Antigen Gene Research Articles

U. Parvum serovars exhibit distinct pathogenicity in Chinese women of childbearing age: a multicentre cross-sectional study

BackgroundUreaplasma spp. can be classified into different serovars. It is unknown whether distinct serovars are associated with clinical signs and symptoms.MethodsWe conducted a multicentre cross-sectional study. U. parvum serovars were identified on the basis of their multiple-banded antigen (MBA) genes. After adjusting for demographic variables and other reproductive tract infections, the odds ratio (OR) and 95% confidence interval (CI) were calculated to determine the impact of U. parvum serovars on clinical symptoms.ResultsAmong 5,277 individuals, U. parvum serovars 3 and 6 were the most prevalent serovars (17.9% and 16.0%, respectively). Potential confounders, such as age, body mass index (BMI), ethnicity, education level, contraceptive methods, number of sexual partners, gravidity, parity, and other sexually transmitted infections (STIs) that are associated with clinical symptoms (P < 0.1) were adjusted for in the univariate analysis. U. parvum serovar 14 was strongly positively associated with certain clinical symptoms, including redness and swelling of the vaginal wall (crude OR: 3.53, 95% CI: 1.92–6.49; adjusted OR: 5.21, 95% CI: 2.56–10.58), cervical bleeding and swelling (crude OR: 3.89, 95% CI: 2.38–6.36; adjusted OR: 7.37, 95% CI: 3.82–14.23), and cervical ectropion (crude OR: 2.08, 95% CI: 1.25–3.45; adjusted OR: 3.04, 95% CI: 1.60–5.74). In contrast, U. parvum serovar 3 was negatively associated with a variety of clinical symptoms, whereas no correlations were detected between U. parvum serovars 1and 6 with clinical symptoms.ConclusionsDifferent U. parvum serovars exhibit distinct correlations with clinical symptoms, suggesting that U. parvum serovars are pathogenically heterogeneous and that further differentiation of serovars may be necessary.Trial registrationThe study was registered with ClinicalTrials.gov (https://www.clinicaltrials.gov; ID: NCT04694495; Registration Date: 2021–01-05).

Comprehensive single-cell profiling of monocytes in HLA-B27-positive ankylosing spondylitis with acute anterior uveitis.

Acute anterior uveitis (AAU) is a common extra-articular manifestation of ankylosing spondylitis (AS), particularly in patients positive for the human leucocyte antigen (HLA)-B27 genetic marker. To explore the underlying mechanisms of HLA-B27+ AS-associated AAU, we employed single-cell RNA sequencing to profile the transcriptomes of peripheral blood mononuclear cells in three HLA-B27+ AS-associated AAU patients and three healthy controls (HCs). We identified 11 distinct immune cell clusters, with a particular focus on monocytes, revealing six subsets, including three previously unidentified subsets, namely, GTPase immune-associated proteins, Th17-related, and lncRNA monocytes, with unique gene expression patterns. Significant differences in monocyte composition, activation states, and gene expression were observed between patients and HCs, particularly within HLA monocyte subpopulations. Notably, enhanced expression of X-inactive specific transcript and myeloid cell nuclear differentiation antigen genes was validated across monocyte subclusters in patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis highlighted significant enrichment in antigen processing and presentation pathways, shedding light on the disease's molecular mechanisms. These findings provide novel insights into the molecular mechanisms of HLA-B27+ AS-associated AAU and may contribute to the development of targeted diagnostic and therapeutic strategies. Further clinical validation is essential.

The Plasmodium falciparum histone methyltransferase PfSET10 is dispensable for the regulation of antigenic variation and gene expression in blood-stage parasites.

