Background Gastric cancer (GC) remains a major therapeutic challenge. Although alterations in the RAS pathway occur in over 50% of tumors, only a limited proportion are clinically actionable. We investigated whether KRAS expression complements genomic profiling for patient stratification and therapeutic vulnerability in GC. Methods Comprehensive genomic profiling was performed in 19 Taiwanese GC patients and compared with TCGA-STAD data (n = 434). KRAS mRNA expression and overall survival were evaluated by meta-analysis of 13 independent cohorts (n = 2,521). Protein-level validation was performed by immunohistochemistry in an independent cohort (n = 121). Functional KRAS dependency and response to combined MEK/SHP2 inhibition were assessed in eight GC cell lines. Results KRAS amplification was entirely contained within the KRAS-high population, whereas most KRAS-high tumors lacked detectable amplification. High KRAS expression was associated with poorer overall survival (HR 1.23, p = 0.001) and remained an independent prognostic factor after multivariable adjustment (adjusted HR 1.24, p = 0.003). Protein-level analysis showed a concordant trend. KRAS expression correlated strongly with functional dependency (R2 = 0.88, p = 0.005), was enriched in MSI and CIN subtypes, and identified cell lines with enhanced sensitivity to combined MEK/SHP2 inhibition. Conclusions KRAS expression complements genomic profiling by identifying biologically relevant KRAS-dependent GCs beyond mutation or amplification alone. Integrating expression-based stratification with genomic profiling may improve patient selection for RAS pathway-directed combination therapies.
BACKGROUND:Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of ocular infections, with evolving molecular epidemiology observed in systemic infections in Taiwan. However, longitudinal data on clonal distribution and antibiotic susceptibility in ocular MRSA isolates remain limited. MATERIAL AND METHODS:Patients with culture-proven S. aureus ocular infection at Chang Gung Memorial Hospital between 2013 and 2022 were included. MRSA isolates were characterized by pulsed-field gel electrophoresis, multilocus sequence typing, and staphylococcal cassette chromosome mec typing, and Panton-Valentine leucocidin genes detection. Antibiotic susceptibility was examined using disk diffusion method and E-test. Temporal trends were analyzed using chi-square tests for trend. RESULTS:A total of 154 MRSA ocular isolates were identified. The predominant clone complex (CC) was CC59 (80/154, 52.0%), followed by CC8 (30/154, 19.5%) and CC45 (25/154, 16.2%). Over the decade, CC59 declined while CC8 increased significantly (P = 0.005 and P = 0.002, respectively), paralleling nationwide systemic MRSA trends. CC8 isolates were more frequently associated with eyelid disorders than CC59 (50.0% vs 28.8%; P = 0.045). CC59 isolates remained highly susceptible to fluoroquinolones (> 95%), while CC8 demonstrated marked resistance (≤ 11% susceptible; P < 0.0001). All isolates were susceptible to vancomycin and teicoplanin. CONCLUSIONS:Ocular MRSA infections in Taiwan demonstrate longitudinal changes in clonal distribution, characterized by declining CC59 and increasing CC8, and a concurrent increase in fluoroquinolone-resistant CC8. This evolution may compromise fluoroquinolone-based empirical therapy, a cornerstone of first-line treatment for ocular infections, and highlights the importance of continued molecular surveillance.
BACKGROUND:The relationship between gastric microbiota composition, Helicobacter pylori infection, and eradication outcomes remains unclear. This study aims to explore the association of gastric microbiota composition among patients with refractory H. pylori infection with the outcomes of rescue therapy. MATERIAL AND METHODS:Patients who failed to respond to second- or third-line eradication therapies were prospectively enrolled. The composition of the gastric microbiota was analyzed using 16S rRNA gene sequencing prior to rescue therapy. The eradication outcomes were confirmed using the [13C]-urea breath test. RESULTS:Among 1,590 screened participants, 23 patients with refractory H. pylori infection who underwent rescue therapy based on antimicrobial susceptibility testing were enrolled. The alpha diversity did not differ between success and failure groups; however, the beta diversity analysis revealed a distinct microbial composition. The success group was enriched in Streptococcus, Neisseria, Cutibacterium, and Staphylococcus, with two significant species, Streptococcus mitis and Streptococcus cristatus. In contrast, Prevotella colorans was enriched in the failure group. CONCLUSIONS:Distinct gastric microbiota signatures were associated with treatment outcomes in patients with refractory H. pylori infection. These findings provide insights that may facilitate the development of microbiota-based diagnostics and interventions to improve eradication success.
