BackgroundThis study meticulously outlines the evolution of the burden of malignant neoplasm of bone and articular cartilage (MNBAC) among different age and sex groups in China from 1990 to 2021, analyzes the global impact of the disease, and predicts the trend of disease burden up to 2035.MethodsLeveraging public data from the Global Burden of Disease (GBD) database spanning 1990 to 2021, this study thoroughly analyzed the characteristics of the burden of MNBAC in China and globally, including its incidence, prevalence, mortality, and disability-adjusted life years (DALYs). The joinpoint analysis method was employed to calculate the average annual percentage change (AAPC) and its 95% uncertainty interval, revealing the trend of MNBAC's impact. Furthermore, Bayesian age-period-cohort (BAPC) model was used to forecast changes in disease burden leading up to 2035.ResultsBetween 1990 and 2021, the age-standardized incidence rate (ASIR) of MNBAC in China increased from 0.65 to 1.42 per 100 000 people, and the global ASIR rose from 0.97 to 1.11 per 100 000. The AAPC for China's ASIR, age-standardized prevalence rate (ASPR), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) were 2.59%, 2.71%, 1.52%, and 1.26%, and the AAPC of ASIR and ASPR of the global burden of MNBAC were 0.44% and 0.51%, respectively. The effect of age and sex on the burden of MNBAC showed significant differences. Forecasting analyses suggest that from 2022 to 2035, the burden of MNBAC in China and globally will show a declining trend.ConclusionsFrom 1990 to 2021, the disease burden of MNBAC in China has been rising among the population, particularly pronounced among older men. Although forecasts indicate a gradual reduction in the future burden of MNBAC, given China's large population base and the increasing trend of population aging, MNBAC will pose a public health challenge in China.

Anticancer therapies frequently compromise skeletal health and increase fracture risk. This narrative review synthesizes information and provides guidance on assessment, prevention, and management of therapy-related bone loss in adults with cancer. Major contributors to bone loss in this population include aromatase inhibitors, androgen deprivation therapy, systemic glucocorticoids, chemotherapy, and selected targeted or immune agents. Recommended assessments include clinical evaluation, laboratory tests (calcium, vitamin D, and renal function), and bone mineral density by dual-energy X-ray absorptiometry with vertebral fracture assessment and, when acute vertebral fracture is suspected, magnetic resonance imaging. Prevention measures include exercise, adequate calcium and vitamin D intake, and fall-reduction strategies. Pharmacological treatment options include bisphosphonates and denosumab. Selection of treatment should consider skeletal efficacy and potential oncological benefits, while ongoing care includes repeat bone density testing at 12-24 months and vigilance for osteonecrosis of the jaw and atypical femoral fractures.

Electroencephalography (EEG) is widely used in both research and clinical settings, yet its accuracy can be significantly impacted by subject-specific anatomical anomalies such as brain lesions and skull defects. This study investigates the effects of glioma-related brain lesions and craniotomy-induced bone discontinuities on scalp-recorded EEG signals. To do this, single- and multi-source simulations were created using individualized forward models with and without these structural anomalies. We assessed changes in signal amplitude and topography, and identified the most affected electrodes. Furthermore, real EEG recordings were also analyzed longitudinally to evaluate how these anomalies influence the topography and source localization of early auditory evoked responses (P1 and N1 ERP components). Both single- and multi-source simulations showed that the distortions in the EEG signals depend on the location of the neural source in relation to the location of the lesion. Electrode-level analyses showed that these distortions were most pronounced at the electrodes near the bone flap, and thus near the lesions. Real ERP data supported these findings: a subject with a lesion near the auditory cortex showed notable topographic deviations longitudinally for the P1 and N1 ERP components, while a subject with a frontal lesion showed minimal changes in the scalp EEG. These results highlight the need to include detailed brain and skull anatomy in EEG models, especially in studies that track longitudinal changes in clinical populations.