The malaria parasite Plasmodium falciparum employs antigenic variation of the virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1) to escape adaptive immune responses during blood infection. Antigenic variation of PfEMP1 occurs through epigenetic switches in the mutually exclusive expression of individual members of the multi-copy var gene family. var genes are located in perinuclear clusters of transcriptionally inactive heterochromatin. Singular var gene activation is linked to locus repositioning into a dedicated zone at the nuclear periphery and deposition of histone 3 lysine 4 di-/trimethylation (H3K4me2/3) and H3K9 acetylation marks in the promoter region. While previous work identified the putative H3K4-specific methyltransferase PfSET10 as an essential enzyme and positive regulator of var gene expression, a recent study reported conflicting data. Here, we used iterative genome editing to engineer a conditional PfSET10 knockout line tailored to study the function of PfSET10 in var gene regulation. We demonstrate that PfSET10 is not required for mutually exclusive var gene expression and switching. We also show that PfSET10 is dispensable not only for asexual parasite proliferation but also for sexual conversion and gametocyte differentiation. Furthermore, comparative RNA-seq experiments revealed that PfSET10 plays no obvious role in regulating gene expression during asexual parasite development and gametocytogenesis. Interestingly, however, PfSET10 shows different subnuclear localization patterns in asexual and sexual stage parasites and female-specific expression in mature gametocytes. In summary, our work confirms in detail that PfSET10 is not involved in regulating var gene expression and is not required for blood-stage parasite viability, indicating PfSET10 may be important for life cycle progression in the mosquito vector or during liver stage development.IMPORTANCEThe malaria parasite Plasmodium falciparum infects hundreds of millions of people every year. To survive and proliferate in the human bloodstream, the parasites need to escape recognition by the host's immune system. To achieve this, P. falciparum can change the expression of surface antigens via a process called antigenic variation. This fascinating survival strategy is based on infrequent switches in the expression of single members of the var multigene family. Previous research reported conflicting results on the role of the epigenetic regulator PfSET10 in controlling mutually exclusive var gene expression and switching. Here, we unequivocally demonstrate that PfSET10 is neither required for antigenic variation nor the expression of any other proteins during blood-stage infection. This information is critical in directing our attention toward exploring alternative molecular mechanisms underlying the control of antigenic variation and investigating the function of PfSET10 in other life cycle stages.

Assessment of the Role of miR-30a-5p on the Proliferation and Apoptosis of Hair Follicle Stem Cells.

To investigate the role of miR-30a-5p on the proliferation and apoptosis of hair follicle stem cells (HFSCs) and whether the Wnt/β-catenin signaling pathway is involved. HFSCs derived from the vibrissa of mammary rats were obtained by enzymatic digestion, and subsequently the obtained HFSCs were treated with Lipofectamine 2000 cell transfection and divided into normal cell culture group (control), miR-30a-5p overexpression group (miR-30a-5p mimic), miR-30a-5p empty vector group (miR-NC), miR-30a-5p inhibitor group (in-miR-30a-5p), and in-miR-30a-5p empty vector group (in-miR-NC). After transfection, the cell proliferation and apoptosis rates were examined separately. In addition, the mRNA expression of β-catenin, proliferating cell nuclear antigen (PCNA) and apoptosis-related genes (Bax and Bcl-2) were examined. The results of cell proliferation ability showed that in-miR-30a-5p group promoted cell proliferation of HFSCs relative to other groups, along with significant upregulation of gene levels of PCNA. Apoptosis analysis indicated that apoptosis rate was reduced in the in-miR-30a-5p group, and the expression of Bax was suppressed, while that of Bcl-2 was promoted. Wnt/β-catenin signaling pathway investigation revealed a significant increase in the levels of β-catenin in HFSCs in the in-miR-30a-5p group. Downregulation of miR-30a-5p levels inhibited HFSCs apoptosis and simultaneously promoted proliferation, furthermore, the increased expression of β-catenin indirectly confirmed the activation of the Wnt/β-catenin signaling pathway.

Novel H-2Db-restricted CD8 epitope derived from mouse MAGE-type antigen P1A mediates antitumor immunity in C57BL/6 mice

BackgroundMelanoma antigen gene (MAGE)-type antigens are promising targets for cancer immunotherapy as they are expressed in cancer cells but not in normal tissues, except for male germline cells. The mouse...

Active immunologic participation and metabolic shutdown of kidney structural cells during kidney transplant rejection

Contrary to immune cells, the response of the kidney structural cells in rejection is less established. We performed single-cell RNA sequencing of 18 kidney transplant biopsies from 14 recipients. Single-cell RNA sequencing identified cells from the major compartments of the kidney, next to infiltrated immune cells. Endothelial cells from the glomerulus, peritubular capillaries, and vasa recta showed upregulation of class I and II human leukocyte antigen genes, adhesion molecules, cytokines, and chemokines, suggesting active participation in the alloimmune process, with compartment-specific differences. Epithelial cells including proximal tubular, loop of Henle, and collecting duct cells, also showed increased expression of immune genes. Strikingly, in proximal tubule cells, a strong downregulation of energy metabolism upon inflammation was observed. There was a large overlap between the cell-specific expression changes upon alloimmune inflammation and those observed in 2 large microarray biopsy cohorts. In conclusion, the kidney structural cells, being the main target of the alloimmune process, appear to actively contribute herein, enhancing the damaging effects of the infiltrating immune cells. In epithelial cells, a profound shutdown of metabolism was seen upon inflammation, which is associated with poor kidney function. These observations highlight the critical role of the graft in triggering and sustaining rejection after transplantation.

