Search Results (420)

Cervical cancer remains a major global public health concern, with persistent infection by high-risk human papillomavirus (hrHPV) types recognized as the primary etiological factor. This review explores the multifactorial nature of the disease, focusing on the complex interplay between host genetic susceptibility and epigenetic alterations that drive cervical carcinogenesis. Evidence from genome-wide association studies (GWAS) is discussed, highlighting the contribution of specific genetic loci, predominantly within the HLA region, to susceptibility to HPV infection and disease progression. In parallel, the review examines the molecular mechanisms by which the viral oncoproteins E6 and E7 promote genetic instability and epigenetic reprogramming, including histone modifications and dysregulation of non-coding RNAs. Particular emphasis is placed on DNA methylation, affecting both the viral genome and host genes such as FAM19A4, CADM1, PAX1, and MAL, as a promising biomarker for triage and detection of high-grade intraepithelial lesions (CIN2+). Finally, the review evaluates currently available methylation-based assays and self-sampling devices, highlighting their potential to enhance diagnostic accuracy and increase participation in cervical cancer screening programs. Full article

Background: Interindividual differences in statin efficacy and tolerability are partly determined by genetic and metabolic factors. The SLCO1B1 c.521T>C polymorphism affects hepatic statin transport, while vitamin D deficiency may influence lipid metabolism and muscular tolerance. This study aimed to assess the impact of SLCO1B1 genotype and vitamin D status on lipid-lowering response and adverse events in postmenopausal women treated with atorvastatin or rosuvastatin. Methods: A total of 145 Croatian postmenopausal women were prospectively followed for 16 weeks. Participants received atorvastatin or rosuvastatin with dose titration to achieve low-density lipoprotein cholesterol (LDL-C) targets. Serum lipids, liver enzymes, and creatine kinase were monitored monthly. Serum levels of 25-hydroxyvitamin D were quantified by LC–MS/MS, while SLCO1B1 c.521T>C genotyping was performed using real-time PCR. Results: Rosuvastatin achieved a higher LDL-C target attainment rate compared with atorvastatin (81.1% vs. 67.6%, p = 0.02). The SLCO1B1 genotype was not associated with lipid response but was significantly associated with adverse effects. In multivariable regression analysis, patients with the T/C genotype had a significantly higher risk of developing adverse effects compared with those with the T/T genotype (OR 7.4, 95% Cl 2.1–26.7, p = 0.002). Vitamin D status showed no significant association with lipid outcomes or adverse events, although participants with severe deficiency exhibited a weaker LDL-C response. Conclusions: Rosuvastatin demonstrated superior lipid-lowering efficacy and tolerability compared with atorvastatin in postmenopausal women. The SLCO1B1 c.521T>C variant primarily affected safety rather than efficacy, while severe vitamin D deficiency might contribute to diminished statin response. Integrating pharmacogenetic and endocrine profiling could enhance individualized statin therapy and cardiovascular prevention in women. Full article

Background/Objectives: The enhancement of antitumor immune responses by radiotherapy (RT) is partially attributed to the activation of the IFN-type-I pathway. However, the loss of HLA-class-I molecules, which occurs in a large percentage of non-small-cell lung cancers (NSCLCs), may block the cytotoxic effect of T-cells and immunotherapy (IO). Moreover, autophagy is also involved in HLA downregulation. We investigated the complex interactions between RT, HLA molecules, autophagy, and IFN-type-I responses. Methods: The A549, H1299, and ATG7-deficient NSCLC cell lines, along with the modified shLC3A H1299 cell line, were used for in vitro experiments. The effect of RT (8 and 3 × 8 Gy) on Interferon beta (IFNβ), IFN-stimulated genes (ISGs), and HLA-class-I expression in combination with IFN-type-I-response inhibitors (Ruxolitinib, Tofacitinib, Amlexanox) targeting the JAK and TBK1 was studied with Flow cytometry and RT-PCR. Results: RT significantly induced HLA-class-I expression. A parallel upregulation of IFNβ and ISGs mRNA levels was also documented. Although the IFN-type-I-response inhibitors suppressed the RT-induced IFNβ and ISGs expression, their effect on HLA-class-I expression was minimal. Blockage of LC3A autophagy (shLC3A cell line) significantly upregulated HLA-class-I basal levels, and RT further enhanced HLA expression. IFN-type-I-response inhibitors blocked the RT-inductive effect in the shLC3A H1299, but had no effect in the ATG7-deficient H1650 cell line. Conclusions: The current study supports the theory that baseline autophagy, RT-induced autophagy blockage, and IFN-type-I response enhancement define the HLA-class-I levels in NSCLC cells. This complex interplay emerges as a promising target for the development of radio-vaccination strategies to enhance the efficacy of radio-immunotherapy. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) show durable efficacy in tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), yet clinical responses remain heterogeneous. This study aimed to define immune subgroups within dMMR/MSI-H tumors and develop a reproducible transcriptomic signature predictive of ICI response. Methods: Four MSI-H-enriched cancer types (UCEC, COAD, READ, STAD) from The Cancer Genome Atlas were analyzed. Tumors were stratified by immune cell infiltration (MCP-counter immune composite score) and T-cell-inflamed gene expression profiles (GEP score). Integrating these two axes defined four immune subgroups. Differential expression, random forest feature selection, and pathway enrichment were performed to identify immune programs. A 20-gene immune signature representing the most immune-active subgroup was developed and validated across TCGA, GEO (GSE39582), and IMvigor210 cohorts. Results: Among the four subgroups, the most immune-active group showed strong activation of interferon signaling, antigen presentation, and T-cell-mediated pathways. The 20-gene signature—including CD74, STAT1, TAP1, and HLA-class genes—achieved high reproducibility (mean AUC = 0.95 ± 0.02; accuracy ≈ 89%). In the IMvigor210 cohort, this signature identified tumors with higher PD-L1 blockade response (55.6% vs. 32.8%, p = 0.034) and improved survival trends in the TMB-high subset. Conclusions: The proposed 20-gene signature quantitatively captures immune heterogeneity in dMMR/MSI-H tumors and serves as a practical, interpretable biomarker to identify true ICI responders and guide precision immunotherapy. Full article

