ImmunoTargets and Therapy最新文献

Introduction: Nasopharyngeal cancer (NPC) is a complex cancer due to its unique genomic features and association with the Epstein-Barr virus (EBV). Despite therapeutic advancements, NPC prognosis remains poor, necessitating a deeper understanding of its genomics. Here, we present a comprehensive whole genome sequencing (WGS) view of NPC genomics and its correlation with the phenotype.

Methods: This study involved WGS of a clinical NPC biopsy specimen. Sequencing was carried out using a long read sequencer from Oxford Nanopore. Analysis of the variants involved correlation with the phenotype of NPC.

Results: A loss of genes within chromosome 6 from copy number variation (CNV) was found. The lost genes included HLA-A, HLA-B, and HLA-C, which work in the antigen presentation process. This loss of the major histocompatibility complex (MHC) apparatus resulted in the tumour's ability to evade immune recognition. The tumour exhibited an immunologically "cold" phenotype, with mild tumour-infiltrating lymphocytes, supporting the possible etiology of loss of antigen presentation capability. Furthermore, the driver mutation PIK3CA gene was identified along with various other gene variants affecting numerous signaling pathways.

Discussion: Comprehensive WGS was able to detect various mutations and genomic losses, which could explain tumour progression and immune evasion ability. Furthermore, the study identified the loss of other genes related to cancer and immune pathways, emphasizing the complexity of NPC genomics. In conclusion, this study underscores the significance of MHC class I gene loss and its probable correlation with the cold tumour phenotype observed in NPC.

Dermatomyositis is a heterogeneous idiopathic inflammatory myopathy associated with various cutaneous manifestations and variable presence of myositis, interstitial lung disease, and other visceral organ involvement. An accurate diagnosis of dermatomyositis requires correlating clinical examination findings with serological and histological findings. Familiarity with pathognomonic and common cutaneous manifestations of dermatomyositis, which are highlighted here, can be especially helpful in making an accurate diagnosis. Additionally, evaluating patients for presence of myositis-specific autoantibodies can further support or refute a dermatomyositis diagnosis. When present, myositis-specific autoantibodies can also help guide workups for various dermatomyositis-associated manifestations, as each is associated with relatively distinct clinical characteristics. Evaluating patients for various systemic manifestations often relies on expert opinion recommendations; however, societal guideline statements concerning the evaluation of some manifestations have recently been described. Although malignancy-associated dermatomyositis is a well-accepted subtype, there is limited evidence to support extensive malignancy screening has a favorable benefit-risk ratio in most dermatomyositis patients. However, recent research has uncovered novel associations between dermatomyositis and malignancy, suggesting the possibility of identifying high-risk subsets of dermatomyositis patients in whom malignancy screening may have a high value. Treatment for dermatomyositis has remained largely unchanged over the past several decades. Although many dermatomyositis patients can be effectively treated with current options, either as monotherapy or with combination regimens, there is a need for more targeted and effective DM therapies, in general, and for MDA5(+) dermatomyositis-associated rapidly progressive interstitial lung disease. Fortunately, significant current and emerging research activities evaluating various novel medications for dermatomyositis provide hope for exciting future advances in patients with this intriguing immune-mediated disease.

Introduction: Various treatments available today for anogenital and cutaneous warts have limitations, including time-consuming, challenging to perform, and the risk of scarring. A new treatment using tuberculin purified protein derivative (PPD) has been developed, which is expected to generate cellular immunity against HPV.

Objective: To assess the evidence for the efficacy and safety of PPD treatment for cutaneous and anogenital warts.

Materials and methods: A literature search was performed with the keyword-based search on digital libraries, including the National Library of Medicine, Cochrane Controlled Register of Trial, and Google Scholar, using the following terms: anogenital warts, condyloma acuminata, cutaneous warts, human papillomavirus, immunotherapy, and tuberculin purified protein derivative. Original studies on treating cutaneous or anogenital warts with PPD were included. The results were 47 clinical trials and 4 case reports. Most of the research was done in countries with common Mycobacterium tuberculosis infection. The treatment showed good efficacy. Comparative studies showed that the treatment has similar efficacy with other immunotherapies. No significant side effects were reported, with evidence of the safety use on the pregnant population.

Conclusion: Based on good efficacy and safety, PPD can be considered an alternative therapy, especially in countries where tuberculosis is frequent.

Background: The specific involvement of the CD8+ T effector memory RA (TEMRA) subset in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has largely not been explored in the literature.

Methods: Targeted single-cell RNA sequencing (scRNA-seq) profiles were generated from peripheral blood mononuclear cells (PBMCs) obtained from two CP/CPPS patients and two healthy controls (HCs) in our recent study. Pseudotime series algorithms were used to reveal the differentiation trajectory, CellChat analysis was used to explore the communication between individual cells, and the SCENIC program was used to identify potential transcription factors (TFs). Based on the cosine similarity, clusters of differentially expressed genes (DEGs) were considered to be further enriched in different pathways. To confirm the functional role of the critical clusters, flow cytometry was employed.

