Diabetes-associated cognitive dysfunction (DACD) is a common and serious diabetic complication, and emerging evidence has identified impaired mitophagy as its potential pathological feature. Metformin (Met) possesses both hypoglycemic and cognitive-enhancing activities, and also exerts modulatory effects on mitophagy. However, the precise mechanisms by which it regulates mitophagy to ameliorate DACD remain poorly understood.

Our present study aims to verify the ameliorative effects of Met on cognitive dysfunction in DACD mice, and to explore its underlying mechanisms.

Cognitive function of type 2 diabetes mellitus (T2DM) mice was evaluated by behavioural tests after Met administration. Proteomic profiling and multiple molecular biology techniques were utilised to explore and validate the effect of Met on mitophagy in T2DM mice, as well as in high glucose (HG)-injured HT22 and SH-SY5Y cells.

We found that Met significantly alleviated cognitive impairment and neuronal damage in T2DM mice. Proteomic analysis indicated that the effect of Met in improving cognition might be closely related to mitophagy regulation. Furthermore, Met markedly downregulated Beclin1, Atg4, Atg7, LC3 II, PINK1, and Parkin in the hippocampus of T2DM mice, while upregulating p62 levels. Simultaneously, Met reduced the colocalisation of mitochondria and autophagosome marker LC3B, and the colocalisation of mitochondria and lysosome. These results indicated that Met could reverse excessive mitophagy activation. Moreover, Met dramatically increased the cytoplasmic expression of p53 and Parkin, while inhibiting the translocation of Parkin to damaged mitochondria. Consistent results were also observed in HG-injured HT22 and SH-SY5Y cells after Met incubation. Notably, the effect of Met on mitophagy and p53 was blocked by the p53 inhibitor PFT-α.

Our study confirmed that Met inhibited the mitochondrial localisation of Parkin by elevating cytosolic p53 levels, thereby preventing excessive mitophagy and ameliorating DACD.

These findings indicated that Met might have potential for clinical repurposing in the treatment of DACD.

The optimal sequencing of brain-directed radiation and systemic therapy in stage IV non-small cell lung cancer (NSCLC) with brain metastases remains uncertain in the era of CNS-active systemic agents. We evaluated survival outcomes using national real-world data.

We conducted a retrospective cohort study of adults diagnosed between 2010 and 2022 with stage IV NSCLC and brain metastases in the National Cancer Database who received both brain-directed radiation and systemic therapy. Treatment sequence was classified as radiation-first or systemic-first based on initiation dates. Multivariable Cox proportional hazards models, stratified by treatment era (pre-2015 vs. 2015+), assessed associations with overall survival (OS), adjusting for demographic, clinical, tumor, and treatment factors. Propensity score matching and delayed-entry sensitivity analyses were performed to address confounding and immortal time bias.

Among 45 577 patients, 78.3% received radiation-first and 21.7% received systemic therapy first. Unadjusted Kaplan-Meier analysis showed no significant difference in OS (log-rank p = 0.624). In multivariable analysis, systemic-first sequencing was associated with a modest increase in mortality (adjusted hazard ratio [aHR] 1.06; 95% CI: 1.04-1.09), which was consistent in propensity-matched (HR 1.07; 95% CI: 1.04-1.11) and delayed-entry analyses (aHR 1.09; 95% CI: 1.07-1.12). The use of systemic-first therapy increased over time. Established prognostic factors demonstrated larger effect sizes.

Systemic-first sequencing was associated with a modest increase in adjusted mortality; however, the effect size was small relative to established prognostic factors and likely influenced by residual confounding and selection bias. These findings support individualized, multidisciplinary treatment decisions rather than a uniform sequencing strategy.