BACKGROUND:Endometriosis is an estrogen-dependent inflammatory disorder marked by ectopic lesions, chronic pelvic inflammation, and frequent recurrence. Extracorporeal shock wave therapy (ESWT) is a non-invasive modality with anti-inflammatory and regenerative potential, but its efficacy under varying estrogen conditions remains unclear. METHODS:Endometriosis-like lesions were induced in female rats by suturing uterine fragments to the peritoneum, followed by daily 17β-estradiol (E2) or PBS for 28 days. Sprague-Dawley rats were assigned to control, E2, E2 + ESWT (0.1 or 0.25 mJ/mm2), or ovariectomy (OVX) + ESWT groups. ESWT was applied twice weekly for three weeks. Body weight, food intake, lesion morphology, histology, and serum E2 were assessed. Inflammatory and fibrotic markers were analyzed as follows: transforming growth factor beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) were evaluated by both immunohistochemistry (IHC) and quantitative real-time RT-PCR (qRT-PCR), whereas interleukin (IL)-6, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), cyclooxygenase (COX)-2, vascular endothelial growth factor (VEGF), cytokeratin (CK)-18, superoxide dismutase (SOD), inducible nitric oxide synthase (iNOS), and hypoxia-inducible factor-1 alpha (HIF-1α) were assessed by qRT-PCR only. RESULTS:E2 reduced body weight and food intake and induced cystic peritoneal lesions with upregulated fibrotic and inflammatory markers. ESWT at both energy levels significantly reduced lesion size, cystic formation, the number of endometrial glands (hematoxylin-eosin, H&E staining), fibrosis area ratio (Masson trichrome staining), and expression of fibrosis-, inflammation- oxidative stress-, and hypoxia-related genes and proteins regardless of ovarian status. OVX combined with ESWT produced comparable or slightly enhanced reductions in several markers. ESWT did not alter systemic E2 levels, whereas OVX resulted in reduced serum estrogen levels. CONCLUSION:Low-energy ESWT attenuated E2-induced endometriotic lesions, accompanied by reductions in proliferation, inflammation, and fibrosis, without altering circulating estrogen levels. These effects were also observed under menopause-mimicking conditions with controlled estrogen exposure. These findings suggest that ESWT may serve as a complementary non-hormonal adjunctive approach and may provide a useful experimental framework for future mechanistic and preclinical studies.
BACKGROUND:Patients initially diagnosed with idiopathic pulmonary fibrosis (IPF) have an underlying risk of being in a preclinical phase of rheumatoid arthritis (RA), but effective biomarkers for early identification of this transition are lacking. OBJECTIVE:This review aims to comprehensively summarize predictive markers for future RA in patients meeting IPF diagnostic criteria, supporting early risk stratification and pre-arthritic intervention. METHODS:Using "idiopathic pulmonary fibrosis", "rheumatoid arthritis", "predictive markers", "markers", "clinical research", "in vitro experiments", "mechanism", and their combinations as keywords, a structured literature search was conducted in the PubMed database for relevant literature from 2001 to 2025. RESULTS:The propensity for RA to develop in patients initially meeting IPF diagnostic criteria has a multi-dimensional basis: genetic susceptibility provides the background; immune dysregulation mediates the dissemination of autoimmunity from a pulmonary origin to systemic involvement; inflammatory markers reflect disease activity; environmental exposure acts as an external trigger. Based on these mechanisms, four predictive marker types were identified: genetic susceptibility, immune activation, inflammatory injury, and environmental exposure. However, current studies are mainly cross-sectional and retrospective, lacking prospective validation of predictive efficacy; combined application strategies, clinical value and microbiome-based indicators all require further clinical verification. CONCLUSION:This review identified four early-warning markers-genetic susceptibility, immune activation, inflammatory injury, and environmental exposure-that may signal future RA in patients initially presenting with IPF. These findings support shifting from passive diagnosis to active screening for earlier intervention. Future research should focus on multi-dimensional prediction models, prospective cohort studies, and ultimately achieving early identification and intervention for this hidden RA-prone population.
