimed to explore the possible inhibitory effect of BAI on M1 macrophage polarisation and CD4+T cell differentiation into Th1 cells via modulation of the JAK-STAT1/4 signalling pathway, which reduces the secretion of pro-inflammatory factors, namely, TNF-α and IFN-γ, and consequently inhibits TNF-α- and IFN-γ-triggered apoptosis in cardiomyocytes of the EAM model mice. STUDY DESIGN AND METHODS: Flow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction (q-PCR), and western blotting were performed to determine whether BAI alleviated M1/Th1-secreted TNF-α- and IFN-γ-induced myocyte death in the EAM model mice through the inhibition of the JAK-STAT1/4 signalling pathway. RESULTS: These results indicate that BAI intervention in mice resulted in mild inflammatory infiltrates. BAI inhibited JAK-STAT1 signalling in macrophages both in vivo and in vitro, which attenuated macrophage polarisation to the M1 type and reduced TNF-α secretion. Additionally, BAI significantly inhibited the differentiation of CD4+T cells to Th1 cells and IFN-γ secretion both in vivo and in vitro by modulating the JAK-STAT1/4 signalling pathway. This ultimately led to decreased TNF-α and IFN-γ levels in cardiac tissues and reduced myocardial cell apoptosis. CONCLUSION: This study demonstrates that BAI alleviates M1/Th1-secreted TNF-α- and IFN-γ-induced cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway.

Unlatching the Additional Zinc Storage Ability of Vanadium Nitride Nanocrystallites.

Vanadium-based materials, due to their diverse valence states and open-framework lattice, are promising cathodes for aqueous zinc ion batteries (AZIBs), but encounters the major challenges of in situ electrochemical activation process, potent polarity of the aqueous electrolyte and periodic expansion/contraction for efficient Zn2+ storage. Herein, architecting vanadium nitride (VN) nanosheets over titanium-based hollow nanoarrays skeletal host (denoted VNTONC) can simultaneously modulate address those challenges by creating multiple interfaces and maintaining the (1 1 1) phase of VN, which optimizes the Zn2+ storage and the stability of VN. Benefiting from the modulated crystalline thermodynamics during the electrochemical activation of VN, two outcomes are achieved; I) the cathode transforms into a nanocrystalline structure with increased active sites and higher conductivity and; II) a significant portion of the (1 1 1) crystal facets is retained in the process leading to the additional Zn2+ storage capacity. As a result, the as-prepared VNTONC electrode demonstrates remarkable discharge capacities of 802.5 and 331.8 mAh g-1 @ 0.5 and 6.0 A g-1 , respectively, due to the enhanced kinetics as validated by theoretical calculations. The assembled VNTONC||Zn flexible ZIB demonstrates excellent Zn storage properties up to 405.6 mAh g-1 , and remarkable robustness against extreme operating conditions.

Cucurbitacin B Inhibits the Malignancy of Esophageal Carcinoma through the KIF20A/JAK/STAT3 Signaling Pathway.

This study intends to explore the effects of Cucurbitacin B (CuB) and KIF20A on esophageal carcinoma (ESCA). Data were downloaded from the Cancer Genome Atlas (TCGA) database. The expression properties of KIF20A have been confirmed by GEPIA and ualcan from TCGA. The expression of KIF20A was determined using western blotting in ECA109 and KYSE150 cells after transfection with KIF20A, KIF20A siRNA, or numerical control siRNA (si-NC). Then, different concentrations of CuB were used to treat ECA109 and KYSE150 cells. CCK-8 and colony formation assays were used to measure cell viability, and a Transwell assay was utilized to assess cell migration and invasion ability. N-cadherin, E-cadherin, snail, p-Janus kinase 2 (JAK2), JAK2, p-signal transducer and activator of transcription 3 (STAT3), and STAT3 expression levels were evaluated using western blot. KIF20A was higher expressed in ESCA than in normal cells, and its overexpression was associated with squamous cell carcinoma, TNM stage, and lymph nodal metastasis of ESCA patients. In ECA109 and KYSE150 cells, increased KIF20A facilitated cell proliferation, migration, and invasion, whereas the knockdown of KIF20A can reverse these effects with N-cadherin. Snail expression diminished and E-cadherin increased. Similarly, CuB treatment could inhibit cell proliferation, migration, and invasion concentration dependently. Furthermore, KIF20A accelerated the expression of p-JAK2 and p-STAT3, while the application of CuB inhibited KIF20A expression and attenuated the activation of the JAK/STAT3 pathway. These findings revealed that CuB could inhibit the growth, migration, and invasion of ESCA through downregulating the KIF20A/JAK/STAT3 signaling pathway, and CuB could serve as an essential medicine for therapeutic intervention.

