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ObjectiveThis study employed Mendelian Randomization (MR) to investigate the causal relationships among immune cells, COPD, and potential metabolic mediators.MethodsUtilizing summary data from genome-wide association studies, we analyzed 731 immune cell phenotypes, 1,400 plasma metabolites, and COPD. Bidirectional MR analysis was conducted to explore the causal links between immune cells and COPD, complemented by two-step mediation analysis and multivariable MR to identify potential mediating metabolites.ResultsCausal relationships were identified between 41 immune cell phenotypes and COPD, with 6 exhibiting reverse causality. Additionally, 21 metabolites were causally related to COPD. Through two-step MR and multivariable MR analyses, 8 cell phenotypes were found to have causal relationships with COPD mediated by 8 plasma metabolites (including one unidentified), with 1-methylnicotinamide levels showing the highest mediation proportion at 26.4%.ConclusionWe have identified causal relationships between 8 immune cell phenotypes and COPD, mediated by 8 metabolites. These findings contribute to the screening of individuals at high risk for COPD and offer insights into early prevention and the precocious diagnosis of Pre-COPD.

IntroductionPatients with relapsed/refractory (r/r) acute T-lymphoblastic leukemia (T-ALL) have a poor prognosis. We developed donor CD7 chimeric antigen receptor T (CAR-T) cells to salvage r/r T-ALL patients and obtained encouraging results. Patients who had not received allogeneic (allo-) hematopoietic stem cell transplantation (HSCT) before CAR-T therapy would develop pancytopenia and immunodeficiency for a long period after CD7 CAR-T therapy; therefore, allo-HSCT is needed in these patients. Here, we report two pediatric r/r T-ALL patients who received donor CD7 CAR-T bridging to allo-HSCT with leukemia-free survival (LFS) and sustained negative minimal residual disease for >2 years.Case presentationPatient 1 was a 10-year-old boy who visited our hospital because of a T-ALL relapse with multiple lymphadenopathies without discomfort. The patient did not achieve remission after one course of induction chemotherapy. The patient then received donor (his father) CD7 CAR-T cells and achieved complete remission (CR). Thirty days after the first CAR-T cell infusion, he received allo-HSCT, and his father was also the donor. His LFS was >3 years. Patient 2 was an 8-year-old boy who was admitted to our hospital with relapsed T-ALL with fever, cough, and mild dyspnea. He did not achieve remission after one course of induction chemotherapy; therefore, he received donor (his father) CD7 CAR-T cells and achieved CR. Twenty-six days after CAR-T cell infusion, the patient received allo-HSCT, with his father as the donor. He has survived for >2 years free of leukemia. At the last follow up, both patients were alive and presented a good quality of lifeConclusionThe long-term survival of these two patients supports the use of CD7 CAR-T therapy bridging to allo–HSCT as an effective and safe treatment with the capacity to make r/r T-ALL a curable disease, similar to r/r acute B-lymphoblastic leukemia.

BackgroundOrigin recognition complex 6 (ORC6) is one of the six highly conserved subunit proteins required for DNA replication and is essential for maintaining genome stability during cell division. Recent research shows that ORC6 regulates the advancement of multiple cancers; however, it remains unclear what regulatory impact it has on the tumor immune microenvironment.MethodsUnpaired Wilcoxon rank sum and signed rank tests were used to analyze the differences in the expression of ORC6 in normal tissues and corresponding tumor tissues. Multiple online databases have evaluated the genetic alterations, protein expression and localization, and clinical relevance of ORC6. To evaluate the potential prognostic impact and diagnostic significance of ORC6 expression, we carried out log-rank, univariate Cox regression, and receiver operating characteristic curve analysis. The ICGC-LIRI-JP cohort, CGGA-301 cohort, CGGA-325 cohort, CGGA-693 cohort, and GSE13041 cohort were used for external validation of the study findings. The associations between ORC6 expression and immune cell infiltration, immune checkpoint expression, and immunotherapy cohorts was further analyzed. To explore the functional and signaling pathways related to ORC6 expression, gene set enrichment analysis was performed. To clarify the expression and function of ORC6 in hepatocellular carcinoma (LIHC) and glioma, we conducted in vitro experiments.ResultsExpression of ORC6 is upregulated in the majority of cancer types and is associated with poor patient prognosis, notably in cases of LIHC and gliomas. In addition, ORC6 may be involved in multiple signaling pathways related to cancer progression and immune regulation. High expression of ORC6 correlates with an immunosuppressive state in the tumor microenvironment. The results of further immunotherapy cohort analysis suggested that patients in the ORC6 high-expression group benefited from immunotherapy. Inhibiting ORC6 expression suppressed the proliferative and migratory abilities of LIHC and glioma cells.ConclusionHigh expression of ORC6 may be used as a biomarker to predict the poor prognosis of most tumor patients. The high expression of ORC6 may be involved in the regulation of the tumor immunosuppressive environment, and it is expected to become a molecular target for inhibiting tumor progression.