Non-communicable diseases (NCDs) account for a major share of global mortality and disability, while their development and outcomes reflect interactions among behavioral, metabolic, socioeconomic, environmental, infectious, and non-modifiable factors. This issue of the Biomedical Journal highlights the breadth of contemporary research across NCD epidemiology, mechanisms, diagnosis, prevention, and treatment. A study from northern Peninsular Malaysia examines age- and sex-specific patterns in the burden of cardiovascular disease, respiratory disease, and diabetes, while a review considers the complex association between diabetes, vascular complications, and dementia. Further reviews address strategies to improve glioblastoma vaccines through enhanced antigen presentation and combination immunotherapy, as well as ultrasound-guided interventions for adhesive capsulitis, including stage-specific and structure-oriented approaches to pain relief and functional recovery. The original articles explore a single-dose, non-waiting neoadjuvant immunotherapy strategy for resectable hepatocellular carcinoma; emerging evidence on problematic ChatGPT use; genomic surveillance following an outbreak of carbapenem-resistant Serratia marcescens; the stage-specific role of miR-7974 in colorectal cancer; and the potential diagnostic relevance of DEC-1 in ischemic stroke. Other contributions investigate extracorporeal shockwave therapy as a means of reducing inflammation in experimental psoriasis and Fu's subcutaneous needling as a potential modulator of mitochondrial quality control and inflammatory signaling in a rat model of sciatica. A correspondence exchange on molecular diagnostic platforms for primary mitochondrial diseases discusses the validation, sensitivity, terminology, clinical practicality, and particular advantages of long-read nanopore sequencing.
Liver cancer, particularly hepatocellular carcinoma (HCC), is among the leading causes of cancer-related mortality worldwide, with drug resistance posing a significant therapeutic challenge. Therefore, overcoming this barrier is a critical step toward improving survival outcomes in patients with drug-resistant disease. Here, we demonstrate that the antidepressant imipramine effectively inhibits tumor growth in vitro and in vivo. Notably, imipramine enhances the anticancer efficacy of sorafenib, resulting in an additive suppression of tumor growth and cell migration. Moreover, imipramine treatment restores sensitivity in sorafenib-resistant hepatoma cells. RNA-sequencing analysis identified increased expression of BLOC1S5 in sorafenib-resistant cells compared to their parental counterparts. Functional assays indicated that overexpression of BLOC1S5 promotes tumor sphere formation, cell migration, sorafenib resistance, and metastasis through suppression of FOXO1. Imipramine treatment significantly reduced BLOC1S5 expression while inducing FOXO1 expression. Crucially, the inhibitory effect of imipramine on cell migration was reversed by BLOC1S5 overexpression, indicating that imipramine acts, at least in part, by suppressing this protein. Clinically, elevated BLOC1S5 expression correlated with poor prognosis, whereas higher FOXO1 levels were associated with favorable outcomes in HCC patients. Collectively, these results highlight the repurposing of imipramine as a promising therapeutic strategy to sensitize HCC cells to sorafenib via modulation of the BLOC1S5/FOXO1 signaling axis.
BACKGROUND:Cancer stem cells (CSCs) drive tumor recurrence and metastasis via metabolic reprogramming. Although pyruvate kinase M2 (PKM2) is associated with poor prognosis in head and neck cancer (HNC), the loss of PKM2 promotes tumor formation in mice. Long non-coding RNAs (lncRNAs) have been widely implicated in cancer stemness regulation. However, their roles in PKM2 deficiency-mediated tumor progression remain unclear. METHODS:PKM2 was knocked out in SAS tongue cancer cells using the CRISPR/Cas9 system. Stemness markers, sphere formation, and drug resistance were examined in CSCs. Whole-transcriptome analysis profiled metabolic, signaling, and lncRNA networks in PKM2-deficient CSCs. Reporter assay and signaling inhibitors were used to validate the pathways for PKM2 knockout-induced H19 expression in CSCs. Lentivirus-mediated shRNA silencing was used to knock down lncRNA H19 for functional analyses. RESULTS:PKM2 knockout inhibited parental SAS cell clonogenicity and motility, but promoted sphere formation, stemness-related gene expression, invasiveness, and chemoresistance in CSCs. Transcriptomic and RT-qPCR analyses revealed lncRNA H19 gene upregulation in PKM2-deficient CSCs. Mechanistically, reporter assays confirmed c-Myc signaling activation, and Hedgehog or c-Myc signaling blockade inhibited this PKM2 deficiency-induced H19 expression. Functionally, H19 silencing further impaired clonogenicity and motility in PKM2-deficient parental cells, and effectively suppressed the sphere formation, stemness-related gene expression, invasive capacity, and chemoresistance of CSCs promoted by PKM2 deficiency. CONCLUSIONS:PKM2 loss promotes tongue cancer stemness via the induction of lncRNA H19. Co-targeting the PKM2/H19 axis may be a promising therapeutic strategy for tongue cancer.