KDM6A is a critical part of the COMPASS-like complex. KDM6A deficiency may result in EZH2 dependency. KDM6A deficiency was analyzed by immunohistochemistry on a tissue microarray containing 14,814 samples from 153 different tumor entities and 76 different normal tissue types. In normal tissues, KDM6A staining was ubiquitously seen in nuclei. In tumors, KDM6A deficiency occurred in 58 of 153 tumor categories. KDM6A deficiency predominated in urothelial carcinomas (17.3-42.0%) and was seen in 4-10% of gastric, pancreatic, prostatic, and gallbladder adenocarcinomas, serous endometrial carcinomas, squamous cell carcinomas, papillary renal cell carcinoma, hepatocellular carcinomas, malignant melanomas, and ovarian serous high-grade carcinomas. Reduced or absent KDM6A expression was associated with advanced pT stage (p = 0.0233), high grade (p = 0.0002), and distant metastasis (p = 0.0152) in breast cancer, nodal metastasis in squamous cell carcinomas (p = 0.0498), advanced pT stage (p = 0.0002), nodal metastasis (p = 0.0112), and mismatch repair deficiency (dMMR; p = 0.0147) in colorectal adenocarcinoma, and with dMMR (p = 0.0033) in gastric adenocarcinoma. KDM6A deficiency was significantly more common in tumors from males (4.3%) than from females (1.9%; p < 0.0001). In summary, KDM6A deficiency predominates in urothelial neoplasms but also occurs in many further tumor entities. Whether KDM6A deficient cancers are susceptible to EZH2 inhibitors remains to be seen.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder increasingly recognized to involve chronic inflammation, autophagy dysfunction, and immune imbalance. The molecular mechanisms connecting autophagy-related genes (ATGs), immune infiltration, and ovarian dysfunction remain unclear.

Transcriptomic data from ovarian granulosa cells (GSE34526 and GSE137684) were analyzed to identify differentially expressed ATGs, followed by functional enrichment, immune cell profiling, and network analysis. Ten hub genes were validated in clinical samples (PCOS and controls, n = 6 per group) and a dehydroepiandrosterone-induced mouse model. HMOX1 function was examined under conditions with and without metformin treatment.

A total of 57 DEATGs were enriched in pathways related to autophagy, immune regulation, and inflammation, including the NOD-like receptor and FoxO signaling pathways. Among the ten identified hub genes, heme oxygenase-1 (HMOX1) was significantly upregulated in PCOS samples and positively associated with M2 macrophage infiltration. In vitro, HMOX1 overexpression led to increased levels of p62 and CD163, indicating impaired autophagic flux and enhanced M2-like polarization. Estradiol secretion was reduced under HMOX1 overexpression, and partially restored by metformin. In the PCOS mouse model, HMOX1 expression was elevated and suppressed following metformin treatment, although ovarian morphology remained abnormal.

HMOX1 appears to act as a molecular nexus connecting impaired autophagy with immune microenvironment alterations in PCOS, highlighting its potential as both a diagnostic marker and a target for immunomodulatory therapy.

Immune checkpoint blockade (ICB) therapy continues to face limitations due to tumor resistance linked to suppressed interferon (IFN) signaling. This suppression can be attributed to multiple mechanisms, among which viral pathogens represent a compelling though not yet fully elucidated factor. Here, we demonstrate that exogenous Epstein-Barr virus-encoded EBNA1 drives immunosuppression via enhanced RNA-editing enzyme ADAR1-mediated RNA editing. Comparative tumor model analyses revealed that EBNA1 overexpression reduced CD8⁺ T-cell infiltration, inhibited IFN responses, polarized macrophages toward the M2 phenotype, and accelerated tumor growth. Mechanistically, EBNA1 forms a trimeric complex with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and eukaryotic translation initiation factor 4G1 (EIF4G1), enhancing ADAR1 translation. Elevated ADAR1 further increased A-to-I editing of dsRNA, particularly within SINE elements near IFN-associated genes. This editing masked immunostimulatory signals, impairing RNA sensor activation and blunting IFN pathways. Notably, combining the EBNA1-targeting PROTAC degrader EP-1215 with anti-PD-1 effectively restored IFN signaling, enhanced T-cell infiltration, and suppressed EBNA1⁺ tumors in humanized mice. This viral exploitation of RNA editing suggests that targeting EBNA1 could be a strategy to convert "cold" tumors into "hot" targets amenable to ICB therapy.