IntroductionNon-alcoholic fatty liver disease (NAFLD), the emerging cause of end-stage liver disease, is the most common liver disease. Determining the independent risk factors of NAFLD and patients who need more monitoring is important.MethodsTwo-Sample Mendelian randomization (MR) was performed in the analysis to investigate the causal association of different autoimmune diseases with NAFLD using summary level data. Genome-wide association study (GWAS) of 5 autoimmune diseases including celiac disease (CeD), Crohn’s disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D) were selected for Instrument variables (IVs). NAFLD was included as outcome.ResultAfter adjusting for confounding factors, genetic predisposition of CeD (OR= 0.973, [0.949,0.997], IVW p-value=0.026), MS (OR= 1.048, [1.012,1.085], IVW p-value= 0.008), RA (OR= 1.036, [1.006,1.066], IVW p-value=0.019), T1D (OR= 1.039, [1.002,1.079], IVW p-value= 0.041) is causally associated with NAFLD. No causal effect was found between CD and NAFLD.ConclusionCeD itself may be a protective factor for NAFLD, the results of previous observational studies have been influenced by confounding factors, and the morbidity of NAFLD may be higher in patients with MS, RA, and T1D than in common populations, and monitoring the prevalence of NAFLD in these populations is considerable.

BackgroundImmune checkpoint inhibitor (ICI)-associated cardiotoxicity is a relatively uncommon immune-related adverse effects (irAEs) with a high mortality rate. There are few recommendations for the replacement of different immune checkpoint inhibitors in domestic and international reports.Case presentationWe report a case of a patient with squamous non-small cell lung carcinoma (squamous NSCLC) who developed cardiotoxicity after being treated with a programmed death-1 (PD-1) inhibitor and then changed to a PD-L1 inhibitor to continue the treatment. A significant benefit was observed after four cycles of immunotherapy, and no further cardiotoxicity occurred after the treatment was started.ConclusionThis case demonstrates that myocardial damage induced by tislelizumab (PD-1 inhibitor) can be improved after switching to sugemalimab (PD-L1 inhibitor) and that antitumor immunotherapy is effective. This result may have important implications for optimizing immunotherapy management regimens in cancer patients.

ObjectiveBehçet’s Disease (BD) is an intractable systemic vasculitis. When accompanied by intestinal symptoms, the prognosis is usually poor. 5-Aminosalicylic acid (5-ASA), corticosteroids, immunosuppressive drugs, and anti-tumor necrosis factor-α (anti-TNF-α) biologics are standard therapies to induce or maintain remission for intestinal BD. However, they might not be effective in refractory cases. Safety should also be considered when patients have an oncology history. Regarding the pathogenesis of intestinal BD and the specific targeting effect of vedolizumab (VDZ) on the inflammation of the ileum tract, previous case reports suggested that VDZ might be a potential treatment for refractory intestinal BD.MethodsWe report a 50-year-old woman patient with intestinal BD who had oral and genital ulcers, joint pain, and intestinal involvement for about 20 years. The patient responds well to anti-TNF-α biologics but not to conventional drugs. However, biologics treatment was discontinued due to the occurrence of colon cancer.ResultsVDZ was intravenously administered at a dose of 300 mg at 0, 2, and 6 weeks and then every eight weeks. At the 6-month follow-up, the patient reported significant improvement in abdominal pain and arthralgia. We observed complete healing of intestinal mucosal ulcers under endoscopy. However, her oral and vulvar ulcers remained unresolved, which disappeared after adding thalidomide.ConclusionVDZ may be a safe and effective option for refractory intestinal BD patients who do not respond well to conventional treatments, especially those with an oncology history.