BACKGROUND:Hydrogen therapy, which involves the intake of hydrogen as an antioxidant, has been reported to be effective against various oxidative stress-related diseases. However, current methods of hydrogen administration present various problems. Therefore, new methods that allow for the safe and sustained delivery of high doses of hydrogen are needed. Si-based agents offer a promising solution because they can easily and continuously generate large amounts of hydrogen in the digestive tract. Asthma is characterized by chronic airway inflammation, and allergic bronchial asthma-its most readily recognized phenotype-is suspected to be related to oxidative stress. We investigated the effects of Si-based agents on allergic bronchial asthma. MATERIAL AND METHODS:Allergic bronchial asthma was induced in female C57BL/6N mice by epicutaneous sensitization and inhalation challenge with ovalbumin. Bronchial asthma was assessed by cell counts in bronchoalveolar lavage fluid (BALF) and lung histopathological analysis. mRNA expression levels of cytokines and chemokine in lung tissue and total IgE concentration in serum were measured. RESULTS:The administration in the diet of this Si-based agent to a model mouse of allergic bronchial asthma significantly suppressed eosinophil counts in the BALF and reduced inflammatory cell infiltration in the lungs. In addition, the expressions of interleukins 5, and 13 and C-C motif chemokine 11 in lung tissue tended to decreased in the Si group compared with those in the control group. We examined the timing of administration of Si-based agents and found that Si-based agents worked during the sensitization and elicitation phases and tended to decrease the total IgE concentration in serum. CONCLUSIONS:Si-based agents are effective against allergic bronchial asthma and may serve as superior materials for hydrogen therapy. We anticipate that our study will provide valuable insights into the mechanisms of Si-based agents against type I allergy and facilitate their clinical application in the future.
BACKGROUND:This study investigated the association between HBsAg levels at end of treatment (EOT) and different HBV relapse patterns or HBsAg seroclearance after discontinuing entecavir or tenofovir disoproxil fumarate (TDF). METHODS:A total of 900 non-cirrhotic patients (616 HBeAg-negative and 284 HBeAg-positive at initiation) who had discontinued entecavir or TDF for at least 12 months were retrospectively analyzed. RESULTS:HBeAg-negative patients achieved significantly higher rates of HBsAg seroclearance than HBeAg-positive patients (10 years: 29.8% vs. 19.7%, p=0.007), despite comparable rates of clinical relapse and retreatment. Among the 118 HBeAg-negative and 35 HBeAg-positive patients who experienced HBsAg seroclearance, 39 (33.1%) and 8 (22.8%) did experience clinical relapse prior to HBsAg seroclearance, respectively. In HBeAg-negative patients who achieved seroclearance, different HBV relapse patterns were associated with distinct HBsAg kinetic profiles. An HBsAg threshold of ≤20 and 20-100 IU/mL identifies patients with a high likelihood of HBsAg loss (10-year cumulative incidence of 82.7% and 50.4%, respectively) with 0% and 31.0% clinical relapse, respectively. In HBeAg-positive patients, those with an EOT HBsAg ≤100 IU/mL achieved the highest rate of HBsAg loss (10-year cumulative incidence of 64.8%) with only 6.7% (1/15) clinical relapse. There was no significant difference in HBsAg seroclearance rates between the initial and subsequent finite therapies. Eight patients developed hepatic decompensation upon clinical relapse (annual incidence rate of 0.13 per 100 person-years). CONCLUSION:HBV relapse patterns strongly affect HBsAg kinetics and HBsAg seroclearance. EOT HBsAg levels predict both HBsAg seroclearance and clinical relapse rates prior to HBsAg seroclearance.
