Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains a leading cause of cancer-related mortality worldwide. Lung adenocarcinoma (AD) and lung squamous cell carcinoma (SCC) represent the two major histological subtypes with distinct molecular characteristics. POU domain class 6 transcription factor 1 (POU6F1) is involved in gene regulation and cellular differentiation, but its clinical significance in NSCLC remains unclear. This study investigated the clinicopathologic and prognostic significance of POU6F1 expression in NSCLC. POU6F1 mRNA expression was analyzed in tumor tissues obtained from 153 patients with NSCLC using quantitative real-time polymerase chain reaction. The associations between POU6F1 expression and clinicopathological characteristics were evaluated, and survival analysis was performed to determine its prognostic value. In addition, publicly available datasets from The Cancer Genome Atlas (TCGA) were analyzed to validate the clinical significance of POU6F1 expression. High POU6F1 expression was observed in 48 patients (31.4%), whereas 105 patients (68.6%) showed low expression. High POU6F1 expression was significantly associated with younger age (p = 0.027), female sex (p = 0.041), non-smoking status (p = 0.002), adenocarcinoma histology (p = 0.021), and the presence of EGFR mutations (p = 0.038). Survival analysis demonstrated that high POU6F1 expression was associated with improved overall survival in patients with NSCLC (p = 0.015). When stratified by histological subtype, higher POU6F1 expression was associated with better survival outcomes in AD but not in SCC. Analysis of TCGA datasets confirmed that elevated POU6F1 expression was significantly associated with favorable survival in AD, whereas no significant prognostic value was observed in SCC. POU6F1 expression is significantly associated with clinicopathological characteristics and improved survival in patients with lung AD. Multivariate Cox regression analysis further confirmed that POU6F1 expression was an independent prognostic factor for overall survival. These findings suggest that POU6F1 may serve as a potential prognostic biomarker based on mRNA expression in NSCLC, particularly in AD. Further studies are warranted to validate these findings at the protein level and to elucidate the underlying biological mechanisms.

Although ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) therapy is highly effective for chronic hepatitis C (CHC), clinicians frequently encounter transient hyperbilirubinemia, which can be misidentified as hepatotoxicity. This study investigated the role of SLCO1B1 (OATP1B1) and SLCO1B3 (OATP1B3) genetic polymorphisms in predicting bilirubin spikes and distinguishing transporter-mediated interference from hepatocellular injury. In this prospective study of 65 patients with HCV genotype 1, genotyping for OATP1B1 (c.388A>G, c.521T>C) and OATP1B3 (c.334T>G, c.699G>A) was performed using PCR-RFLP and capillary electrophoresis (QIAxcel Advanced System). Clinical and biochemical parameters were monitored over a 12-week treatment period. Hyperbilirubinemia (total bilirubin >1.1 mg/dL) developed in 18.5% of the cohort, typically within the first month. A distinct ‘AST-dominant’ biochemical signature, elevated bilirubin and AST paired with stable ALT, was identified, suggesting transporter-specific interference rather than hepatocyte damage. Statistical analysis pinpointed the OATP1B3 c.699G>A (rs7311358) variant as the sole genetic driver (p = 0.007). Carriers of the c.699G>A allele faced a 6.3-fold higher risk of developing hyperbilirubinemia (OR: 6.30, 95% CI: 1.48–26.80, p = 0.032), while no significant associations were found for OATP1B1 variants. We conclude that OATP1B3 c.699G>A is a potent predictor of OPrD-induced hyperbilirubinemia. Identifying this genotype pre-treatment allows clinicians to anticipate transient, benign bilirubin elevations and prevent unnecessary drug discontinuation, thereby mitigating therapeutic inertia and ensuring treatment continuity for CHC patients.

Amino acids play a dual role in milk protein synthesis, functioning as both metabolic precursors and signaling molecules. This study aimed to elucidate the molecular mechanism by which glycine regulates α-casein production in bovine mammary epithelial cells (MAC-T). Under serum-free conditions, MAC-T cells were exposed to graded concentrations of glycine (1.105, 2.209, 4.418, 8.836, 17.673, and 35.345 mM) for 24 h. α-Casein levels in cell lysates and culture supernatants were quantified by ELISA. Transcriptional activity of casein-encoding genes (CSN1S1, CSN1S2) and PI3K-AKT-mTOR pathway components was assessed by RT-qPCR. Phosphorylation status of pathway proteins was analyzed by Western blot. The functional involvement of the PI3K-AKT-mTOR pathway was validated using the specific inhibitor LY294002. Glycine stimulated α-casein synthesis and secretion in a concentration-dependent manner, with maximal efficacy at 4.418 mM. At this concentration, glycine upregulated CSN1S1, CSN1S2, and PI3K-AKT-mTOR pathway gene expression, and enhanced phosphorylation of the corresponding proteins. Inhibition of PI3K-AKT-mTOR signaling by LY294002 abolished glycine-induced α-casein synthesis, and this effect was reversed by glycine co-treatment. These findings demonstrate that glycine enhances α-casein synthesis through activation of the PI3K-AKT-mTOR pathway.

