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Patients with locally advanced non-small cell lung cancer (NSCLC) who undergo concurrent chemoradiotherapy (CCRT) followed by consolidation immunotherapy show heterogeneous survival outcomes. Accurate prognostic prediction remains a major challenge in clinical practice. This study aimed to develop machine learning models to enhance personalized outcome prediction and guide precision immuno-radiotherapy. A total of 219 patients with locally advanced NSCLC were retrospectively enrolled. All patients received standard CCRT followed by consolidation immunotherapy. Prognostic variables were first selected using least absolute shrinkage and selection operator (LASSO) regression. A multivariate Cox proportional hazards model and a random survival forest (RSF) model were then constructed in the training cohort and validated in the independent cohort. LASSO regression identified four prognostic variables: Age, T stage, Stage, and Pathology. Multivariate Cox analysis confirmed Stage and Pathology as independent predictors of OS. The Cox model achieved a C-index of 0.62 and Area Under the Receiver Operating Characteristic Curve (AUC-ROC) of 0.748 and 0.736 for 1-and 2-year OS in the validation cohort. The RSF model demonstrated higher predictive accuracy, with a C-index of 0.67 and AUC-ROC of 0.79 and 0.78 for 1-and 2-year OS, respectively. Variable importance analysis indicated that Stage and Pathology were the most influential factors. Based on RSF-derived risk scores, patients were stratified into high-and low-risk groups, and the high-risk group showed significantly poorer survival. The RSF model demonstrated improved performance compared to the conventional Cox model in predicting survival and stratifying risk among patients with locally advanced NSCLC undergoing CCRT and consolidation immunotherapy.

Symbiotic flora exhibits a strong association with the pathogenesis of allergic disorders. Certain Bacteroides species have demonstrated potential in ameliorating allergic conditions. However, the specific role of Bacteroides uniformis in allergic asthma and its underlying mechanisms remain incompletely understood. This study demonstrates that oral administration of B.uniformis IM01 significantly enhanced the production of indole-3-acetic acid (IAA), suppressed airway inflammatory cell airway infiltration and aberrant T helper 2 (Th2) immune responses, and improved the epithelial barrier function in a murine model of asthma. Mechanistically, B.uniformis IM01 upregulated tryptophan metabolism, elevating IAA levels in both colon and serum, which activated the aryl hydrocarbon receptor (AhR) and induced interleukin-22 (IL-22) production. Activated AhR may inhibit NF-κB/NLRP3 signaling pathway and facilitate the splenic differentiation of Foxp3 + regulatory T cells (Tregs), thus attenuating lung barrier dysfunction and improving allergic asthma symptoms. In summary, our results revealed that B.uniformis IM01 upregulated production of IAA to activate AhR leading to inhibited NF-κB/NLRP3-mediated immune responses, and ameliorated allergic asthma through the gut-lung axis. Graphical abstract B.uniformis IM01 upregulated production of IAA to active AhR leading to inhibited NF-κB/NLRP3-mediated immune responses, and ameliorated allergic asthma symptoms through the gut-lung axis.

Wolfram syndrome is an autosomal recessive disorder characterized by juvenile diabetes and neurodegeneration, and is considered a prototype of human endoplasmic reticulum (ER) disease. Wolfram syndrome is caused by loss of function mutations of Wolfram syndrome 1 or Wolfram syndrome 2 genes, which encode transmembrane proteins localized to the ER. Despite its rarity, Wolfram syndrome represents the best human disease model currently available to identify drugs and biomarkers associated with ER health. Furthermore, this syndrome is ideal for studying the mechanisms of ER stress-mediated death of neurons and β cells. Here we report that the pathway leading to calpain activation offers potential drug targets for Wolfram syndrome and substrates for calpain might serve as biomarkers for this syndrome. Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 ( WFS1 ) and Wolfram syndrome 2 ( WFS2 ), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.