Interstitial lung disease (ILD) is one of the most serious lung complications of connective tissue disease (CTD). The application of proteomics in the past decade has revealed that various proteins are involved in the pathogenesis of each subtype of CTD-ILD through different pathways, providing novel ideas to study pathological mechanisms and clinical biomarkers. On this basis, a multidimensional diagnosis or prediction model is established. This paper reviews the results of proteomic detection of different subtypes of CTD-ILD and discusses the role of some differentially expressed proteins in the development of pulmonary fibrosis and their potential clinical applications.

The contour of the tumor immune microenvironment (TIME) is very important for tumor prognostic prediction but hard to be characterized in clinical practice. It is unclear practice whether the peripheral immune signature (pIS) reflects the TIME as a feasible prognostic indicator for head and neck squamous cell carcinoma (HNSCC) patients. Here, we enrolled 599 HNSCC patients from three domestic institutes to explore the relationship between the pIS and survival. The peripheral neutrophil-to-lymphocyte ratio (pNLR) was screened out as a significant prognostic variable through multivariable COX regression analyses. An inverse correlation between pNLR and survival was found in the data of these 599 patients. Meanwhile, the bulk tumor RNA-seq data of 913 cases were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify the prognosis-associated TIME features. The TIME feature was consistent to the finding of clinical data, in which high tissue NLR predicted a poor prognosis. Differentially expressed immune-related gene (DEIRG) enrichment analysis also showed a trend that the gene sets in patients with a good prognosis were enriched in lymphocyte-related functions, while those with a poor prognosis were enriched in neutrophil-related functions. At the same time, the well prediction performance of our model based on DEIRGs was verified in both TCGA and GEO cohorts. Finally, the correlation between pIS and the TIME was confirmed in a small independent cohort of 30 HNSCC patients. A positive correlation was confirmed prospectively between the pNLR and the TIME pattern in our independent cohort. Our findings provide evidence that the pNLR is a feasible prognostic signature that reflects the TIME patterns to some extent in HNSCC.

The use of chimeric antigen receptor T cells (CAR-Ts) is effective in the treatment of hematological malignancies. It has been reported that HBV is reactivated after CAR-T immunotherapy for refractory/relapsed hematological malignant B-cell tumors. However, there is little literature on donor-derived CAR-T therapy combined with allogeneic hematopoietic stem cell transplantation in hepatitis B patients with acute T-lymphocytic leukemia. We report the case of one patient with hepatitis B associated with relapsed/refractory acute T-lymphocytic leukemia (T-ALL) treated with donor-derived CD7 CAR-T therapy and allogeneic hematopoietic stem cell transplantation. During treatment, the copy number of hepatitis B virus continuously decreased, and AST, ALT, DBIL and TBIL remained within the controllable ranges. CD7-negative MRD recurred 4.5 months after transplantation, and the flow cytometry results became negative after immunosuppressive reduction. Seven months after transplantation, the patient had complete remission, and the copy number of hepatitis B virus decreased to below 102. This is the first study on the safety and effectiveness of donor-derived CD7 CAR-T therapy bridging to allogeneic hematopoietic stem cell transplantation in a patient with relapsed/refractory acute T-lymphocytic leukemia and hepatitis B.

Ischemia-reperfusion injury (IRI) is considered an inherent component involved in liver transplantation, which induce early organ dysfunction and failure. And the accumulating evidences indicate that the activation of host innate immune system, especially hepatic macrophages, play a pivotal role in the progression of LIRI. Inflammasomes is a kind of intracellular multimolecular complexes that actively participate in the innate immune responses and proinflammatory signaling pathways. Among them, NLRP3 inflammasome is the best characterized and correspond to regulate caspase-1 activation and the secretion of proinflammatory cytokines in response to various pathogen-derived as well as danger-associated signals. Additionally, NLRP3 is highly expressed in hepatic macrophages, and the assembly of NLRP3 inflammasome could lead to LIRI, which makes it a promising therapeutic target. However, detailed mechanisms about NLRP3 inflammasome involving in the hepatic macrophages-related LIRI is rarely summarized. Here, we review the potential role of the NLRP3 inflammasome pathway of hepatic macrophages in LIRI, with highlights on currently available therapeutic options.