Cystic lesions of the ovaries are common in adolescent girls. Follow-up is recommended to monitor any changes in size. In more than 90% of cases, these cysts are benign. Our aim is to draw attention to the fact, that even extremely large lesions can develop during puberty and in every case our goal is to perform accurate imaging and organ-preserving surgical management. Between 2023 and 2025, four adolescent girls underwent surgery for giant cystic ovarian lesions at the Department of Pediatric Surgery of the Győr-Moson-Sopron County Petz Aladár University Teaching Hospital. We performed a detailed retrospective analysis of the patients' medical histories and a review of the relevant literature. In all four cases, pediatric surgical and gynecological examinations, tumor marker level assessments, abdominal ultrasound, and abdominopelvic magnetic resonance imaging were performed within a short period of time. Based on the findings, surgery was carried out within a few days. Laparoscopic surgery was performed in two patients, open surgery in the other two. In every case, a large cystic lesion was identified, and no clear evidence of malignancy arose during the operations. Organ-preserving surgery was successfully performed in two patients; in the remaining cases, removal of the affected ovary and fallopian tube was necessary. The histopathological findings differed in all four cases. In the first patient, a mucinous cystadenoma was confirmed, which recurred, and needed reoperation. In the second patient, histology revealed mucinous adenocarcinoma, which is a particularly rare malignancy in this age group. In the third case, fluid accumulation caused by torsion was identified as the underlying condition. In the fourth patient, the histopathological diagnosis was a mature cystic teratoma. Although cystic ovarian lesions are common during adolescence, they rarely grow to an extreme size. Accurate imaging and analysis of tumor marker levels are essential for surgical planning. Minimally invasive procedures and organ-preserving surgery should always be preferred if possible. Histopathological findings greatly influence the need for further follow-up or additional treatment. Orv Hetil. 2026; 167(29): 1164-1171.

At present, colorectal cancer (CRC) ranks as the third most prevalent cancer globally and is the second most common cause of mortality associated with cancer. The expression of A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS5) is upregulated in CRC, and high ADAMTS5 expression strongly correlates with an unfavorable prognosis. However, the function of ADAMTS5 in CRC remains unknown. This study aimed to investigate the role of ADAMTS5 in CRC and its potential mechanisms of action. The results showed that ADAMTS5 expression was higher in CRC tissues than in paracancerous tissues. Bioinformatics analysis revealed that its expression gradually increased with tumor progression and that high expression was correlated with poor prognosis. ADAMTS5 knockdown suppressed the proliferation and migration of HCT116 and HT29 cells, and ADAMTS5 inhibition suppressed epithelial-mesenchymal transition (EMT) in HCT116, HT29, and patient-derived organoids. Mechanistic analysis using the STRING database revealed that ADAMTS5 expression was strongly correlated with the Wnt signaling pathway. Western blotting analysis confirmed that ADAMTS5 inhibition suppressed tumor cell invasion and migration and blocked EMT in vitro through the PEDF/Wnt/β-catenin pathway. Furthermore, ADAMTS5 inhibition significantly inhibited tumor proliferation and metastasis within a nude mouse CRC liver metastasis model. These findings indicated that inhibition of ADAMTS5 could suppress CRC progression and metastasis via the PEDF/Wnt/β-catenin pathway.

To evaluate the diagnostic accuracy of preoperative imaging in patients with suspected primary facial nerve tumours and to assess interobserver agreement in radiological interpretation.

A retrospective study included patients who underwent surgical treatment for suspected primary facial nerve tumours between 1990 and 2024. Concordance between the primary radiological diagnosis and histopathology was analysed. Diagnostic performance metrics were calculated using histopathology as the reference standard. A secondary blinded imaging review was performed by three radiologists. Interobserver agreement was assessed using Cohen's and Fleiss' kappa coefficients.

Twenty-eight patients were included in the primary analysis. Schwannoma was the most frequent radiological diagnosis (53.6%) and histopathological subtype (50%). Overall concordance between the primary radiological diagnosis and histopathology was 57.1%. In the blinded radiological review (n = 23), diagnostic accuracy ranged from 47.8% to 60.9%. Overall interobserver agreement for the final diagnosis was fair (Fleiss' κ = 0.30). Accuracy was higher for common tumours (schwannomas and haemangiomas) than for rare tumours (68.9% vs. 25%, p = 0.001). Haemangioma showed high diagnostic performance (sensitivity and specificity) in the primary analysis but lower reproducibility in the blinded review.