A preliminary indication that HLA-A*03:01 may be associated with visceral leishmaniasis development in people living with HIV in Ethiopia.

Human immunodeficiency virus (HIV) co-infection is a major challenge for visceral leishmaniasis (VL) control, particularly in Ethiopia where the incidence of both pathogens is high. VL-HIV often leads to high rates of antileishmanial treatment failure and recurrent VL disease relapses. Considering the high prevalence of HIV and Leishmania in the Ethiopian population, preventing the progression of asymptomatic Leishmania infection to disease would be a valuable asset to VL disease control and to the clinical management of people living with HIV (PLWH). However, such a strategy requires good understanding of risk factors for VL development. In immunocompetent individuals living in Brazil, India, or Iran, the Human Leukocyte Antigen (HLA) gene region has been associated with VL development. We used NanoTYPE, an Oxford Nanopore Technologies sequencing-based HLA genotyping method, to detect associations between HLA genotype and VL development by comparing 78 PLWH with VL history and 46 PLWH that controlled a Leishmania infection, all living in a VL endemic region of North-West Ethiopia. We identified an association between HLA-A*03:01 and increased risk of VL development (OR = 3.89). These data provide candidate HLA alleles that can be further explored for inclusion in a potential Leishmania screen-and-treat strategy in VL endemic regions.

Skewed epithelial cell differentiation and premature aging of the thymus in the absence of vitamin D signaling.

Central tolerance of thymocytes to self-antigen depends on the medullary thymic epithelial cell (mTEC) transcription factor autoimmune regulator (Aire), which drives tissue-restricted antigen (TRA) gene expression. Vitamin D signaling regulates Aire and TRA expression in mTECs, providing a basis for links between vitamin D deficiency and autoimmunity. We find that mice lacking Cyp27b1, which cannot produce hormonally active vitamin D, display profoundly reduced thymic cellularity, with a reduced proportion of Aire+ mTECs, attenuated TRA expression, and poorly defined cortical-medullary boundaries. Markers of T cell negative selection are diminished, and organ-specific autoantibodies are present in knockout (KO) mice. Single-cell RNA sequencing revealed that loss of Cyp27b1 skews mTEC differentiation toward Ccl21+ intertypical TECs and generates a gene expression profile consistent with premature aging. KO thymi display accelerated involution and reduced expression of thymic longevity factors. Thus, loss of thymic vitamin D signaling disrupts normal mTEC differentiation and function and accelerates thymic aging.

A review of the genetics of type I diabetes

Type I diabetes susceptibility is caused by both environmental and genetic factors, the latter comprising approximately half of the total risk as evidenced by the fact that identical twins have approximately 50% concordance, suggesting 50% of the disease risk is environmental. The human leukocyte antigen (HLA) genes account for approximately half of the genetic risk, as demonstrated by the concordance between HLA identical siblings. Because environmental and genetic differences vary between racial groups, the incidence of type 1 diabetes (TID) differs across the world, being highest in Caucasians. Recent GWAS (genome-wide association studies) studies have suggested there may be up to 50 genomic regions contributing to the non-major histocompatibility complex (MHC) genetic risk contribution. This review presents and discusses the latest research on the MHC and non-MHC genes. Only the non-MHC regions, which have been confirmed in multiple studies and which are considered definite regions of genetic susceptibility, are included in the review.

Identification of novel bovine leukocyte antigen alleles and association of BoLA-DRB3.2*020:02:01 with resistance to Theileria orientalis infection in crossbred Kedah-Kelantan cattle: a pilot study.