Results: The results revealed the molecular landscape of these clusters, with TEMRA cells exhibiting pronounced cytokine-mediated signaling pathway enrichment. Pseudotime trajectory analysis further mapped the evolution from naïve T cells to that of TEMRA cells, elucidating the developmental pathways involved in the immune context. A significant finding from CellChat analysis was the differential expression of ligands and receptors, with CD8+ TEMRA cells showing enhanced signaling, particularly in the CP/CPPS context, compared to HCs. Flow cytometry confirmed these results, revealing a heightened proinflammatory cytokine profile in patients with chronic prostatitis-like symptoms (CP-LS), suggesting that TEMRA cells play a significant role in disease pathogenesis. TF profiling across the T-cell clusters identified key regulators of cellular identity, identifying novel therapeutic targets. Elevated TNF signaling activity in CD8+ TEMRA cells underscored the involvement of these cells in disease mechanisms.

Conclusion: This study elucidates the pivotal role of the CD8+ TEMRA cell subset in CP/CPPS, which is characterized by increased TNF signaling and proinflammatory factor expression, highlighting potential biomarkers and opening new avenues for therapeutic intervention.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a treatable autoimmune disorder, for which different treatment options are available. Current first-line evidence-based therapies for CIDP include intravenous and subcutaneous immunoglobulins, corticosteroids and plasma exchanges. Despite lack of evidence, cyclophosphamide, rituximab and mycophenolate mofetil are commonly used in circumstances of refractoriness and, more debatably, of perceived overdependence on first-line therapies. Rituximab is currently the object of a randomized controlled trial for CIDP. Based on case series, and although rarely considered, haematopoietic autologous stem cell transplants may be effective in refractory disease, with low mortality and high remission rates. A new therapeutic option has appeared with efgartigimod, a neonatal Fc receptor blocker, recently shown to significantly lower relapse rate versus placebo, after withdrawal from previous immunotherapy. Other neonatal Fc receptor blockers, nipocalimab and batoclimab, are under study. The C1 complement-inhibitor SAR445088, acting in the proximal portion of the classical complement system, is currently the subject of a new study in treatment-responsive, refractory and treatment-naïve subjects. Finally, Bruton Tyrosine Kinase inhibitors, which exert anti-B cell effects, may represent another future research avenue. The widening of the therapeutic armamentarium enhances the need for improved evaluation of treatment effects and reliable biomarkers in CIDP.

The human papillomavirus is known to cause cervical and anogenital cancer and benign anogenital and cutaneous warts. Both males and females can contract the virus during sexual intercourse and skin-to-skin contact. Communities in low- and middle-income countries, including Africa, are particularly suffering from human papillomavirus-related diseases, mainly cervical cancer. Vaccination is the most economical and efficient prevention strategy to control human papillomavirus-related diseases. Undoubtedly, to control all types of human papillomavirus-related morbidity and mortality, the entire at-risk, sexually active population needs to be vaccinated regardless of their sex. However, the vaccination program, particularly in Africa, the world's most resource-limited region, is habitually limited to the female population, considering only the burden of cervical cancer. We think that it is impossible to fully mitigate the human papillomavirus infection by vaccinating only the female population, while males can carry and pass the virus. In addition, marginalizing males from this program seems to violate gender inequality and their sexual and reproductive health rights. Hence, we voice the need for global and local governments to consider and customize human papillomavirus vaccination programs for the male population. Also, it is better to consider the male population in different research studies regarding human papillomavirus-related malignant and benign conditions.

Objective: The current study is conducted to investigate the potential prognostic value of the age-male-albumin-bilirubin-platelets (aMAP) score in breast cancer patients with liver metastasis after surgery.

Methods: This is a retrospective study of 178 breast cancer patients who developed liver metastasis after surgery. These patients were treated and followed up from 2000 to 2018 at our hospital. The aMAP risk score was estimated in accordance with the following formula: . The optimal cutoff value of the aMAP was evaluated via X-tile. Kaplan-Meier, Log-rank and Cox proportional hazards regression models were applied to determine the clinical influence of the aMAP score on the survival outcomes. The nomogram models were established by multivariate analyses. The calibration curves and decision curve analysis were applied to evaluate the estimated performance of the nomogram models.

Results: A total of 178 breast cancer patients were divided into low aMAP score group (<47.6) and high aMAP score group (≥47.6) via X-tile plots. The aMAP score was a potential prognostic factor in multivariate analysis. The median disease free survival (p=0.0013) and overall survival (p=0.0003) in low aMAP score group were longer than in high aMAP score group. The nomograms were constructed to predict the DFS with a C-index of 0.722 (95% CI, 0.673-0.771), and the OS with a C-index of 0.708 (95% CI, 0.661-0.755). The aMAP-based nomograms had good predictive performance.

Conclusion: The aMAP score is a potential prognostic factor in breast cancer with liver metastasis after surgery. The aMAP score-based nomograms were conducive to discriminate patients at high risks of liver metastasis and develop adjuvant treatment and prevention strategies.

Background: Eosinophilic esophagitis (EoE) is a complex allergic condition frequently accompanied by various atopic comorbidities in children, which significantly affects their life qualities. Therefore, this study aimed to evaluate pivotal molecular markers that may facilitate the diagnosis of EoE in pediatric patients.