3-D Point Cloud Attribute Compression With -Laplacian Embedding Graph Dictionary Learning.

3-D point clouds facilitate 3-D visual applications with detailed information of objects and scenes but bring about enormous challenges to design efficient compression technologies. The irregular signal statistics and high-order geometric structures of 3-D point clouds cannot be fully exploited by existing sparse representation and deep learning based point cloud attribute compression schemes and graph dictionary learning paradigms. In this paper, we propose a novel p-Laplacian embedding graph dictionary learning framework that jointly exploits the varying signal statistics and high-order geometric structures for 3-D point cloud attribute compression. The proposed framework formulates a nonconvex minimization constrained by p-Laplacian embedding regularization to learn a graph dictionary varying smoothly along the high-order geometric structures. An efficient alternating optimization paradigm is developed by harnessing ADMM to solve the nonconvex minimization. To our best knowledge, this paper proposes the first graph dictionary learning framework for point cloud compression. Furthermore, we devise an efficient layered compression scheme that integrates the proposed framework to exploit the correlations of 3-D point clouds in a structured fashion. Experimental results demonstrate that the proposed framework is superior to state-of-the-art transform-based methods in M-term approximation and point cloud attribute compression and outperforms recent MPEG G-PCC reference software.

A platform for whole-genome speed introgression from Aegilops tauschii to wheat for breeding future crops.

Breeding new and sustainable crop cultivars of high yields and desirable traits has been a major challenge for ensuring food security for the growing global human population. For polyploid crops such as wheat, introducing genetic variation from wild relatives of its subgenomes is a key strategy to improve the quality of their breeding pools. Over the past decades, considerable progress has been made in speed breeding, genome sequencing, high-throughput phenotyping and genomics-assisted breeding, which now allows us to realize whole-genome introgression from wild relatives to modern crops. Here, we present a standardized protocol to rapidly introgress the entire genome of Aegilops tauschii, the progenitor of the D subgenome of bread wheat, into elite wheat backgrounds. This protocol integrates multiple modern high-throughput technologies and includes three major phases: development of synthetic octaploid wheat, generation of hexaploid A. tauschii-wheat introgression lines (A-WIs) and homozygosis of the generated A-WIs. Our approach readily generates stable introgression lines in 2 y, thus greatly accelerating the generation of A-WIs and the introduction of desirable genes from A. tauschii to wheat cultivars. These A-WIs are valuable for wheat-breeding programs and functional gene discovery. The current protocol can be easily modified and used for introgressing the genomes of wild relatives to other polyploid crops.

Variance Reduced Domain Randomization for Reinforcement Learning With Policy Gradient.

By introducing randomness on the environments, domain randomization (DR) imposes diversity to the policy training of deep reinforcement learning, and thus improves its capability of generalization. The randomization of environments, however, introduces another source of variability for the estimate of policy gradients, in addition to the already high variance incurred by trajectory sampling. Therefore, with standard state-dependent baselines, the policy gradient methods may still suffer high variance, causing a low sample efficiency during the training of DR. In this paper, we theoretically derive a bias-free and state/environment-dependent optimal baseline for DR, and analytically show its ability to achieve further variance reduction over the standard constant and state-dependent baselines for DR. Based on our theory, we further propose a variance reduced domain randomization (VRDR) approach for policy gradient methods, to strike a tradeoff between the variance reduction and computational complexity for the practical implementation. By dividing the entire space of environments into some subspaces and then estimating the state/subspace-dependent baseline, VRDR enjoys a theoretical guarantee of variance reduction and faster convergence than the state-dependent baselines. Empirical evaluations on six robot control tasks with randomized dynamics demonstrate that VRDR not only accelerates the convergence of policy training, but can consistently achieve a better eventual policy with improved training stability.

Effect of ZrC on the Microstructure and Properties of CrMnFeCoNi High-Entropy Alloy Coatings Prepared by a Plasma Transferred Arc Process.