Chondrosarcoma (CHS), the second most common primary malignant cartilage tumor, is largely resistant to conventional therapies, making surgical resection the standard treatment. Proton therapy offers a physical advantage through the Bragg peak, enabling targeted irradiation while sparing surrounding tissues. However, differential biological responses between malignant and normal cartilage cells remain poorly understood. In this study, CHS SW1353 cells and normal chondrocytes (MC615) were exposed to proton irradiation. Biological responses were assessed via clonogenic survival, cell viability, apoptosis (caspase 3/7), micronucleus formation, cell cycle profiling, and oxidative stress markers. Proteomic changes were analyzed using mass spectrometry and bioinformatics. CHS cells exhibited higher radioresistance (D10 = 6.45 Gy) than normal chondrocytes (D10 = 5.08 Gy), oxidative stress adaptation, G1 arrest and proteomic plasticity, whereas normal chondrocytes displayed increased oxidative stress, extracellular matrix fragility and impaired integrin signaling. Notably, the tumor-specific increased levels of Tyrosine-protein kinase Fyn and Yes1-associated transcriptional regulator (YAP1) signaling suggest molecular drivers of radioresistance. Overall, proton irradiation elicits distinct biological and proteomic responses in malignant versus normal cartilage cells. These findings highlight potential radiosensitization targets, including Fyn/Src and YAP1/Hippo pathways, while underscoring the need to optimize proton therapy to enhance tumor control while minimizing damage to healthy cartilage.

The WW domain-containing oxidoreductase (WWOX) gene, well-known as a tumor suppressor, also has a crucial role as a transcription factor in the developing brain. The bi-allelic loss of the WWOX gene causes a condition characterized by drug-resistant epilepsy, developmental delay, and neurological impairments, often resulting in mortality within the first year of life, known as WWOX-related epileptic encephalopathy (WOREE) syndrome (MIM: 616211). Whole Exome Sequencing (WES) analysis was performed on a female patient who died within three months of birth and was diagnosed with microcephaly, severe early-onset refractory seizures, and drug-resistant epileptic encephalopathy. WES revealed a 38 kb CNV deletion spanning WWOX exons 6–7, and a known frameshift variant in exon 8, impairing a highly clinically significant region of the encoded protein. Clinical and genetic features of reported WOREE patients with WWOX gene deletions similar to our patient were analyzed. Our case highlights the clinical heterogeneity of WWOX variants in WOREE syndrome and expands the spectrum of reported compound heterozygous deletions. Further research needs to elucidate WWOX pathophysiology and improve diagnostic and therapeutic strategies.

Since chemical anti-allergic compounds have adverse effects, many investigators pay attention to relatively safe natural products. Twenty-four newly crossbred rosebuds were extracted with 80% ethanol and analyzed for polyphenols, flavonoids, tannins, proanthocyanidins, and pyrogallol (1,2,3-benzenetriol). The extracts’ antioxidative, anti-allergic, and anti-inflammatory activities were assessed in vitro and in vivo. Among candidates, Lover Shy, Pretty Velvet, Ice Wing, Red Perfume, Onnuri, Jaemina Red, and Hanggina were found to possess high concentrations of antioxidant components and antioxidative activity. By comparison, Pretty Velvet, Red Perfume, Jaemina Red, Hanggina, Onnuri, and Ice Wing were highly effective in anti-allergic and anti-inflammatory activities in vitro, in parallel with their concentrations of pyrogallol. Their anti-allergic effects were confirmed in mice: The six extracts protected against Compound 48/80-induced mortality and scratching behaviors in a dose-dependent manner. The allergen-induced increases in serum IgE and histamine, as well as inflammatory cytokines, tumor-necrosis factor-α, and interleukin-1β, were remarkably attenuated following treatment with the rosebud extracts. These findings suggest that the extracts and active ingredients from cross-bred rosebuds exert anti-allergic and anti-inflammatory activities through their high levels of pyrogallol and antioxidants, and that they could be promising candidates to overcome allergic responses such as atopic dermatitis.

Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive memory and cognitive decline. Conventional genome-wide association studies (GWAS) comparing AD cases and controls may miss genetic influences that act along a continuum of cognitive function. Using data from 3007 participants in the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study (NIA-LOAD GWAS), we conducted a family-based GWAS of eight quantitative cognitive phenotypes encompassing episodic memory (Logical Memory IA and IIA), working memory (Digit Span Forward, Backward, and Ordering), and semantic fluency (Animal, Fruit and Vegetable, and Vegetable Fluency). Family-based association testing in PLINK v1.9 identified numerous single nucleotide polymorphisms (SNPs) associated with cognitive phenotypes at genome-wide significant (p < 5 × 10−8) levels. Notably, genome-wide significant variants with cognatic functions were localized to genes implicated in synaptic function, neurodevelopment, and neurodegeneration, including TOMM40 (rs2075650), ERBB4 (rs1521543), APLP2 (rs12281267, rs959354), PTPRD (rs1353983, rs970347, rs1392511), NCAM2 (rs2826728), GRM7 (rs6788201), PAX5 (rs2988003, rs2381595), NRG1 (rs16875655), and NRG3 (rs1937957). Furthermore, the TOMM40 (rs2075650) was significantly associated with AD as a binary outcome (p = 4.60 × 10−24) and APLP2 (rs12281267, rs959354), APOE (rs405509), PTPRD (rs1353983, rs970347, rs1392511) were associated with AD (p < 0.001). Additionally, several pathways including the ERBB4 signaling pathway (adjusted p = 2.82 × 10−3), driven by ERBB4, NRG1, and NRG3 may contribute to cognitive impairments. This study provides a comprehensive resource of cognitive endophenotype associations in AD families, advancing understanding of the genetic architecture underlying memory, executive function, and cognitive aging, and highlights new therapeutic targets for replication and functional follow-up.