The bovine leukocyte antigen (BoLA) gene is a significant genetic part of the immune system and has been used as a disease marker in cattle. In this study, we detected Theileria orientalis, T. sinensis, Anaplasma marginale, Anaplasma platys, Candidatus Mycoplasma haemobos and Trypanosoma evansi by PCR amplification and sequencing of the amplicons. The allelic association of the BoLA-DRB3.2 gene with blood pathogen disease resistance and susceptibility in 87 Kedah-Kelantan x Brahman (KKB) and 38 Bali cattle was determined by Fisher's exact test and Cochran Mantel Haenszel (CMH) correction test. Sequence-based typing of the BoLA-DRB3.2 gene identified 43 alleles (27 previously reported alleles and 16 novel alleles) across the two cattle breeds. Alignment analysis of the 16 novel alleles revealed 90.7-95.8% and 85-92% nucleotide and amino acid identities, with the reference allele, BoLA-DRB3*016:01 cDNA clone NR-1. BoLA-DRB3*009:02 (25.6%) and BoLA-DRB3*036:01 (36%) were the most frequent alleles in KKB and Bali cattle, respectively. In KKB cattle, BoLA-DRB3*020:02:01 was significantly associated with resistance to T. orientalis whereas *007:01 and *009:02 were significantly associated with resistance to C. Mycoplasma haemobos. Also, DRB3*017:01 was associated with susceptibility to T. orientalis in KKB cattle. In the Bali cattle, BoLA-DRB3*015:01 was found to be a genetic marker of susceptibility to C. Mycoplasma haemobos infection. Therefore, this study identified BoLA-DRB3.2 alleles associated with resistance and susceptibility to T. orientalis infection in KKB cattle and susceptibility to C. Mycoplasma haemobos infection in Bali cattle for the first time. Therefore, this study suggests that these BoLA-DRB3 resistance alleles could be used as candidate markers for selection, whereas susceptibility alleles could be used as candidate markers for culling in the beef industry.

The Zpr-3 Antibody Recognizes the 320-354 Region of Rho and Labels Both Rods and Green Cones in Zebrafish.

Retinal markers with high quality and specificity are important for the observation of pathologic changes of retinal cells during retinal development, degeneration, and regeneration. The zpr-3 antibody is widely used to label rods in zebrafish, but the exact antigen is still unknown. In this study, we provided evidence to demonstrate that the antigen gene of zpr-3 is rho, which encodes the rod opsin, and the exact epitope of zpr-3 is the 320-354 region of Rho protein. More importantly, our immunofluorescence assays indicated that zpr-3 labels both the outer segments of rods and green cones on zebrafish retinal sections, probably due to the cross-reaction with the green-cone opsin. Our work is valuable for the scientific community to interpret the experimental data involving the zpr-3 antibody.

Variation within the non-coding genome influences genetic and epigenetic regulation of the human leukocyte antigen genes.

Variation within the non-coding genome may influence the regulation and expression of important genes involved in immune control such as the human leukocyte antigen (HLA) system. Class I and Class II HLA molecules are essential for peptide presentation which is required for T lymphocyte activation. Single nucleotide polymorphisms within non-coding regions of HLA Class I and Class II genes may influence the expression of these genes by affecting the binding of transcription factors and chromatin modeling molecules. Furthermore, an interplay between genetic and epigenetic factors may also influence HLA expression. Epigenetic factors such as DNA methylation and non-coding RNA, regulate gene expression without changing the DNA sequence. However, genetic variation may promote or allow genes to escape regulation by epigenetic factors, resulting in altered expression. The HLA system is central to most diseases, therefore, understanding the role of genetics and epigenetics on HLA regulation will tremendously impact healthcare. The knowledge gained from these studies may lead to novel and cost-effective diagnostic approaches and therapeutic interventions. This review discusses the role of non-coding variants on HLA regulation. Furthermore, we discuss the interplay between genetic and epigenetic factors on the regulation of HLA by evaluating literature based on polymorphisms within DNA methylation and miRNA regulatory sites within class I and Class II HLA genes. We also provide insight into the importance of the HLA non-coding genome on disease, discuss ethnic-specific differences across the HLA region and provide guidelines for future HLA studies.

HLA-Cw6 Polymorphism in Autoimmune Blistering Diseases.

Autoimmune blistering diseases of the pemphigus and pemphigoid groups are immune-mediated disorders due to circulating pathogenetic autoantibodies. Multiple human leukocyte antigen (HLA) genes have been associated with predisposition to these disorders. HLA-Cw6 is involved in antigen presentation processes and has been linked to psoriasis. The aim of our study was to investigate the association between the presence of the HLA-Cw6 allele and susceptibility to pemphigus vulgaris and bullous pemphigoid. A genetic study in vitro with a cross-sectional design was performed enrolling forty patients with pemphigus vulgaris and forty patients with bullous pemphigoid. The detection of HLA-Cw6 was performed through the EUROArray test on DNA obtained from whole blood samples. The polymorphism was detected in 3/40 genotypes in the pemphigus vulgaris group and in 4/40 genotypes of patients with bullous pemphigoid, unveiling a non-statistically significant different frequency in pemphigus (p = 0.6368) and in pemphigoid (p = 0.62) compared to the reference frequency from the literature of 0.086. Further research is needed to better investigate the role of HLA-Cw6 in immune-mediated diseases and to identify novel genetic markers associated with susceptibility to autoimmune blistering diseases and with disease severity and response to immunosuppressive therapies.