Autophagy is an intracellular recycling system that contributes to the maintenance of cellular homeostasis. However, by providing tolerance to various stressors, autophagy promotes the survival and proliferation of cancer cells and confers resistance to chemotherapy. Anticancer drugs activate autophagy, leading to drug resistance in cancer cells. Autophagy inhibitors, such as chloroquine and hydroxychloroquine, enhance the antitumor effects of anticancer drugs when used in combination with them. However, these inhibitors are associated with several adverse effects. Here, using genome-wide RNA sequencing analysis, we deciphered a novel function of electrolyzed hydrogen water (EHW) in suppressing autophagy by activating mammalian target of rapamycin complex 1 signalling. The combination of EHW with anticancer drugs, such as 5-fluorouracil or paclitaxel, which activate autophagy, significantly decreased the viability of cervical and colorectal cancer cells. Mechanistically, molecular hydrogen and trace elements in EHW may suppress autophagy and potentiate anticancer effects. Considering its safety, we propose that EHW can act as a novel adjuvant to anticancer therapy.

Precision oncology relies on precision diagnostics, and histopathological diagnosis, along with biomarker evaluation, currently represents the cornerstone for personalized treatment. In gastrointestinal neoplasms, diagnostic assessment and molecular profiling are often performed on biopsy tissue, which may be quantitatively/qualitatively limited. Therefore, appropriate sample management is essential to avoid unnecessary waste and to obtain all the information necessary for treatment planning. Several factors may significantly impact biomarker testing: (i) pre-analytical issues; (ii) heterogeneity in biomarker expression; (iii) lack of standardization in biomarker testing and evaluation. Moreover, in the metastatic setting, inadequate/incomplete clinical information can lead to inappropriate sample handling, with negative implications. The application of appropriate guidelines in testing and reporting biomarker status according to clinical context is, therefore, strongly encouraged. In this position paper, the Italian Group of Gastrointestinal Pathologists (GIPAD), a section of the Italian Society of Pathological Anatomy and Cytology (SIAPeC-IAP), aims to summarize all the clinical and pathological requirements for adequate assessment of prognostic and predictive biomarkers in the gastrointestinal oncology patient, from biopsy acquisition to diagnostic reporting.

Internal tandem duplications in the gene encoding the membrane domain of FLT3 (FLT3-ITD) are the most common genetic alteration and an unfavorable prognostic factor in the patients with acute myeloid leukemia (AML). New-generation FLT3 inhibitors effectively induce cell death in the AML cells with the FLT3-ITD-positive phenotype (FLT3-ITD⁺) and potentially exhibit cytotoxic activity against the AML cells with the FLT3-ITD-negative phenotype (FLT3-ITD^-), but at higher concentrations. However, potential impact of the new-generation FLT3 inhibitors on the cytotoxic activity of molecular effectors of antitumor immunity - particularly in the context of heterogeneity of the primary clonal composition of AML, which includes both FLT3-ITD⁺ and FLT3-ITD^- cells - remains unclear. This study demonstrated that the use of quizartinib, a new-generation FLT3 inhibitor, increased resistance of the FLT3-ITD^- AML cells, but not of the FLT3-ITD⁺ AML cells, to the cytotoxic action of the key molecular effector of antitumor immunity, the cytokine Apo2L/TRAIL. This effect was mediated by the changes in the expression of proapoptotic TRAIL receptors, content of the cFLIP protein, and expression of the genes encoding proteins of the IAP and BCL-2 families. Additionally, the quizartinib-induced changes in the intracellular signaling pathways that potentially regulate TRAIL resistance in the AML cells were identified. The identified quizartinib-induced transcriptional changes are of interest not only in the context of combination therapy with TRAIL but also have broader implications for understanding the mechanisms of drug resistance in the AML cells.

Mosaicism refers to the presence of multiple cell clones with distinct genotypes arising from a single zygote. The phenotype of mosaic individuals depends on the extent of mosaicism, ranging from localised to almost generalised. We report three diagnostically challenging cases with previously unrecognised mosaicism in the tumour predisposition syndromes (TPS) von Hippel-Lindau syndrome, neurofibromatosis type 1 and neurofibromatosis type 2. In all three patients there was a strong clinical suspicion for a TPS; however, no pathogenic variant (PV) was detected in these patients in DNA extracted from blood. With next generation sequencing (NGS) analysis of multiple affected tissue samples of these patients we were able to detect a recurrent PV at varying variant allele fractions. In all three patients, low-grade mosaicism was in retrospect confirmed in normal tissue and blood (variant allele frequency: 1%-7%). Therefore, we conclude that NGS on multiple affected tissues is an effective strategy to detect low-level mosaicism. Identification of previously unrecognised low-grade mosaic cases not only allows for more precise diagnosis and management advice for the index patient, but also accurate genetic counselling for family members.