Preoperative imaging shows moderate diagnostic accuracy and limited interobserver agreement. Diagnostic performance appears to be higher for common tumours such as schwannomas, whereas haemangiomas and other lesions may show more variable and less reproducible imaging features. Despite these limitations, imaging remains essential for tumour localisation and clinical decision-making.

Cancer cachexia is a debilitating systemic syndrome that affects a substantial proportion of patients with advanced malignancy and is associated with impaired treatment tolerance, reduced quality of life, and increased mortality. While skeletal muscle wasting is a defining clinical feature, cachexia involves coordinated dysfunction across multiple organs, yet it remains unclear whether cachexia imposes a unified, body-wide transcriptional program or primarily induces organ-specific responses. Here, we leveraged an isogenic xenograft model derived from human duodenal neuroendocrine carcinoma in which the cachexia-inducing subline AkuNEC was established through in vivo serial passaging from the parental, largely non-cachexia-inducing line TCC-NECT-2. We performed bulk RNA sequencing of skeletal muscle, liver, kidney, and heart from cachectic AkuNEC-bearing mice, non-cachectic TCC-NECT-2-bearing mice, and uninoculated controls. Differential expression analyses identified organ-dependent sets of transcripts associated with cachexia. However, unsupervised analyses of global expression patterns consistently showed that tissue identity dominated transcriptome structure and samples did not segregate by cachexia status. In addition, comparisons of tumor-bearing vs uninoculated controls revealed broadly similar transcriptional shifts for AkuNEC and TCC-NECT-2 within each organ. Together, these data indicate that cachexia-associated transcriptional changes are present but remain modest relative to dominant tissue-specific programs at the whole-transcriptome level. The AkuNEC/TCC-NECT-2 system provides a controlled platform for future studies incorporating cell-type-resolved, spatial, and multi-omic approaches to delineate the mechanisms linking tumor evolution to multi-organ remodeling in cancer cachexia.

Manganese metabolism may be involved in the malignant progression of lung adenocarcinoma (LUAD). Clarifying the roles of manganese metabolism-related genes (MMRGs) in LUAD may provide potential therapeutic targets for LUAD treatment. Mendelian randomization analysis and machine learning methods were applied to analyze transcriptome data for screening prognosis-related genes in LUAD. Subsequently, a risk model was constructed and a nomogram was plotted. Meanwhile, a series of analyses were carried out focusing on the immune microenvironment, drug sensitivity, and the single-cell level. Finally, the expression of relevant proteins was further verified by combining RT-qPCR and Western Blot. We have screened out six risk genes for LUAD: TXNRD1, CDKN3, BTG2, SELENBP1, DTYMK, and CHEK1. Subsequently, a risk model was constructed, which effectively predicts the survival of LUAD patients. Gene Set Enrichment Analysis (GSEA) revealed that these six genes may be involved in the regulation of the cell cycle in LUAD. In addition, they may modulate the tumor immune microenvironment and induce resistance to chemotherapeutic drugs. RT-qPCR and Western Blot confirmed low BTG2 and SELENBP1 and high CDKN3, CHEK1, DTYMK, and TXNRD1 expression in LUAD tissues and cell lines. Our study indicates that TXNRD1, CDKN3, BTG2, SELENBP1, DTYMK, and CHEK1 may be important biomarkers for the prognosis of LUAD, providing potential approaches for prognostic evaluation and medication strategies in LUAD.

Breast cancer is a molecularly heterogeneous disease in which conventional prognostic factors do not fully predict clinical outcome or therapeutic response. Proteins associated with multidrug resistance (MDR) may contribute to tumor progression and treatment failure. This study evaluated the prognostic relevance of p53, glutathione S-transferase P1 (GSTP1), and P-glycoprotein (P-gp) in invasive breast carcinoma.