The deficiency of TCOF1 is closely associated with multiple cellular dysfunctions, but its function in mitochondrial homeostasis and cytoskeletal regulation remains unclear. First, our research revealed that TCOF1 deficiency significantly inhibits tumor cell migration, suggesting TCOF1 plays a crucial role in cellular motility. Further studies demonstrated that TCOF1 deficiency disrupts normal F-actin polymerization, compromises cytoskeletal structural integrity, and impairs the dynamic assembly of F-actin, thereby affecting cell morphology and motility functions. Additionally, TCOF1 deficiency leads to mitochondrial dysfunction characterized by aberrant energy metabolism. Mechanistically, TCOF1 deficiency decreased the protein levels of p53, subsequently affecting mitochondrial biogenesis and functional maintenance, suggesting TCOF1 may regulate mitochondrial homeostasis via a p53-dependent pathway. Collectively, our study reveals TCOF1’s role in regulating tumor cell migration by influencing F-actin assembly and the p53-mitochondrial axis, playing a critical role in maintaining cytoskeletal dynamics and energy metabolism.

Background and Objectives: The integration of chemotherapy (ChT) and immune checkpoint inhibitors (ICIs) has become a standard approach in oncology. Although the addition of ICIs to double-agent ChT regimens has demonstrated clinical benefit in multiple studies, other trials have reported no significant improvement. ChT is hypothesized to potentiate the effects of ICIs through multiple mechanisms, including tumor antigen release and modulation of the tumor microenvironment. This study aimed to evaluate whether nivolumab enhances the cytotoxic effects of cisplatin or paclitaxel in lung adenocarcinoma (A549) cell lines under immune-independent conditions. Materials and Methods: A549 lung alveolar carcinoma cell lines were treated with varying concentrations of nivolumab, cisplatin, and paclitaxel, individually and in combinations. Cytotoxicity and apoptosis were assessed using mitochondrial membrane potential analysis, cell viability assays, and morphological evaluation of cellular and nuclear alterations characteristic of apoptotic cell death. Results: Nivolumab alone exhibited no cytotoxic activity. The combination of cisplatin at its IC50 (half-maximal inhibitory concentration) (3 µg/mL) with 13 µg/mL nivolumab yielded the most pronounced cytotoxicity (89%) compared to cisplatin alone (49%, p < 0.001). Paclitaxel combined with nivolumab increased cytotoxicity to 69% versus 51% for paclitaxel alone (p < 0.05). The enhancement effect was greater with cisplatin than with paclitaxel. Notably, adding nivolumab to the cisplatin–paclitaxel combination reduced cytotoxicity from 73% to 64%. Mechanistic analysis revealed a significant reduction in Rhodamine 123 fluorescence intensity in drug-treated groups versus controls (p < 0.001), indicating loss of mitochondrial membrane potential, a hallmark of intrinsic apoptotic activation, suggesting apoptotic priming. Conclusions: Nivolumab potentiates the cytotoxic effects of cisplatin and paclitaxel in A549 lung adenocarcinoma cells, with a more pronounced effect observed in combination with cisplatin. This enhancement is associated with mitochondrial membrane potential loss, supporting mitochondrial apoptotic priming as a potential underlying mechanism of drug synergy.

Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, and effective therapeutic options for advanced disease are still limited. Oridonin (ORI), a naturally derived diterpenoid compound, has shown anti-tumor activity in several malignancies, but its molecular mechanisms in CRC remain incompletely understood. In this study, the anti-cancer effects of ORI were evaluated in HT-29 and HCT116 colorectal cancer cells using in vitro assays, integrated transcriptomic and proteomic analyses, Western blotting, and an HT-29 xenograft model. ORI reduced cell viability in a time- and concentration-dependent manner, induced G1-phase cell cycle arrest, increased cell death, and reduced wound closure under the tested in vitro conditions. Integrated omics analyses in HT-29 cells identified extensive alterations in gene and protein expression, with significant enrichment of pathways related to cell cycle regulation and apoptosis. Western blotting further showed that ORI increased the expression of BAX, BID, CYCS, and CASP3 while decreasing BCL2 expression. In vivo, ORI significantly inhibited tumor growth in nude mice bearing HT-29 xenografts. These findings indicate that ORI suppresses CRC growth through coordinated regulation of cell cycle progression and apoptosis and suggest that ORI may serve as a potential therapeutic candidate for colorectal cancer.