BACKGROUND:Chronic atrophic gastritis (CAG) is a progressive gastric disorder with the potential for malignant transformation. Conventional treatments primarily focus on Helicobacter pylori eradication and symptom management; however, long-term use may be associated with hepatic or renal adverse effects. Although acupuncture has demonstrated therapeutic benefits in CAG, its underlying mechanisms remain insufficiently understood. This study aimed to investigate the multi-target mechanisms of acupuncture in CAG through an integrated strategy combining network pharmacology and experimental validation. METHODS:An integrative approach involving bioinformatics, text mining, and network analysis was employed, followed by in vivo validation in a rat model of CAG. Bioactive compounds generated following acupuncture intervention were identified through literature retrieval, and their potential targets were predicted using Search Tool for Interacting Chemicals (STITCH) and SwissTargetPrediction. CAG-related targets were collected from the GeneCards, OMIM, and UniProt databases. The overlapping targets were used to construct a protein-protein interaction network in Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using DAVID. For experimental validation, CAG was induced in rats, followed by acupuncture treatment. Gastric antral tissues were evaluated by histological staining, including hematoxylin-eosin and Prussian blue staining, as well as molecular assays, including western blotting, immunohistochemistry, immunofluorescence, and ELISA, to assess the expression of IL-6, TNF-α, IL-1β, GSH, mTOR, GPX4, FTH1, TP53, and Fe3+. RESULTS:A total of 98 potential therapeutic targets and 159 signaling pathways associated with acupuncture treatment for CAG were identified, with TP53- and mTOR-related signaling pathways emerging as key regulatory pathways. In the rat model, CAG induced marked gastric pathological injury, iron accumulation, and increased inflammatory cytokine levels, accompanied by reduced levels of GSH, TP53, mTOR, GPX4, and FTH1. Acupuncture treatment significantly alleviated gastric mucosal atrophy and inflammation, reduced Fe3+ deposition and pro-inflammatory cytokine levels, and upregulated ferroptosis-related proteins. CONCLUSION:Acupuncture may ameliorate CAG by modulating the TP53 and mTOR signaling pathways, regulating ferroptosis, attenuating mucosal injury, and improving gastric pathological alterations.
BACKGROUND:Estimation of lumbar spinal loads is important for understanding low back pain, guiding ergonomic interventions, and informing surgical and rehabilitation planning. Historically, intradiscal pressure (IDP) provided one of the few internal in vivo measures of disc loading; more recently, telemetry, musculoskeletal (MS) modeling, finite element (FE) analysis, hybrid MS-FE approaches, displacement/control-based methods, and AI surrogates have expanded the toolbox for estimating spinal loads. MATERIAL AND METHODS:We present a narrative perspective review based on a literature search in PubMed, Scopus, and Web of Science using terms related to spinal loads, IDP, telemeterized implants, MS modeling, FE analysis, hybrid MS-FE coupling, displacement/control-based methods, wearable/EMG-based approaches, and AI/machine learning surrogates. Human lumbar studies and methodological contributions relevant to load estimation or validation were included; animal models were excluded. RESULTS:Invasive approaches (needle-based IDP, discography, intra-abdominal pressure, and telemeterized implants) provide task-dependent internal pressures or forces in small, selected cohorts and now primarily serve as benchmarks for model validation. MS models estimate segmental compression, shear, and net moments from motion and EMG, with typical L4-L5 compressive forces of ∼1-2 kN in relaxed standing and ∼3-5 kN during common lifting tasks. FE and hybrid MS-FE simulations resolve how these loads are distributed across discs, facets, and ligaments and relate segmental forces to internal stresses. Displacement-driven/control-based models and emerging AI/wearable-based surrogates provide additional non-invasive pathways for task-specific lumbar load estimation. CONCLUSIONS:This methods-focused synthesis outlines how invasive data support MS, FE, hybrid, and AI-based approaches and highlights recurring challenges in muscle redundancy, constitutive and parameter uncertainty, limited in vivo benchmarks, and heterogeneous model reporting. Within this framework, IDP is best regarded as an internal benchmark rather than a stand-alone metric of "spinal load" which is more fully described by compression, shear, moments, and internal stresses.