Immunohistochemical expression of p53, GSTP1, and P-gp was assessed in formalin-fixed, paraffin-embedded samples of invasive breast carcinomas and compared with normal breast tissue. Associations between protein expression and clinicopathological parameters were statistically analyzed.

Normal breast tissue was negative for p53 expression, whereas overexpression of dysfunctional p53 was detected in 24% of carcinomas. p53 positivity was significantly associated with higher histological grade and HER2 positivity (p < 0.05), indicating a correlation with aggressive tumor phenotype. GSTP1 expression was observed in 58% of carcinomas, while all normal tissues were GSTP1-positive. In some tumors, both cytoplasmic and nuclear GSTP1 staining was detected, possibly reflecting adaptive survival mechanisms. However, GSTP1 expression was not significantly associated with standard clinicopathological parameters. P-gp positivity was identified in 42% of carcinomas, and all normal tissues expressed P-gp. Despite its established role in drug efflux, P-gp expression did not correlate significantly with established prognostic factors.

Among the evaluated MDR-associated proteins, only p53 expression demonstrated a significant association with adverse clinicopathological features, suggesting potential prognostic relevance. The roles of GSTP1 and P-gp remain uncertain and require validation in larger prospective clinical studies.

The CRISPR/Cas12a system holds great promise for nucleic acid detection, but its strict dependence on the protospacer adjacent motif (PAM) severely limits its application in gene point mutation analysis, with fewer than 2% of known mutation sites naturally harboring adjacent PAM sequences. Herein, we developed a PAM-free Cas12a system with double-stranded substrate positioning-unwinding (dsPU-Cas12a), wherein "bubble" structures formed by unpaired base pairs release partial single-stranded target strand as a toehold, and excess auxiliary strands induce local unwinding of double-stranded DNA to facilitate R-loop formation. After optimization, the dsPU-Cas12a system achieved an ultra-low limit of detection of 0.013% for gene point mutations, with excellent linearity over the mutation abundance range of 0-10%. Furthermore, it exhibited robust feasibility and accuracy in detecting the JAK2 V617F mutation in blood samples from patients with myeloproliferative neoplasms. This simple and universal strategy overcomes the sequence limitation of Cas12a, providing a high-performance tool for clinical gene point mutation detection.

UFMylation, a recently identified ubiquitin-like modification, is essential for cellular stress homeostasis, particularly endoplasmic reticulum (ER) stress regulation. However, its biological and therapeutic exploration has been hindered by the absence of potent small-molecule inhibitors. Here, we report the first discovery of two compounds targeting the UFMylation E3 ligase complex core protein DDRGK1: Osimertinib, originally designed as an EGFR T790M selective inhibitor, acting through a previously unrecognized covalent mechanism, and CP-24, a novel non-covalent inhibitor. Both compounds disrupt the DDRGK1-UFL1 interaction, globally suppress UFMylation, inhibit ER-phagy, and induce ER stress. In glioblastoma (GBM), pharmacological UFMylation inhibition markedly reduces tumor cell viability and sensitizes cells to Temozolomide and radiotherapy. Both compounds also exert strong immunomodulatory activity, promoting macrophage polarization toward an anti-tumor M1 state. In vivo, Osimertinib, benefiting from superior pharmacokinetics, significantly suppresses tumor growth in immunodeficient models and achieves tumor-free outcomes in 65% of immunocompetent mice. These tumor-free mice develop durable anti-GBM immune memory, rapidly clearing tumors upon rechallenge, an outcome unattainable by previous GBM treatments. Mechanistically, Osimertinib enhances anti-tumor immunity by promoting macrophage M1 polarization, T cell expansion, and reducing PD-1 protein levels. Collectively, our study introduces Osimertinib and CP-24 as valuable chemical probes for dissecting UFMylation biology and highlights Osimertinib's potential for off-label use in EGFR-wildtype GBM. More broadly, we establish UFMylation inhibition as a dual-targeting therapeutic strategy that disrupts tumor survival pathways and reprograms the immune microenvironment, offering a promising avenue for durable GBM control.