Introduction: Allogeneic penetrating limbo-keratoplasty (limbo-PK) is one of the surgical methods for the treatment of limbal stem cell deficiency (LSCD). We report real-life results on different entities. Methods: Patients treated with limbo-PK at the Department of Ophthalmology of the University Medical Center Mainz were evaluated retrospectively. The primary endpoint was the epithelialization of the graft one year postoperatively. In addition, the postoperative best corrected visual acuity (BCVA), ocular concomitant diseases, drug treatment, and the need for further eye surgery postoperatively were examined. Results: We included 14 eyes of 13 patients (4 female) aged 59.8 ± 14.1 years who underwent limbo-PK between 2020 and 2024. Indications for limbo-PK included chemical burns (n = 4), blast injuries (n = 4), thermal burns (n = 2), trauma (n = 1) graft-versus-host disease (n = 1), and ectrodactyly-ectodermal dysplasia (EEC) (n = 1). The mean preoperative BCVA was 2.2 ± 0.6 logMAR (range: light perception to 0.7 logMAR). Four limbo-PK-grafts were HLA-typed. All limbo-PKs were combined with amniotic membrane transplantation; three with cataract surgery and one with tarsorrhaphy. Postoperatively, all patients received local immunosuppression, and 12 (85.7%) received additional systemic immunosuppression. At one-year follow-up mean BCVA increased to 1.0 ± 0.7 logMAR (range: 2.3 to 0.1, p-value = 0.03) and 11 of 14 eyes showed a functional graft with closed epithelium. In the further postoperative course, four patients needed a further Limbo-PK due to graft failure (n = 2), immune graft rejection after stopping local immunosuppressive therapy (n = 1) and perforation of the graft in a severe case of GvHd (n = 1). Conclusions: Limbo-PK is an effective surgical method for the treatment of LSCD. In our study cohort, we observed a significant improvement in mean BCVA one year postoperatively, with a functional, epithelialized graft achieved in 11 of 14 eyes. Full article

Celiac disease (CeD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals, with a heterogeneous clinical spectrum spanning classical gastrointestinal symptoms, extraintestinal manifestations, and subclinical forms. We synthesize contemporary epidemiology, immunopathogenesis, and the updated 2025 European Society for the Study of Coeliac Disease diagnostic framework. Adaptive responses to deamidated gliadin peptides presented by human leukocyte antigen (HLA)-DQ2/DQ8, together with interleukin-15-driven activation of intraepithelial lymphocytes (IELs), culminate in villous atrophy, crypt hyperplasia, and increased IELs. Serology centered on tissue transglutaminase immunoglobulin A (tTG-IgA) with total immunoglobulin A assessment remains first-line, complemented by standardized duodenal sampling (≥4 distal + 2 bulb biopsies) and selective HLA typing. The guidelines conditionally endorse a no-biopsy pathway for adults <45 years with tTG-IgA ≥10× upper limit of normal confirmed on a second sample, emphasizing shared decision-making and exclusion of red flags. We delineate differential diagnoses (tropical sprue, Crohn’s disease, common variable immunodeficiency, small intestinal bacterial overgrowth) and contrast CeD with non-celiac gluten sensitivity, which lacks villous atrophy, disease-specific serology, and HLA association. Emerging tools (immunohistochemistry, CD3/CD8/γδ IELs, video capsule endoscopy, confocal laser endomicroscopy) and the limitations of salivary/fecal assays are reviewed. Early detection improves quality of life and reduces healthcare utilization. Future directions include artificial intelligence-assisted imaging, molecular immunophenotyping, and non-dietary therapeutics. Full article