Immunogenetic profiles of 9 human herpes virus envelope glycoproteins

Human herpes viruses (HHV) are ubiquitous and have been implicated in numerous long-term health conditions. Since the association between viral exposure and long-term health impacts is partially influenced by variation in human leukocyte antigen (HLA) genes, we evaluated in silico the binding affinities of 9 HHV envelope glycoproteins with 127 common HLA Class I and Class II molecules. The findings show substantial variability in HHV binding affinity across viruses, HLA Class, HLA genes, and HLA alleles. Specific findings were as follows: (1) the predicted binding affinities of HHVs were characterized by four distinct groupings—[HHV1, HHV2], [HHV3, HHV4, HHV5], [HHV6A], [HHV6B, HHV7, HHV8]—with relatively lower binding affinities for HHV1, HHV2, and HHV6a compared to other HHVs; (2) significantly higher binding affinity was found for HLA Class I relative to Class II; (3) analyses within each class demonstrated that alleles of the C gene (for Class I) and DRB1 gene (for Class II) had the highest binding affinities; and (4) for each virus, predicted binding affinity to specific alleles varied, with HHV6a having the lowest affinity for HHV-HLA complexes, and HHV3, HHV4, and HHV5 having the highest. Since HLA-antigen binding is the first step in initiating an immune response to foreign antigens, these relative differences in HHV binding affinities are likely to influence long-term health impacts such that the cells infected with viruses associated with higher binding affinities across common HLA alleles may be more reduced in numbers, thereby lowering the potential for long-term sequelae of their infections.

Nab-paclitaxel plus S-1 followed by gemcitabine-oxaliplatin as first-line alternating sequential treatment of pancreatic ductal adenocarcinoma.

Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC). This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes. Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months. The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867).

Research of recombinant influenza A virus as a vector for Mycoplasma pneumoniae P1a and P30a.

Mycoplasma pneumoniae (MP) is a common respiratory pathogen affecting the longevity of the elderly and the health of children. However, the human vaccine against MP has not been successfully developed till now due to the poor immunogenicity and side effects of MP inactivated or attenuated vaccine. Therefore, it is necessary to develop a MP genetic engineering vaccine with influenza virus strain as vector. In this study, the major antigen genes P1a of MP adhesion factor P1(3862-4554 bases) and P30a of P30(49-822 bases) were inserted into the nonstructural protein (NS) gene of Influenza A virus strain A/Puerto Rio/8/34(H1N1), PR8 for short, to construct the recombinant vectors NS-P1a or NS-P30a. The recombinant pHW2000 plasmids containing NS-P1a or NS-P30a were cotransfected with the rest 7 fragments of PR8 into HEK293T cells. After inoculating chicken embryos, the recombinant influenza viruses rFLU-P1a and rFLU-P30a were rescued. RT-PCR and sequencing were used to identify the recombinant viruses. The hemagglutination titers of rFLU-P1a and rFLU-P30a were determined after five successive generations in chicken embryos so as to indicate the genetic stability of the recombinant viruses. The morphology of recombinant influenza viruses was observed under electron microscopy. P1a or P30a was designed to be inserted into the modified NS gene sequence separately and synthesized successfully. RT-PCR identification of the recombinant viruses rFLU-P1a and rFLU-P30a showed that P1a (693 bp), P30a (774 bp), NS-P1a (1992bp) and NS-P30a (2073 bp) bands were found, and the sequencing results were correct. After five successive generations, each virus generation has a certain hemagglutination titer (from 1:32 to 1:64), and the band of P1a or P30a can be seen in the corresponding positions. The virus particles under the electron microscope appeared as spheres or long strips connected by several particles, revealing a complete viral membrane structure composed of virus lipid bilayer, hemagglutinin, neuraminidase, and matrix proteins. The recombinant viruses rFLU-P1a and rFLU-P30a which carried the advantaged immune regions of the P1 and P30 genes in MP were successfully constructed and identified. And the genetic stability of rFLU-P1a or rFLU-P30a was relatively high. The typical and complete morphology of influenza virus was observed under the electron microscope. Our research provided a foundation for the further development of MP vaccines for human.

