Ovarian cancer (OC) is a lethal malignancy often diagnosed at a late stage with frequent recurrence and immunotherapy resistance. PANoptosis is a novel programmed cell death regulating tumors and immunity. We constructed a prognostic model based on PANoptosis-related genes (PRGs) and evaluated its value for predicting immunotherapy response and survival in OC.

Noninvasive prenatal testing (NIPT) has been widely used in various monogenic recessive disorders based on relative haplotype dosage (RHDO) analysis. We accepted a congenital adrenal hyperplasia (CAH) pedigree with highly similar parental pathogenic haplotypes. The initial monogenic NIPT attempt was unsuccessful due to a paucity of informative single-nucleotide polymorphisms (SNPs), prompting improvement of the current method. With a refined algorithm that deduces the fetal genotype based on dosage changes at SNPs located on a specific parental haplotype, while also effectively sidestepping allele bias introduced by hybrid capture, monogenic NIPT was successfully carried out in this family, yielding results consistent with invasive prenatal diagnosis. Theoretically, this algorithm can be employed in scenarios involving consanguineous marriages or when parents share a highly homologous haplotype, thereby broadening its applicability. Detailed methodology is described, and the advantages of our algorithm are discussed.

Tumor microenvironment (TME) is a significant factor regulating the malignant phenotype and drug resistance of kidney renal clear cell carcinoma (KIRC). The identification of biomarker signatures mediating immune infiltration in TME is of significance for prognostic assessment and personalized therapy of KIRC.

Cystic fibrosis (CF) is the most common life-shortening monogenic autosomal recessive disease in Caucasians with diverse and extensive comorbidities. Where the majority of studies have focused on the respiratory and digestive systems, there has been a paucity of research focusing on pain, even though people living with CF have reported a high prevalence and increased severity of pain. Many studies have identified the complex relationship between genotype and phenotype, and growing evidence suggests that the phenotypic variation observed not only depends on the variations in the CF transmembrane conductance regulator () gene but also on modifier genes. Gene modifiers (GMs) have been reported to affect many organs or systems in CF. However, there have been no studies on how GMs may influence pain. Therefore, this study is aimed at highlighting potential modifier genes that may affect pain perception in CF and possible responses to therapeutics.

RyR1-related disorders, arising from variants in the RYR1 gene encoding the skeletal muscle ryanodine receptor, encompass a wide range of dominant and recessive phenotypes. The extensive length of RyR1 and diverse mechanisms underlying disease variants pose significant challenges for clinical interpretation, exacerbated by the limited performance and biases of current variant effect predictors (VEPs). This study evaluates the efficacy of 70 VEPs for distinguishing pathogenic RyR1 missense variants from putatively benign variants derived from population databases. Existing VEPs show variable performance. Those trained on known clinical labels show greater classification performance, but this is likely inflated by data circularity. In contrast, VEPs using methodologies that avoid or minimise training bias show limited performance, likely reflecting difficulty in identifying gain-of-function variants. Leveraging protein structural information, we introduce Spatial Proximity to Disease Variants (SPDV), a novel metric based solely on three-dimensional clustering of pathogenic mutations. We determine ACMG/AMP PP3/BP4 classification thresholds for our method and top-performing VEPs, allowing us to assign PP3/BP4 evidence levels to all RyR1 missense variants of uncertain significance. Thus, we suggest that our protein structure-based approach represents an orthogonal strategy over existing computational tools for aiding in the diagnosis of RyR1-related diseases.

Colorectal cancer is acknowledged as the fifth most common cause of cancer-related mortality, presenting significant challenges for patient outcomes due to its relatively gradual progression and the subtle nature of its initial symptoms. Carbohydrates, essential nutrients in cellular function, participate in various metabolic processes, including glycolysis, oxidative phosphorylation, and the pentose phosphate pathway. Recent studies have established that irregularities in carbohydrate metabolism play a critical role in tumor cell growth, development, and treatment resistance. Glycolysis serves as a crucial regulatory component of metabolism in cancer cells, influencing cell growth, proliferation, and functionality by modifying carbohydrate utilization. By diminishing oxidative phosphorylation activity and enhancing energy production through glycolysis, tumor cells augment their proliferative capacity and partially evade immune responses. As a result, glycolysis significantly contributes to tumor progression. We have comprehensively outlined the functions of glycolysis and its key enzymes concerning the diagnosis, treatment strategies, and immune microenvironment of colorectal cancer, with the goal of delivering innovative insights and perspectives for the clinical management and diagnosis of this condition.