The low strength caused by the single FCC structure of the CrMnFeCoNi high entropy alloy (HEA) limits its application in the field of coating. Here, we prepared high-entropy alloy coatings of CrMnFeCoNi with different ZrC contents on Q235 steel by a plasma transferred arc process. The effects of ZrC on the microstructure and properties of the CrMnFeCoNi HEA coating were investigated by optical microscopy, scanning electron microscope, and X-ray diffraction and by employing a potensiostat/galvanostat. The results showed that ZrC mainly existed in the coatings as a second phase, having little influence on the main crystal structure and micromorphology of the CrMnFeCoNi HEA coating. The hardness of the CrMnFeCoNi HEA coating increased with the ZrC content. ZrC can effectively improve the corrosion resistance of the CrMnFeCoNi HEA coating. In a 1 mol/L NaCl solution with 4 wt% ZrC, the annual corrosion rate was only 5.997% of that of the HEA coating. Nevertheless, the improvement in the wear resistance of CrMnFeCoNi high-entropy alloy coatings was not apparent with the addition of ZrC. Consequently, the addition of ZrC to the FeCoCrNiMn high-entropy alloy coating holds promise for applications in corrosion resistance, particularly in oceanic environments.

Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation.

BACKGROUNDS: Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties. METHODS: Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells. RESULTS: Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role. CONCLUSION: IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.

Single-cell transcriptomics reveals heterogeneity in esophageal squamous epithelial cells and constructs models for predicting patient prognosis and immunotherapy.

Background: Esophageal squamous cell carcinoma (ESCC), characterized by its high invasiveness and malignant potential, has long been a formidable challenge in terms of treatment. Methods: A variety of advanced analytical techniques are employed, including single-cell RNA sequencing (scRNA-seq), cell trajectory inference, transcription factor regulatory network analysis, GSVA enrichment analysis, mutation profile construction, and the inference of potential immunotherapeutic drugs. The purpose is to conduct a more comprehensive exploration of the heterogeneity among malignant squamous epithelial cell subgroups within the ESCC microenvironment and establish a model for predicting the prognosis and immunotherapy outcomes of ESCC patients. Results: An analysis was conducted through scRNA-seq, and three Cluster of malignant epithelial cells were identified using the infer CNV method. Cluster 0 was found to exhibit high invasiveness, whereas Cluster 1 displayed prominent characteristics associated with epithelial-mesenchymal transition. Confirmation of these findings was provided through cell trajectory analysis, which positioned Cluster 0 at the initiation stage of development and Cluster 1 at the final developmental stage. The abundance of Cluster 0-2 groups in TCGA-LUAD samples was assessed using ssGSEA and subsequently categorized into high and low-expression groups. Notably, it was observed that Cluster 0-1 had a significant impact on survival (p<0.05). Furthermore, GSVA enrichment analysis demonstrated heightened activity in hallmark pathways for Cluster 0, whereas Cluster 1 exhibited notable enrichment in pathways related to cell proliferation. It is noteworthy that a prognostic model was established utilizing feature genes from Cluster 0-1, employing the Lasso and stepwise regression methods. The results revealed that in TCGA and GSE53624 cohorts, the low-risk group demonstrated significantly higher overall survival and increased levels of immune infiltration. An examination of four external immunotherapy cohorts unveiled that the low-risk group exhibited improved immunotherapeutic efficacy. Additionally, more meaningful treatment options were identified for the low-risk group. Conclusion: The findings revealed distinct interactions between malignant epithelial cells of ESCC and subgroups within the tumor microenvironment. Two cell clusters, strongly linked to survival, were pinpointed, and a signature was formulated. This signature is expected to play a crucial role in identifying and advancing precision medicine approaches for the treatment of ESCC.

Serum osmolality was non-linearly associated with the risk of all-cause and cardiovascular mortality in patients with diabetes.

AIMS: This study aimed to evaluate the relationship between both low and high osmolarity and the risk of all-cause and cause-specific mortality in diabetic population. METHODS: All participants were included from the National Health and Nutrition Examination Survey 1999-2014. Baseline serum osmolality was determined from laboratory tests and cause of death from national death records. HRs and 95% CIs for all-cause mortality and cardiovascular mortality in diabetes were estimated using Cox proportional regression analysis. The non-linear relationship was explored using restricted cubic splines regression. RESULTS: Among 7622 individuals with diabetes, 1983 (12.4%) died during a total of 3.26 thousand person-years of follow-up. Compared with the reference category (281-284 mmol/kg), the multivariable-adjusted HRs and 95% CIs for all-cause mortality were 1.27 (1.16-1.40; p<0.001) in the lowest osmolality category (<201 mmol/kg) and 1.18 (1.09-1.28; p<0.001) in the highest osmolality category (>312 mmol/kg). Restricted cubic splines results showed that serum levels of osmolality had a U-shaped association with the risk of all-cause mortality, and L-shaped relationship with the risk of cardiovascular death. CONCLUSIONS: Both low osmolality and high osmolality were predictive of increased all-cause mortality in patients with diabetes, supporting a U-shaped relationship. Also, a lower serum osmolality increased the risk of cardiovascular mortality.