The human leukocyte antigen (HLA) system plays a crucial role in regulating the immune response and is significant in organ transplantation, disease association studies, and population genetics. But does it influence longevity? The present study aims to explore the frequency of HLA alleles in a cohort of 100 individuals in the 65–90 age bracket from Romania, providing insights into genetic diversity and potential implications in longevity. High-resolution HLA typing was performed using next-generation sequencing (NGS) technology, allowing for precise identification of HLA alleles with a high degree of accuracy. The results reveal significant genetic diversity within the cohort, with prevalent alleles such as HLA-A*02:01:01:01, HLA-B*08:01:01:01, and DRB1*01:01:01:01 potentially influencing disease susceptibility and longevity. The study reveals the genetic diversity of HLA alleles in elderly Romanians, highlighting prevalent alleles that could be linked to longevity and disease resistance. Different results from previous research are attributed to the high-resolution analysis and small cohort size. Further studies with larger samples are needed to confirm findings and uncover their implications for healthy aging and healthcare. Full article

Establishing a mathematical model of a Francis turbine is the foundation for the simulation of hydropower station operation and is of great significance for the analysis of the hydropower station’s transient process. Currently, in engineering practice, the model is often established based on the comprehensive characteristic curves of the Francis turbine provided by the manufacturer, using the external characteristic method. Traditional modeling methods mostly adopt manual reading of points or the use of dedicated numerical software for curve tracing to discretely sample the comprehensive characteristic curves of the turbine. This method is labor-intensive, inefficient, and relies on manual experience, with a small sample size, which, to some extent, affects the accuracy and reliability of the numerical processing results and cannot meet the needs of transient process simulation analysis. To address these shortcomings, this paper proposes a refined modeling method based on image numerical processing and an RBF neural network. Taking the HLA685 Francis turbine as an example, the method first uses image processing to achieve large-scale automated discrete sampling of the turbine’s high-efficiency zone characteristic data, then reasonably extends the small-opening and low-speed regions, and finally uses the RBF neural network method for interpolation and extrapolation to obtain the full characteristic data. This method can effectively improve the efficiency and accuracy of comprehensive characteristic modeling of the turbine and has good reference significance for the comprehensive characteristic modeling of blade-type machinery. Full article

Background/Objectives: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with over 50% of individuals succumbing to the disease annually. This study aimed to assess the correlation between human leukocyte antigen (HLA) genes and acute myeloid leukemia (AML) in an adult Moroccan cohort. We included 60 persons with acute myeloid leukemia (AML) who were eligible for hematopoietic stem cell transplantation and compared them to a control group of 90 healthy adults. Methods: Patients and controls were subjected to HLA class I and II typing utilizing either sequence-specific primers (SSP) or sequence-specific oligonucleotides (SSO) in polymerase chain reaction-based methodologies. Results: The AML categories were predominantly represented by AML2, AML3, and AML4, comprising 36.66%, 30%, and 16.66%, respectively. We identified a notable correlation between HLA-A*11 (p = 0.003) and HLA-B*27 (p = 0.005) with acute myeloid leukemia (AML), and for HLA class II allele groups, we detected an elevated frequency of HLA-DQB1*05 (p = 0.002) in adult AML patients. We identified a notable correlation between AML 2 and the allele groups examined, namely with HLA class I: HLA-A*11 (p = 0.0003) and HLA-B*27 (p = 0.00006). Conclusion: Our study suggests a potential association between specific HLA alleles and the development of AML specifically AML type 2 in adults. Further larger studies are needed to confirm these findings. Full article