Cancer is a major threat to human health today. Although the existing anticancer treatments have effectively improved the prognosis of some patients, there are still other patients who cannot benefit from these well-established strategies. Reprogramming of lipid metabolism is one of the typical features of cancers. Recent studies have revealed that key enzymes involved in lipid metabolism may be effective anticancer therapeutic targets, but the development of therapeutic lipid metabolism targets is still insufficient. ECHS1 (enoyl-CoA hydratase, short chain 1) is a key enzyme mediating the hydration process of mitochondrial fatty acid β-oxidation and has been observed to be abnormally expressed in a variety of cancers. Therefore, with ECHS1 and cancer as the main keywords, we searched the relevant studies of ECHS1 in the field of cancer in Pubmed, summarized the research status and functions of ECHS1 in different cancer contexts, and explored its potential regulatory mechanisms, with a view to finding new therapeutic targets for anti-metabolic therapy. By reviewing and summarizing the retrieved literatures, we found that ECHS1 regulates malignant biological behaviors such as cell proliferation, metastasis, apoptosis, autophagy, and drug resistance by remodeling lipid metabolism and regulating intercellular oncogenic signaling pathways. Not only that, ECHS1 exhibits early diagnostic and prognostic value in clear cell renal cell carcinoma, and small-molecule inhibitors that regulate ECHS1 also show therapeutic significance in preclinical studies. Taken together, we propose that ECHS1 has the potential to serve as a therapeutic target of lipid metabolism.

The spirochetal pathogen Treponema pallidum causes 5 million new cases of venereal syphilis worldwide each year. One major obstacle to syphilis prevention and treatment is the lack of suitable experimental animal models to study its pathogenesis. Accordingly, in this study, we further evaluated the responses of mice to Treponema pallidum . Quantitative polymerase chain reaction showed that Treponema pallidum could colonize the heart, liver, spleen, kidneys, and testicles of C57BL/6 mice, and the organism may be able to rapidly penetrate the blood-brain barrier in mice by 24 h after infection. In subsequent rabbit infectivity tests, we observed evident signs of the microorganism in the mouse lymph node suspension. After infection, bacterial loads were higher in the tissues than in the blood of C57BL/6 mice. Moreover, a significant Th1 immune response was recorded by cytokine assays. Flow cytometric analysis suggested an obvious increase in the proportion of CD3 + T and CD4 + T cells in the spleen cells in the infected mice. Thus, improving our understanding of the response of C57BL/6 mice for Treponema pallidum will help to comprehensive elucidate the pathogenic mechanisms of this bacterium and lay the foundation for the development of a new research model of Treponema pallidum.

Background The role of the gut microbiome in respiratory infections is increasingly recognized. We have found that a gut commensal strain, Bacteroides dorei RX2020 ( B. dorei ) previously isolated from healthy human fecal microbiota, alleviates influenza virus infection, but the underlying mechanisms remain elusive. Methods To explore the mechanism by which B. dorei alleviates influenza, we administered it via gavage to influenza virus-infected mice. Gene knockout mice were then used to verify the underlying signaling pathways involved in the antiviral action of B. dorei. Metabolomics analysis was conducted to identify effective metabolites of B. dorei against influenza, followed by complementary verification to confirm these metabolites. Results Metabolomics reveals that influenza virus infection significantly reduced the concentrations of secondary bile acid (BA) in feces at 7 post-infection (dpi). Oral administration of B. dorei increased bile salt hydrolase (BSH) activity and restored the BA metabolism, thereby protecting wild-type but not TGR5-deficient mice from influenza virus infection. B.dorei -mediated TGR5 activation inhibited influenza virus-induced lung inflammation via cAMP-PKA pathway. Supplementing exogenous Ursodeoxycholic acid (UDCA) and Hyodeoxycholic acid (HDCA), two metabolites changed dramatically after B. dorei treatment, reproduced the protective effect of B. dorei . Conclusions Overall, our work elucidates the protective efficacy of commensal microbes against influenza virus infection by modulating lung immunity and restoring BA metabolism, suggesting a potential strategy to intervene in distal infections by regulating gut microbial metabolism.

Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Our results indicate that molecular pathways regulated by MANF are promising therapeutic targets for regenerative therapy of ER stress-related disorders, including diabetes, retinal degeneration, neurodegeneration, and Wolfram syndrome. Wolfram syndrome is a prototype of endoplasmic reticulum (ER) stress disorder characterized by diabetes, visual impairment, and neurodegeneration. Currently, there is no treatment that can halt or reverse the disease progression. Here, the authors show that mesencephalic astrocyte-derived neurotrophic factor-based regenerative gene therapy is an emerging therapeutic strategy for Wolfram syndrome and other ER stress-related disorders.