Glucokinase regulatory protein (GCKR) is a metabolic regulator implicated in glucose homeostasis, but its genetic and functional roles in cancer remain poorly understood. Through integrated pan-cancer multiomics and experimental analyses, we mapped the expression and mutational landscape of GCKR with a focus on gastric cancer. GCKR expression was downregulated in most tumors but upregulated in subsets such as kidney renal papillary carcinoma (KIRP) and lung adenocarcinoma (LUAD). Genomic profiling revealed recurrent alterations, with the highest mutation frequencies observed in sarcoma (SARC) and uterine corpus endometrial carcinoma (UCEC), and missense mutations representing the predominant variant type, particularly in breast cancer (BRCA). Functionally, reduced GCKR expression in gastric cancer was associated with an immune-cold phenotype characterized by diminished cytotoxic T cell infiltration, impaired antigen presentation, and metabolic reprogramming. Spatial transcriptomics and single-cell analyses highlighted compartment-specific heterogeneity and links with cancer-associated fibroblasts and macrophages. Clinically, low GCKR expression predicted poorer survival and reduced immunotherapy benefit, while higher expression indicated selective sensitivity to MEK inhibitors including refametinib and PD0325901. These findings define GCKR as both a mutation- and expression-driven biomarker that connects metabolic regulation with immune remodeling, offering translational value for prognosis and precision therapy in gastric cancer.

Polycystic ovary syndrome is a common clinical condition often linked to insulin resistance (IR) and primarily affects women at reproductive age. Previous research has indicated a close association between mitochondrial tRNA (mt-tRNA) mutations and this syndrome; however, the range of mt-tRNA mutations in PCOS-IR remains largely unclear. In this study, we examined mt-tRNA mutations in 302 Han Chinese women with PCOS-IR and 589 control subjects, identifying a novel m.7544C>T mutation potentially related to this syndrome. At the molecular level, the m.7544C>T mutation occurs at a highly conserved nucleotide within the anticodon stem of mt-tRNA, disrupting the 30C-40G base-pairing. Using cybrids cells derived from two individuals carrying this mutation and two controls without it, we observed that the m.7544C>T decreased the steady-state levels of tRNA, altered mitochondrial RNA transcripts, impaired the activities of respiratory chain enzymes and oxygen consumption rates (OCRs), compromised mitochondrial functions, and increased oxidative stress. Overall, our findings strongly suggest that the m.7544C>T mutation contributes to the development of PCOS-IR, offering new insights into the pathophysiology of PCOS-IR driven by tRNA mutation-induced mitochondrial dysfunction and oxidative stress.

Atrial fibrillation (AF) and atherosclerosis (ATH) are increasingly recognized as interconnected cardiovascular conditions with shared immune and inflammatory underpinnings. However, the molecular mechanisms linking their pathogenesis remain poorly defined.

Liver damage caused by chronic liver disease frequently leads to hepatic fibrosis. A pivotal step in the fibrotic process is the activation of hepatic stellate cells (HSCs). Previous studies have suggested that enhanced aerobic glycolysis is closely associated with HSC activation. However, a comprehensive analysis of the relationship between hepatic fibrosis and aerobic glycolysis remains lacking.

Prostate cancer (PCa) ranks among the most prevalent malignancies, with prognosis heavily influenced by diagnostic stage. The role of PANoptosis in T cell-based immunotherapy has garnered growing attention recently. This study is aimed at establishing a T cell-specific PANoptosis signature (TSPS) to predict prognosis and immunotherapy response in patients with PCa.

Epithelial ovarian cancer (EOC) ranks as the most lethal of gynecological cancers. Despite advances in therapeutic interventions that have marginally extended survival rates, the early detection and management of EOC pose significant hurdles. Consequently, identifying novel therapeutic targets is imperative for enhancing the survival outcomes of patients afflicted with this malignancy.

The biomarkers associated with gestational diabetes mellitus (GDM) remain incompletely understood. This article is aimed at investigating whether inflammatory factors may contribute as risk factors for GDM.

Microsatellite instability (MSI) serves as a crucial biomarker for immune checkpoint blockade therapy in colorectal cancer (CRC). However, only around 40% of MSI CRC patients benefit from ICB. Investigating the mechanisms underlying MSI CRC, particularly its association with cell death and the immune microenvironment, can provide insights to improve immunotherapy efficacy.