Methods: Three available EoE-associated gene expression datasets in children: GSE184182, GSE 197702, GSE55794, along with GSE173895 were downloaded from the GEO database. Differentially expressed genes (DEGs) identified by "limma" were intersected with key module genes identified by weighted gene co-expression network analysis (WGCNA), and the shared genes went through functional enrichment analysis. The protein-protein interaction (PPI) network and the machine learning algorithms: least absolute shrinkage and selection operator (LASSO), random forest (RF), and XGBoost were used to reveal candidate diagnostic markers for EoE. The receiver operating characteristic (ROC) curve showed the efficacy of differential diagnosis of this marker, along with online databases predicting its molecular regulatory network. Finally, we performed gene set enrichment analysis (GSEA) and assessed immune cell infiltration of EoE/control samples by using the CIBERSORT algorithm. The correlations between the key diagnostic biomarker and immune cells were also investigated.

Results: The intersection of 936 DEGs and 1446 key module genes in EoE generated 567 genes, which were primarily enriched in immune regulation. Following the construction of the PPI network and filtration by machine learning, CXCR2 served as a potential diagnostic biomarker of pediatric EoE with a perfect diagnostic efficacy (AUC = ~1.00) in regional tissue/peripheral whole blood samples. Multiple infiltrated immune cells were observed to participate in disrupting the homeostasis of esophageal epithelium to varying degrees.

Conclusion: The immune-correlated CXCR2 gene was proved to be a promising diagnostic indicator for EoE, and dysregulated regulatory T cells (Tregs)/neutrophils might play a crucial role in the pathogenesis of EoE in children.

Purpose: The pathogenesis of T cell subsets in sepsis during the body's resistance to infection is currently unknown. We aimed to investigate the dynamics and molecular mechanisms of T cells during the development of sepsis.

Patients and methods: Perform single-cell data analysis on peripheral blood mononuclear cells (PBMCs) specimen samples from seven healthy controls, five early-stage sepsis patients, and four late sepsis patients, and the atlas were mapped and analyzed using reference mapping to identify the T cell subpopulations specific to early sepsis. Expression network upstream to investigate the changes of regulatory transcription factors and pathways by pySCENIC.

Results: Twenty-two CD4⁺ T-cell subpopulations and 10 CD8⁺ T-cell subpopulations were identified by mapping analysis. At the early stage of sepsis, we observed altered ratios of multiple immune cells in PBMCs. Three cell types CD4 Tn cells, CD8 (GZMK⁺ early Tem), and CD8 (ZNF683⁺CXCR6^- Tm) showed an upward trend (p < 0.05) in the early stages of sepsis compared to normal and returned to normal levels after two weeks. In addition, we found the presence of four sepsis-specific transcription factors (MXI1, CHD1, ARID5A, KLF9) in these three types of cells, which were validated in two external datasets. The differentially expressed genes in CD4 Tn cells, CD8 (GZMK⁺ early Tem), and CD8 (ZNF683⁺CXCR6^- Tm) cells between the healthy group and the early-stage sepsis group are commonly enriched in the allograft rejection pathway. In addition, it was found that CD8 cells exhibit a trend towards differentiation into CD8 Temra cells in sepsis.

Conclusion: We successfully depicted the dynamic changes of T cell subsets during sepsis onset and progression, which provides important clues for an in-depth understanding of T cells' function and regulatory mechanisms during sepsis pathogenesis.

Introduction: Chemotherapy combined with immune checkpoint inhibitors (ChIM) is used to treat advanced pancreatic ductal adenocarcinoma (PDAC). However, the efficacy of ChIM is similar to that of chemotherapy alone.

Methods: To assess potential factors affecting the effectiveness of ChIM, we analyzed the clinical data of 359 patients with PDAC who visited the hospital during June 2017 to December 2022.

Results: Surgical resection, diabetes, and ChIM were risk factors for pancreatic exocrine insufficiency (PEI). The adjusted odds ratio of ChIM was 2.63 (95% confidence interval (CI) 1.492-4.626) (P = 0.001). The incidence of PEI in the ChIM group (76.9%) was significantly higher than that of the chemotherapy group (60.2%) (P = 0.004). Survival analysis showed that ChIM did not improve the survival rate of patients with PDAC (hazard ratio (HR) 0.92, 0.707-1.197) (P = 0.534) in comparison with that of the chemotherapy group. However, in patients without PEI, those receiving ChIM showed a higher 1-year overall survival (OS) rate of 70.8% (two-sided, P = 0.045) and a median OS of 22.0 months (95% CI 11.5-32.5). Moreover, pancreatic enzyme replacement therapy significantly improved the OS of patients with PDAC (HR = 0.73, 95% CI = 0.561-0.956) (P = 0.022).

Conclusion: Immune checkpoint inhibitors (ICIs) increased the incidence of PEI in patients with PDAC. The OS was not different between patients receiving chemotherapy and ChIM due to irregular PERT treatment. The finding show that pancreatic enzyme replacement therapy may improve the response rate of patients with PDAC to ICIs.