Immunology, mutations, biology

Analysis of genetically defined immunodeficient patients allows study of the effect of the absence of specific proteins on human immune function in real-world conditions. Here we have addressed the importance of type I interferon signalling for human NK cell development by studying the phenotype and function of circulating NK cells isolated from patients suffering primary immunodeficiency disease due to mutation of either the human interferon regulatory factor 9 (IRF9) or the signal transducer and activator of transcription 2 (STAT2) genes...

Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8+ effector T (TEFF ) cells and TIM3+ PD1+ , hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells...

Disulfidptosis is a newly discovered mode of cell death. However, its biological mechanism in bladder cancer (BLCA) is still uncharacterized. In this investigation, we firstly examined the expression and mutation of disulfidptosis-related genes (DRGs) in BLCA. Two disulfidptosis phenotypes associated with DRGs expression patterns and immune cell infiltration were built. A disulfidptosis risk score signature was constructed based on ten differentially expressed genes (DEGs) between the disulfidptosis subtypes, which allowed patients to be stratified into high- and low-risk groups...

NUP155 is reported to be correlated with tumor development. However, the role of NUP155 in tumor physiology and the tumor immune microenvironment (TIME) has not been previously examined. This study comprehensively investigated the expression, immunological function, and prognostic significance of NUP155 in different cancer types. Bioinformatics analysis revealed that NUP155 was upregulated in 26 types of cancer. Additionally, NUP155 upregulation was strongly correlated with advanced pathological or clinical stages and poor prognosis in several cancers...

Cell cycle-dependent protein kinase 12 (CDK12) plays a key role in a variety of carcinogenesis processes and represents a promising therapeutic target for cancer treatment. However, to date, there have been no systematic studies addressing its diagnostic, prognostic and immunological value across cancers. Here, we found that CDK12 was significantly upregulated in various types of cancers, and it expression increased with progression in ten cancer types, including breast cancer, cholangiocarcinoma and colon adenocarcinoma...

Dendritic cells (DC) are mediators between innate and adaptive immune responses to pathogens and tumors. DC development is determined by signaling through the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3) in bone marrow myeloid progenitors. Recently the naming conventions for DC phenotypes have been updated to distinguish between "Conventional" DCs (cDCs) and plasmacytoid DCs (pDCs). Activating mutations of FLT3, including Internal Tandem Duplication (FLT3-ITD), are associated with poor prognosis for acute myeloid leukemia (AML) patients...

BACKGROUND: There is an ongoing debate on whether sex affects immune-suppressive tumor microenvironment and immunotherapy. Here, we explored the underlying molecular bases for sex dimorphisms and their impact on the efficacy of immunotherapy in esophageal cancer (EC). METHODS: 2360 EC patients from phase 3 trials were pooled to compare overall survivals by calculating hazard ratios (HRs) and their 95% confidence intervals (CIs). Genomic data of 1425 samples were integrated to depict the genomic landscapes and antigenic features...

Caspase (CASP) is a family of proteases involved in cleavage and activation of gasdermin, the executor of pyroptosis. In humans, CASP3 and CASP7 recognize the same consensus motif DxxD, which is present in gasdermin E (GSDME). However, human GSDME is cleaved by CASP3 but not by CASP7. The underlying mechanism of this observation is unclear. In this study, we identified a pyroptotic pufferfish GSDME that was cleaved by both pufferfish CASP3/7 and human CASP3/7. Domain swapping between pufferfish and human CASP and GSDME showed that the GSDME C-terminus and the CASP7 p10 subunit determined the cleavability of GSDME by CASP7...

Foot and mouth Disease virus (FMDV) belongs to Picornaviridae family and Aphthovirus genus causing Foot and mouth disease (FMD) in cloven-hoofed animals. FMDV, a prevalent virus induces both acute and chronic infections with high mutation rates resulting in seven primary serotypes, making vaccine development indispensable. Due to time and cost effectiveness of the immunoinformatic approach, we designed in-silico polyepitope vaccine (PEV) for the curtailment of FMDV. Structural and immunogenic parts of FMDV (Viral Protein 1 (VP1), Viral Protein 2 (VP2), Viral Protein 3 (VP3), and Viral Protein 4 (VP4)) were used to design the cytotoxic T Lymphocyte (CTL), Helper T Lymphocyte (HTL), and B-cell epitopes, followed by screening for antigenic, non-allergenic, Interferon (IFN) simulator, and non-toxicity, which narrowed down to 7 CTL, 3 HTL, and 12 B-cell epitopes...

BACKGROUND: Cancer is a common cause of death around the world. Immunotherapy plays a significant role in cancer treatment but still has limitations. The ankyrin-3 ( ANK3 ) gene has been shown to have a variety of biological roles and has also been shown to be closely linked to individual cancers. METHODS: We systematically investigated the role of ANK3 in pan-cancer, particularly in relation to immunity. We collected data from a number of databases, including the The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), tumor-immune system interactions (TISIDB), cBioPortal, Tumor Immune Estimation Resource (TIMER), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), BioGRID, and SangerBox databases...