Background: Azathioprine (AZA)-associated acute pancreatitis (AP) and gastrointestinal intolerance (GI-INT) are major causes of drug discontinuation in inflammatory bowel disease (IBD). This study compared HLA alleles, demographics, and clinical variables between AZA-AP and AZA-GI-INT. Methods: Data from five IBD centers included control (n = 88), AZA-AP (n = 44), and GI-INT (n = 44) groups. AP was defined by the Atlanta criteria, and GI-INT as acute dyspeptic symptoms related to AZA that resolved after withdrawal. Demographics, disease features, and HLA-DQA1/DRB1 alleles were assessed for associations. Results: Among 176 patients, female sex was more frequent in AZA-AP and GI-INT than controls (p = 0.018, p < 0.001). AZA-AP patients were older at diagnosis vs. controls (p = 0.016) but not vs. GI-INT (p = 0.15). Smoking and alcohol were more common in AZA-AP. The median onset of AP was four weeks, with 91% occurring within three months. GI-INT occurred rapidly, with a median of one day and a maximum of three days after the first dose. HLA-DQA1/DRB1 positivity was comparable in GI-INT and controls (9.2% vs. 14.8%, p = 0.42) but higher in AZA-AP (27.3% vs. 14.8%, p = 0.08). Regression identified female sex, smoking, alcohol, budesonide, and HLA-DQA1/DRB1 positivity (OR 3.01, 95% CI 1.004–9.058; p = 0.049) as independent risk factors for AZA-AP. Conclusions: AZA-AP, but not GI-INT, appears genetically influenced, with HLA-DQA1/DRB1 association extending across populations. In IBD, AZA-AP usually emerges within three months and is linked to female sex, smoking, alcohol, and budesonide. GI-INT typically develops within hours to three days of initiation. These findings support AZA-AP and GI-INT as distinct idiosyncratic entities shaped by genetic, metabolic, and sensitivity factors. Full article

Background: Postoperative delirium (POD) is known to involve systemic inflammatory responses, but the characteristics of the immune cell types involved in these responses are unclear. Methods: In this prospective study, we compared relative abundances and transcriptomes of circulating immune cells between patients who experienced POD (n = 11) or not (n = 109) within 7 days after elective cardiac surgery with cardiopulmonary bypass. Blood was sampled before and at 24 h after surgery; features of immune cells were profiled using multi-channel spectral flow cytometry, 10× single-cell RNA sequencing, and measurement of plasma levels of cytokines. Results: Patients with POD were older and with higher incidence of congestive heart failure than patients without POD, and these risk factors in turn positively correlated with preoperative proportion of CD40+/HLA-DR+ monocytes and CD69+CD8+ T cells. In addition, preoperative activation of antigen presentation in monocytes and chemotaxis in CD8+ T cells, as well as elevated plasma levels of chemokines CCL3 and CXCL8, were detected in patients with POD. After cardiac surgery, activation of antigen presentation and chemotaxis were also found in patients with POD. Conclusions: This study described the perioperative landscape of immune cells in POD and found possible links between preoperative immune dysfunction and risk factors, which may guide future research to explore how the immune system contributes to POD and to design preventive strategies. Full article

Preeclampsia (PE) is a serious gestational complication that affects the lives of the mother and the child. Women with PE showed higher levels of pro-inflammatory cytokines secreted by leukocytes compared with women with normal pregnancies. The differences are most noticeable in the percentage of CD16+ monocytes, although the mechanism underlying this increase remains unclear. The CD16 receptor is critical for antibody-dependent cellular cytotoxicity, and by binding to antibodies on the surface of target cells, it activates their death. In this study, we examined the effect of soluble placental factors on the expression of CD16 monocytes and the potential role the soluble form of human leukocyte antigen (HLA) has on CD16 monocyte expression. At the first stage of our study, we collected samples of placental villi fragments from 58 pregnant women (38 women with PE and 20 with a healthy pregnancy). Then we studied the effect of placental villus-conditioned culture medium on CD16 expression by monocytes derived from the same women. It was shown that the content of CD16+ monocytes increased significantly in women with PE within 3 h and to a lesser extent in women with a healthy pregnancy (p = 0.009). Also, the addition of the recombinant histocompatibility HLA-B to the placental villus-conditioned culture medium blocks the induction of CD16 expression on monocytes. At the second stage of our study, we typed HLA class I and class II alleles in the umbilical cord blood samples and the venous blood samples taken from 38 women with PE and 40 women with a normal pregnancy. It was found that certain HLA class II alleles predominate in women with preeclampsia. The DRB1*01:01:01G allele showed the greatest difference (p < 0.001). Analyzing five alleles simultaneously makes it possible to predict the PE with AUC = 0.76. Evaluation of unique children’s alleles also showed that class II alleles have greater differences among them than class I alleles. The DQB1*06:03:01G allele had the greatest differences with p = 0.03 (the number was higher in the control group). Performing an analysis of four alleles of children simultaneously allowed us to predict PE with an AUC of 0.64. This work suggests that the activation of CD16+ monocyte expression occurs due to the interaction of soluble placental antigens with monocytes. The most likely way to activate CD16 expression on monocytes is by HLA class II (both maternal and fetal) interaction with CD4 receptors on the surface of monocytes, whereas HLA class I is capable of blocking this process. Evaluation of maternal HLA alleles may be a significant marker for predicting PE. Full article