Head and neck squamous cell carcinoma (HNSCC) ranks second among men and sixth globally, with a notable increase in HPV-associated cases. However, the molecular underpinnings and immune landscape of HPV+ HNSCC remain incompletely understood. In this study, we first retrieved and harmonized single-cell RNA sequencing (RNA-Seq), bulk RNA-Seq, and spatial transcriptomic profiles from public repositories. We then applied high-dimensional weighted gene coexpression network analysis (hdWGCNA) and gene nonnegative matrix factorization (GeneNMF) to dissect HPV+ epithelial subpopulations, their extracellular matrix (ECM)-interacting ligand programs, and CXCL/complement immune circuits. Furthermore, we mapped the spatial niches of malignant and immune cells and constructed a consensus prognostic index using 101 machine learning algorithms. Our findings revealed transcriptionally distinct HPV+ epithelial clusters that activate viral oncogenesis, inflammatory pathways, and ECM-sensing pathways. These cells communicate with stromal and immune compartments via CXCL axes and complement cascades, yet they are spatially segregated from lymphocytes. A high-risk signature, identified as HPV-related risk genes including TRMT112, stratified the TCGA-HNSC and GSE65858 cohorts into patients with markedly worse 1-, 2-, and 3-year survival rates (ROC-AUC 0.934, 0.968, and 0.973) and poor responses to immunotherapy. Notably, TRMT112 expression inversely correlated with cytotoxic T-cell infiltration, mechanistically linking it to the formation of "cold" tumors. Our integrative analysis defines HPV-driven epithelial subpopulations whose TRMT112-enriched, immune-excluded microenvironment contributes to therapeutic resistance, thus providing robust prognostic biomarkers and actionable targets for precision immunotherapy in HPV+ HNSCC.

Genomic matchmaking-the process of identifying individuals with overlapping phenotypes and rare variants in the same gene-is an important tool facilitating gene discoveries for unsolved rare genetic disease (RGD) patients. Current approaches are two-sided, meaning both patients being matched must have the same candidate gene flagged. This limits the number of RGD patients eligible for matchmaking. One-sided matchmaking, in which a gene of interest is queried in the genome-wide sequencing data of RGD patients, would make matchmaking possible for previously undiscoverable individuals. However, platforms and workflows for this approach have not been well established.

[This corrects the article DOI: 10.1155/2024/5518289.].

While hypoxia-driven nucleolar stress (NS) has been recognized as a critical modulator of the immunosuppressive tumor microenvironment in clear cell renal cell carcinoma (ccRCC), its mechanistic contribution to disease progression remains poorly defined. To address this gap, we systematically mapped NS-associated molecular landscapes through integrated spatial transcriptomics and single-cell RNA sequencing of ccRCC specimens. Our analysis stratified tumors into two distinct NS subtypes, revealing that high-NS tumors exhibit aggressive clinical behavior, elevated expression of immunosuppressive checkpoints, and significantly reduced survival. At single-cell resolution, high-NS malignant cells displayed enhanced proliferative activity, glycolytic metabolic reprograming, and marked chromosomal instability. Mechanistic investigations demonstrated that hypoxia-induced ETS1 activation orchestrates NS via the MYC/NPM1/DDX17 signaling axis, directly promoting tumor proliferation and metabolic adaptation in preclinical models. Spatial multiomics further uncovered coordinated niche formation between high-NS cells and OLR1 macrophages, with ligand-receptor profiling identifying the EDN1-EDNRA-OLR1 axis as a central mediator of this immunosuppressive crosstalk. Functional validation in syngeneic mouse models confirmed that ETS1 overexpression accelerates tumor growth while enriching OLR1 macrophages with immunosuppressive phenotypes. Clinically, high OLR1 macrophage infiltration correlated with shorter survival across independent cohorts. These findings establish a hypoxia-ETS1-NS-macrophage axis as a key mechanism sustaining ccRCC progression and highlight actionable targets for disrupting protumorigenic immune niches through modulation of the NS pathway.

Cholangiocarcinoma exhibits a complex tumor microenvironment, yet the cellular interactions governing its progression remain poorly understood. Here, through integrated analysis of two independent single-cell RNA sequencing datasets comprising both complete tissue and immune-focused profiling, we comprehensively mapped the cellular landscape and intercellular communication networks in human cholangiocarcinoma. Our analysis revealed significant remodeling of immune cell compositions and interaction patterns in the tumor microenvironment. Notably, we identified enhanced ICOS signaling between dendritic cells and T cells as a prominent feature of cholangiocarcinoma. Using CellChat analysis, we demonstrated that tumor-associated dendritic cells, particularly plasmacytoid DCs, exhibit stronger ICOS-mediated communication with T cells compared to their counterparts in normal tissues. Functional validation experiments confirmed that tumor-conditioned dendritic cells upregulate ICOSL expression and promote CD8+ T-cell activation through the ICOS-ICOSL axis, as evidenced by increased CD69 and CD25 expression. This activation was specifically abolished by ICOSL blockade, establishing the functional significance of this pathway. Our findings provide novel insights into tumor-immune interactions in cholangiocarcinoma and suggest the ICOS-ICOSL axis as a potential therapeutic target for immunotherapy.

[This corrects the article DOI: 10.1155/humu/8369299.].

Cancers are characterized by high heterogeneity. This study seeks to identify the factors driving hepatocellular carcinoma (HCC) heterogeneity to aid in prognostic stratification and inform personalized treatment approaches.