BACKGROUND:Aberrant regulation of autophagy and persistent activation of the phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) signaling axis are recognized hallmarks of cancer progression, therapeutic resistance, and disease relapse. Coumarins, a chemically diverse class of natural and synthetic benzopyranone derivatives, have recently emerged as promising modulators of both autophagy and PI3K/mTOR signaling, positioning them as attractive candidates for next-generation anticancer strategies. AIM:This review critically examines current evidence on the ability of coumarin derivatives to regulate autophagy and PI3K/mTOR signaling in cancer, with emphasis on their mechanistic intersections, therapeutic implications, and translational potential. METHODS:A structured and integrative analysis of preclinical studies was conducted using major scientific databases, including PubMed, Scopus, and Web of Science. Relevant articles were identified using combinations of keywords such as "coumarins", "autophagy", "PI3K/mTOR", and "cancer". Only peer-reviewed studies written in English and reporting data from cellular or animal cancer models were included. Mechanistic evidence related to autophagy induction or inhibition, modulation of the PI3K/mTOR pathway, pharmacokinetic properties, safety considerations, and combination therapy strategies was systematically evaluated. RESULTS:Accumulating evidence demonstrates that coumarins can either induce or inhibit autophagic flux in a context-dependent manner, often through direct or indirect modulation of PI3K/mTOR signaling. These dual actions influence cancer cell survival, apoptosis, senescence, and sensitivity to chemotherapy. Several coumarins exhibit multitarget activity, addressing therapy resistance while maintaining favorable safety profiles. Emerging data further support their use in rational combination strategies and patient-stratified therapeutic approaches. CONCLUSION:Coumarins represent versatile molecular scaffolds capable of fine-tuning autophagy and PI3K/mTOR signaling in cancer. A deeper mechanistic understanding, alongside optimization of pharmacokinetics and patient stratification, will be essential for translating coumarin-based modulators into clinically effective anticancer therapies.
BACKGROUND:Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) followed by post-transplant cyclophosphamide (CPA) treatment is an avenue to expand the pool of potential donors. This study aimed to investigate whether the gene polymorphisms related to CPA activation and metabolism are associated with the clinical outcomes of patients receiving haplo-HSCT. METHODS:Genomic DNA from 35 haplo-HSCT patients were subject to analysis of 34 genetic polymorphisms located in CYP2B6, CYP2C19, ALDH1A1, ALDH3A1, GSTA1, GSTP1, GSTM1, and GSTT1 genes. The association of these gene polymorphisms with the occurrence of graft-versus-host disease (GVHD), relapse, and survival status of patients were analyzed by chi-square or Fisher's exact test under five genetic models, logistic regression analysis, and cumulative hazard curve analysis. RESULTS:Age, gender, conditioning regimens, and the use of phenytoin were not associated with the clinical outcomes post-haplo-HSCT. Five SNPs in CYP2B6 (rs3745274 and rs8192719), CYP2C19 (rs 4244285 and rs3758580), and ALDH3A1 (rs2228100) genes were associated with chronic GVHD (cGVHD), acute GVHD (aGVHD) grade I-II, and GVHD, respectively. No SNPs were linked to survive or relapse. Logistic regression analysis adjusting for the use of phenytoin and conditional regimens and cumulative hazard curve analysis further demonstrated that rs375274 in the CYP2B6 gene was associated with the development of cGVHD, while rs222810 in the ALDH3A1 gene was associated with the development of aGVHD and aGVHD I-II for patients receiving haplo-HSCT. CONCLUSIONS:This study highlights the impacts of genetic polymorphisms related to CPA bioactivation and metabolism on the clinical outcomes of haplo-HSCT with post-transplant CPA. Despite the limited sample size and retrospective nature, identifying risk loci to enhance the transplant success rates for patients receiving haplo-HSCT is warranted.