Inclusion membrane proteins (Incs) play an important role in the structure and stability of chlamydial inclusion and the interaction between Chlamydia spp. and their hosts. Following Chlamydia infection through the respiratory tract, human polymorphonuclear neutrophils (hPMN) not only act as the primary immune cells reaching the lungs, but also serve as reservoir for Chlamydia. We have previously identified a Chlamydia psittaci hypothetical protein, CPSIT_0556, as a medium expressed inclusion membrane protein. However, the role of inclusion membrane protein, CPSIT_0556 in regulating hPMN functions remains unknown. In the present study, we found that CPSIT_0556 could not only inhibit hPMN apoptosis through the PI3K/Akt and NF-κB signaling pathways by releasing IL-8, but also delays procaspase-3 processing and inhibits caspase-3 activity in hPMN. Up-regulating the expression of anti-apoptotic protein Mcl-1 and down-regulating the expression of pro-apoptotic protein Bax could also inhibit the translocalization of Bax in the cytoplasm into the mitochondria, as well as induce the transfer of p65 NF-κB from the cytoplasm to the nucleus. Overall, our findings demonstrate that CPSIT_0556 could inhibit hPMN apoptosis through PI3K/Akt and NF-κB pathways and provide new insights towards understanding a better understanding of the molecular pathogenesis and immune escape mechanisms of C. psittaci .

Background: Studies on the prognostic significance of site-specific distant metastasis, multiple-site metastases, and the impact of surgery of the primary tumor and metastatic lesion on survival outcomes of patients with metastatic gastric cancer (GC) remain elusive. Therefore, this study aimed to investigate the prognostic significance of the site of distant metastasis among patients with metastatic GC. Furthermore, the effect of surgery of the primary tumor and metastatic lesion on the prognosis of metastatic GC was also analyzed. Methods: The data of 4,221 eligible patients, who were diagnosed with metastatic GC between 2010 and 2015, were identified from the Surveillance Epidemiology and End Results (SEER) database. Multivariate logistic regression analysis was performed to assess the association between potential prognostic factors, including the site of metastasis and surgery, and survival of patients with metastatic GC. Overall survival (OS) and cause-specific survival (CSS) were determined using the Kaplan-Meier survival curves and differences were assessed using the Log-rank test. Results: Out of the total 4,221 GC patients with definite organ metastases, 3312 patients had single-site metastasis while 909 patients had multiple-site metastases. GC patients with single-site metastasis of liver or lung exhibited better CSS and OS compared to those with bone metastasis. Furthermore, GC patients with liver metastasis benefited from surgery of both the primary and metastatic lesions, while those with lung metastasis benefited from surgery of metastasis resection only. Multivariate Cox regression analysis revealed that GC patients with single-site metastasis, well-differentiated tumors, GC patients who underwent surgery of the primary tumor and those who received chemotherapy exhibited favorable prognosis. Conclusions: The site of metastasis was an independent prognostic factor for metastatic GC. Surgery had survival benefits in certain cases of metastatic GC; however, further studies are warranted to clarify these benefits in carefully selected patients.

Lactiplantibacillus plantarum GUANKE (L. plantarum GUANKE) is a Gram-positive bacterium isolated from the feces of healthy volunteers. Whole-genome sequencing analysis (WGS) revealed that the genome of L. plantarum GUANKE consists of one chromosome and two plasmids, with the chromosome harbors 2955 CDS, 66 tRNAs, and 5 rRNAs. The genome is devoid of virulence factors and Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems. It contains three intact prophage regions and bacteriocin biosynthesis genes (plantaricins K, F, and E), as well as seventeen genomic islands lacking antibiotic resistance or pathogenicity determinants. Functional prediction outcomes identified that the genome of L. plantarum GUANKE is closely related to transcription, carbohydrate transport and metabolism, and amino acid transport and metabolism. Carbohydrate-active enzymes (CAZymes) analysis and GutSMASH analysis revealed that the genome of L. plantarum GUANKE contained 100 carbohydrate-active enzyme genes and two specialized metabolic gene clusters. Safety assessments confirmed that L. plantarum GUANKE neither exhibited β-hemolytic activity nor harbored detectable transferable drug resistance genes. The strain exhibited remarkable acid tolerance and bile salt resistance. Cellular adhesion assays demonstrated moderate binding capacity to Caco-2 intestinal epithelium (4.3 ± 0.007)%. In vitro analyses using lipopolysaccharide (LPS)-stimulated macrophage models demonstrated that L. plantarum GUANKE significantly suppressed the secretion of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), exhibiting dose-dependent anti-inflammatory activity. In vivo experiments showed that L. plantarum GUANKE was involved in the regulation of the apical junction pathway and interferon pathway in colon tissue of normal mice.