Integrative analysis of the role of the DPH gene family in hepatocellular carcinoma and expression validation.

The diphthamide (DPH) gene family is a group of genes that encode a set of enzymes that specifically modify eukaryotic elongation factor 2 (eEF2). Although previous studies have shown a link between the DPH genes (DPHs) and carcinogenesis, it is still unknown how the DPHs affect hepatocellular carcinoma (HCC). This study aimed to describe the expression, clinical significance, and potential mechanisms of DPHs in HCC. Real-time quantitative polymerase chain reaction (RT-qPCR), Genotype-Tissue Expression (GTEx), and The Cancer Genome Atlas (TCGA) databases were utilized to research the expression of DPHs in HCC. The relationship between the expression of DPHs and the clinicopathological characteristics of HCC patients was investigated using TCGA data, and their diagnostic value was evaluated using receiver operating characteristic (ROC) curves and their prognostic value was analyzed using Kaplan-Meier curves and univariate and multivariate Cox regression analyses. Potential reasons for the upregulation of DPH2 and DPH3 (DPH2,3) expression in HCC were analyzed using multiple databases. Additionally, this study also explored the potential biological functions of DPH2,3 in HCC via gene sets enrichment analysis (GSEA). Correlation analysis of DPH2,3 expression with immune-related genes and immune checkpoints was performed using Spearman's correlation analysis, and single-sample GSEA was used to assess the distribution of tumor-infiltrating immune cell types. DPH1,7 expression was downregulated in tumor tissues while DPH2,3,5,6 expression was upregulated and showed a similar expression pattern in HCC. The results of the ROC analysis suggested that DPHs had valuable diagnostic properties in HCC. Kaplan-Meier analysis demonstrated that DPH2,3,7 had prognostic predictive value in HCC. Furthermore, univariate and multivariate Cox regression suggested that DPH2,3 was an independent predictive factor for HCC. GSEA analysis revealed that DPH2,3 might be tightly associated with Pathways in cancer, cell cycles, Fc gamma R mediated phagocytosis, etc. Additionally, DPH2,3 expression and numerous immune-related genes showed a positive connection, including chemokines receptor genes, immunosuppressive genes, chemokines genes, human leukocyte antigen (HLA) genes, and immunostimulatory genes. Further analysis of the association between 24 immune infiltrating cells and DPH2,3 revealed the greatest negative correlation between natural killer (NK) cells and Th17 cells, but the greatest positive correlation with Th2 cells. DPHs significantly influence the development and progression of HCC. DPH2,3 has significant diagnostic and prognostic potential and may be a promising target for immunotherapy.

Neutrophil estimation and prognosis analysis based on existing lung squamous cell carcinoma datasets: the development and validation of a prognosis prediction model.

Notwithstanding the rapid developments in precision medicine in recent years, lung cancer still has a low survival rate, especially lung squamous cell cancer (LUSC). The tumor microenvironment (TME) plays an important role in the progression of lung cancer, in which high neutrophil levels are correlated with poor prognosis, potentially due to their interactions with tumor cells via pro-inflammatory cytokines and chemokines. However, the precise mechanisms of how neutrophils influence lung cancer remain unclear. This study aims to explore these mechanisms and develop a prognosis predictive model in LUSC, addressing the knowledge gap in neutrophil-related cancer pathogenesis. LUSC datasets from the Xena Hub and Gene Expression Omnibus (GEO) databases were used, comprising 473 tumor samples and 195 tumor samples, respectively. Neutrophil contents in these samples were estimated using CIBERSORT, xCell, and microenvironment cell populations (MCP) counter tools. Differentially expressed genes (DEGs) were identified using DEseq2, and a weighted gene co-expression network analysis (WGCNA) was performed to identify neutrophil-related genes. A least absolute shrinkage and selection operator (LASSO) Cox regression model was constructed for prognosis prediction, and the model's accuracy was validated using Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC) curves. Additionally, genomic changes, immune correlations, drug sensitivity, and immunotherapy response were analyzed to further validate the model's predictive power. Neutrophil content was significantly higher in adjacent normal tissue compared to LUSC tissue (P<0.001). High neutrophil content was associated with worse overall survival (OS) (P=0.02), disease-free survival (DFS) (P=0.02), and progression-free survival (PFS) (P=0.03) using different software estimates. Nine gene modules were identified, with blue and yellow modules showing strong correlations with neutrophil prognosis (P<0.001). Eight genes were selected for the prognostic model, which accurately predicted 1-, 3-, and 5-year survival in both the training set [area under the curve (AUC) value =0.60, 0.63, 0.66, respectively] and validation set (AUC value =0.58, 0.58, 0.59, respectively), with significant prognosis differences between high- and low-risk groups (P<0.001). The model's independent prognostic factors included risk group, pathologic M stage, and tumor stage (P<0.05). A further molecular mechanism analysis revealed differences between risk groups were revealed in immune checkpoint and human leukocyte antigen (HLA) gene expression, hallmark pathways, drug sensitivity, and immunotherapy responses. This study established a risk-score model that effectively predicts the prognosis of LUSC patients and sheds light on the molecular mechanisms involved. The findings enhance the understanding of neutrophil-tumor interactions, offering potential targets for personalized treatments. However, further experimental validation and clinical studies are required to confirm these findings and address study limitations, including reliance on public databases and focus on a specific lung cancer subtype.