Background: Accurate human leukocyte antigen (HLA) genotyping is a critical step in the implementation of neoantigen peptide-based cancer immunotherapy. Existing computational tools for HLA genotyping using high-throughput sequencing data often lack sufficient accuracy when used individually. Employing an ensemble of multiple software tools and sequencing sources can potentially address this limitation; however, this approach is hindered by increased processing time. Methods: We evaluated an ensemble method that utilizes four HLA-genotyping software tools applied to three sequencing sources—tumor exome, normal exome, and tumor RNA-seq—from the same individual to achieve high-confidence HLA genotyping. To reduce processing time, we incorporated an HLA region-specific FASTQ read-filtering strategy. With this protocol we also provide a Docker implementation of the FASTQ read-filtering pipeline and a software tool for the analysis of HLA genotypes. Results: Consensus HLA genotypes for HLA class I alleles, derived from filtered FASTQ files, showed complete concordance with those obtained from unfiltered original FASTQ files. The use of filtered FASTQ files significantly reduced the time required for HLA genotyping. Conclusions: These findings demonstrate the utility of the proposed HLA genotyping approach in achieving rapid and high-confidence two-field HLA genotyping. Full article

Background: Fixed drug eruption (FDE) is a non-immediate, CD8+ T cell–mediated hypersensitivity reaction characterized by well-demarcated erythematous–violaceous plaques that recur at the same site after re-exposure to the causative drug. Although NSAIDs and antibiotics are the most common triggers, various other medications may induce FDE, and genetic susceptibility has been linked to specific HLA alleles. Methods: We conducted a clinical evaluation supported by patch testing, oral drug provocation, and assessment of therapeutic alternatives to identify the causative agent and confirm delayed-type hypersensitivity. Results: We report the case of a 53-year-old woman with essential hypertension, autoimmune thyroiditis, and renal lithiasis who developed well-demarcated erythematous plaques with central vesiculation and moderate pruritus on the dorsal hand and posterior calf approximately 8 h after ingestion of a 60 mg etoricoxib tablet. Patch testing was negative, while oral challenge confirmed etoricoxib-induced FDE; celecoxib was subsequently evaluated as a potential safe alternative. Conclusions: This case underscores the importance of an integrated diagnostic approach—including careful history, clinical examination, and confirmatory testing—to accurately diagnose delayed cutaneous drug reactions and to identify safe therapeutic options for patients. Full article

Background: Ulcerative colitis (UC) is a major form of inflammatory bowel disease affecting the gastrointestinal tract. Increasing evidence suggests UC is predisposed to co-occurring with other autoimmune diseases, yet its pathogenesis remains insufficiently understood. Large-scale biobank-based cross-trait genetic analyses may provide insights into the origins of UC and its comorbidities. Methods: Using the UK Biobank and Mount Sinai BioMe Biobank, we conducted genome-wide association studies (GWASs) in individuals of European ancestry. High-impact rare variants were aggregated for collapsing analysis. Genome-wide significant variants were tested in a phenome-wide association study (PheWAS) to explore UC comorbidities. Polygenic risk scores (PRSs) were derived from large-scale GWASs under different thresholds and functionalities, and the best-performing PRS was further applied in a PRS-based PheWAS. Genetic correlation between UC and highly associated traits was evaluated. Results: GWASs identified four genome-wide significant loci, including two novel variants (rs2314757, p = 4.82 × 10⁻¹¹, OR = 0.81; rs6869382, p = 2.48 × 10⁻⁸, OR = 0.83) and two previously reported UC-associated sites (rs4654925, p = 1.85 × 10⁻⁸, OR = 0.84; rs2836882, p = 1.23 × 10⁻¹¹, OR = 0.78) outside the HLA region. The optimal PRS, constructed with SNPs at p < 0.05, conferred an odds ratio of 5.86 (95% CI: 5.05–6.86) for UC in individuals with the highest versus lowest quintile. Both variant- and PRS-based PheWASs consistently highlighted type 1 diabetes (T1D) as the most significant comorbidity, confirmed by genetic correlation analysis. Conclusions: This study reveals novel loci contributing to UC and highlights comorbidities with shared genetic bases. UC PRSs demonstrated strong utility beyond risk prediction, effectively identifying UC-associated traits. A robust genetic correlation was established between UC and T1D. Full article