BACKGROUND:Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has significantly improved outcomes in non-small cell lung cancer (NSCLC), yet resistance remains a major clinical challenge. Protein arginine methyltransferase 5 (PRMT5) is an oncogenic regulator associated with poor prognosis, but its role in immune checkpoint modulation and underlying molecular mechanisms remain incompletely defined. MATERIALS AND METHODS:PRMT family expression and clinical correlations were analyzed using Oncomine, TCGA, and CPTAC databases. The effect of PRMT5 on PD-L1 was examined in LKB1-proficient and LKB1-deficient NSCLC cell lines using pharmacological inhibitors (GSK3326595, JNJ-64619178) and shRNA knockdown. Mechanistic analyses included co-immunoprecipitation (Co-IP), cycloheximide chase assays, and site-directed mutagenesis of LKB1 arginine residues. T-cell activation was evaluated using co-culture models. RESULTS:Elevated PRMT5 expression in NSCLC was associated with poor survival, reduced CD4+/CD8+ T-cell infiltration, and higher PD-L1 expression in clinical datasets. Functional analyses revealed context-dependent regulation of PD-L1 by PRMT5. PRMT5 inhibition reduced or failed to induce PD-L1 in LKB1-deficient cells but upregulated PD-L1 in LKB1-proficient cells. Mechanistically, PRMT5 interacted with LKB1 and promoted its degradation through symmetric arginine dimethylation at R409. Conversely, PRMT5 inhibition stabilized LKB1, activated AMPK signaling, and induced PD-L1 expression in LKB1-proficient cells. Combination treatment with a PRMT5 inhibitor and anti-PD-L1 antibody further enhanced T-cell activation in co-culture models. CONCLUSION:These findings identify a PRMT5-LKB1-AMPK regulatory axis controlling PD-L1 expression in a cell-context-dependent manner and suggest that LKB1 status may serve as a predictive biomarker for combining PRMT5 inhibitors with ICB in NSCLC. This strategy offers a potential therapeutic avenue to overcome immunotherapy resistance in LKB1-proficient NSCLC.
Adhesive capsulitis is a painful and disabling shoulder condition characterized by progressive synovial inflammation, capsular fibrosis, and global restriction of motion. Conventional treatment strategies, including physical therapy and landmark-guided intra-articular corticosteroid injection, often yield variable outcomes. Ultrasound-guided interventions have emerged as a precision-based therapeutic approach, enabling real-time visualization of pathological structures, accurate needle placement, and dynamic assessment of capsular mechanics. This narrative review summarizes current evidence on ultrasound-guided corticosteroid injection, hydrodilatation, coracohumeral ligament–targeted procedures, suprascapular nerve block, and silent manipulation under cervical nerve root block. Across studies; injection target, injectate composition, and mechanical distension strategy appear to influence short-term pain relief and functional improvement. Rotator interval–targeted injections and coracohumeral ligament release specifically address anterior capsular contracture and loss of external rotation. Hydrodilatation provides mechanical capsular expansion, although superiority over corticosteroid injection alone remains inconsistent. Suprascapular nerve block primarily facilitates early analgesia to support rehabilitation, whereas silent manipulation restores mobility through structured capsular release under ultrasound-guided anesthesia. Collectively, contemporary evidence supports a shift from uniform application of technique toward stage-specific, structure-oriented, and pathology-driven management. Integration of dynamic ultrasound assessment into treatment planning may further refine patient selection and optimize long-term functional recovery. Future investigations should focus on long-term durability, optimal injectate parameters, and individualized intervention algorithms.
Background: ChatGPT has rapidly permeated various domains, including education, industry, creativity, and daily life. While offering efficiency and emotional engagement, excessive reliance may lead to problematic use with adverse effects on mental health, cognition, and social functioning. This review synthesizes current evidence on manifestations, etiologies, assessment, and neurophysiological correlates of problematic ChatGPT use. Material and methods: A narrative review of empirical studies, psychometric developments, theoretical models, and preliminary electroencephalogram findings was conducted, with cross-cultural comparisons across Taiwan, Turkey, China, Korea, Singapore, and the United States. Results: Problematic ChatGPT use is prevalent among young adults and associated with depression, stress, impaired self-control, and functional difficulties. Psychometric tools such as the Problematic ChatGPT Use Scale, Conversational AI Dependence Scale, and Generative AI Dependency Scale provide initial frameworks but require further validation. Theoretical models (Interaction of Person–Affect–Cognition–Execution model, compensatory Internet use, dual-system theory) have been used to explain the roles of emotional regulation deficits, cognitive biases, and intuitive processing for the development of problematic ChatGPT use. Preliminary electroencephalogram studies suggest altered functional connectivity, paralleling digital addiction patterns. Conclusions: Problematic ChatGPT use involves psychological, behavioral, and neurobiological mechanisms. Future research should strengthen psychometric validation, expand electroencephalogram investigations, and evaluate interventions such as digital literacy education, behavioral self-regulation, cognitive-behavioral therapy, and neurofeedback to promote healthier AI engagement.