Deciphering the Genetic Landscape: Exploring the Relationship Between HLA-DQA1, HLA-DQB1, and HLA-DRB1 Genes in Diabetes Mellitus

Abstract: Diabetes mellitus (DM) is a complex and multifactorial metabolic disorder with a significant genetic component. The human leukocyte antigen (HLA) genes, specifically HLA-DQA1, HLA-DQB1, and HLA-DRB1, have been implicated in the susceptibility and pathogenesis of DM. This review delves into the intricate interplay of these HLA genes, seeking to unravel the genetic tapestry that contributes to the development and progression of diabetes. We begin by providing an overview of the HLA system and its critical role in immune regulation. Subsequently, we explore the current state of knowledge regarding the association between HLA-DQA1, HLA-DQB1, and HLADRB1 polymorphisms and susceptibility to both type 1 and type 2 diabetes. Emphasis is placed on recent advancements in genetic research methodologies, including genomewide association studies and next-generation sequencing, that have provided deeper insights into the genetic architecture of DM. The review also scrutinizes the functional implications of specific HLA alleles in modulating immune responses and the potential mechanisms by which they contribute to the autoimmune processes observed in type 1 diabetes. Additionally, we examine the role of HLA genes in the context of insulin resistance and beta-cell dysfunction in type 2 diabetes, shedding light on the shared and distinct genetic underpinnings of these two major forms of DM. Furthermore, we discuss the clinical implications of HLA genotyping in predicting disease risk, prognosis, and personalized treatment strategies. The integration of genetic information into clinical practice holds promise for precision medicine approaches in diabetes management.

Machine learning developed a macrophage signature for predicting prognosis, immune infiltration and immunotherapy features in head and neck squamous cell carcinoma

Macrophages played an important role in the progression and treatment of head and neck squamous cell carcinoma (HNSCC). We employed weighted gene co-expression network analysis (WGCNA) to identify macrophage-related genes (MRGs) and classify patients with HNSCC into two distinct subtypes. A macrophage-related risk signature (MRS) model, comprising nine genes: IGF2BP2, PPP1R14C, SLC7A5, KRT9, RAC2, NTN4, CTLA4, APOC1, and CYP27A1, was formulated by integrating 101 machine learning algorithm combinations. We observed lower overall survival (OS) in the high-risk group and the high-risk group showed elevated expression levels in most of the immune checkpoint and human leukocyte antigen (HLA) genes, suggesting a strong immune evasion capacity. Correspondingly, TIDE score positively correlated with risk score, implying that high-risk tumors may resist immunotherapy more effectively. At the single-cell level, we noted macrophages in the tumor microenvironment (TME) predominantly stalled in the G2/M phase, potentially hindering epithelial-mesenchymal transition and playing a crucial role in the inhibition of tumor progression. Finally, the proliferation and migration abilities of HNSCC cells significantly decreased after the expression of IGF2BP2 and SLC7A5 reduced. It also decreased migration ability of macrophages and facilitated their polarization towards the M1 direction. Our study constructed a novel MRS for HNSCC, which could serve as an indicator for predicting the prognosis, immune infiltration and immunotherapy for HNSCC patients.