PURPOSE: NLRP3-associated autoinflammatory disease (NLRP3-AID) is characterized by gain-of-function variants in the NLRP3 gene. Since there are little literature focusing on pediatric NLRP3-AID in China, we aimed to elucidate the phenotypic and genotypic profiles of Chinese patients with NLRP3-AID. METHODS: Patients with NLRP3-AID at three rheumatology centers in China were genotyped through whole exome sequencing or gene panel sequencing. Sanger sequencing was performed on all patients and their parents...

Hereditary spastic paraplegias (HSPs) comprise a family of degenerative diseases mostly hitting descending axons of corticospinal neurons. Depending on the gene and mutation involved, the disease could present as a pure form with limb spasticity, or a complex form associated with cerebellar and/or cortical signs such as ataxia, dysarthria, epilepsy, and intellectual disability. The progressive nature of HSPs invariably leads patients to require walking canes or wheelchairs over time. Despite several attempts to ameliorate the life quality of patients that have been tested, current therapeutical approaches are just symptomatic, as no cure is available...

Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671 -ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT -ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2rs671 gene knock-in mice...

Synaptic abnormalities are a hallmark of several neurological diseases, and clarification of the underlying mechanisms represents a crucial step toward the development of therapeutic strategies. Rett syndrome (RTT) is a rare neurodevelopmental disorder, mainly affecting females, caused by mutations in the X-linked methyl-CpG-binding protein 2 ( MECP2 ) gene, leading to a deep derangement of synaptic connectivity. Although initial studies supported the exclusive involvement of neurons, recent data have highlighted the pivotal contribution of astrocytes in RTT pathogenesis through non-cell autonomous mechanisms...

BACKGROUND: The Golgi apparatus (GA) is crucial for protein synthesis and modification, and regulates various cellular processes. Dysregulation of GA can lead to pathological conditions like neoplastic growth. GA-related genes (GARGs) mutations are commonly found in cancer, contributing to tumor metastasis. However, the expression and prognostic significance of GARGs in osteosarcoma are yet to be understood. METHODS: Gene expression and clinical data of osteosarcoma patients were obtained from the TARGET and GEO databases...

A20, encoded by TNFAIP3, is a critical negative regulator of immune activation. A20 is a ubiquitin editing enzyme with multiple domains, each of which mediates or stabilizes a key ubiquitin modification. A20 targets diverse proteins that are involved in pleiotropic immunologic pathways. The complexity of A20-mediated immunomodulation is illustrated by the varied effects of A20 deletion in different cell types and disease models. Clinically, the importance of A20 is highlighted by its extensive associations with human disease...

Over the past year, an unexpected surge in human monkeypox (hMPX) cases has been observed. This outbreak differs from previous ones, displaying distinct epidemiological characteristics and transmission patterns, believed to be influenced by a newly emerging monkeypox virus (MPXV) lineage. Notably, this emerging MPXV lineage has exhibited several non-synonymous mutations, some of which are linked to immunomodulatory activities and antigenic characteristics that aid in host detection. However, specific treatments or vaccines for human monkeypox are currently lacking...

The survival of hosts during infections relies on their ability to mount effective molecular and behavioral immune responses. Despite extensive research on these defense strategies in various species, including the model organism Caenorhabditis elegans , the neural mechanisms underlying their interaction remain poorly understood. Previous studies have highlighted the role of neural G-protein-coupled receptors (GPCRs) in regulating both immunity and pathogen avoidance, which is particularly dependent on aerotaxis...

In this report we provide a summary of the presentations and discussion of the latest knowledge regarding the buccal micronucleus (MN) cytome assay. This information was presented at the HUMN workshop held in Malaga, Spain, in connection with the 2023 European, Environmental Mutagenesis and Genomics conference. The presentations covered the most salient topics relevant to the buccal MN cytome assay including (i) the biology of the buccal mucosa, (ii) its application in human studies relating to DNA damage caused by environmental exposure to genotoxins, (iii) the association of buccal MN with cancer and a wide range of reproductive, metabolic, immunological, neurodegenerative and other age-related diseases, (iv) the impact of nutrition and lifestyle on buccal MN cytome assay biomarkers; (v) its potential for application to studies of DNA damage in children and obesity, and (vi) the growing prospects of enhancing the clinical utility by automated scoring of the buccal MN cytome assay biomarkers by image recognition software developed using artificial intelligence...

BACKGROUND: Investigations elucidating the complex immunological mechanisms involved in colorectal cancer (CRC) and accurately predicting patient outcomes via bulk RNA-Seq analysis have been notably limited. This study aimed to identify the immune status of CRC patients, construct a prognostic model, and identify prognostic signatures via bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq). METHODS: The scRNA-seq data of CRC were downloaded from Gene Expression Omnibus (GEO)...