Ko-Ting Chen

Background Substantial cardiovascular and kidney risk persists after successful weight loss. Whether features that genetics implicates in cardiovascular-kidney-metabolic (CKM) disease show larger short-term responses to weight-loss and cardiometabolic interventions than other features is unknown. Methods Across four molecular layers (proteome, transcriptome, methylome, metabolome), we applied layer-specific cis-Mendelian randomization with colocalization or summary-data shared-signal filtering against eight CKM genome-wide association studies. Within 13 omics-by-intervention analyses (diet, bariatric surgery, empagliflozin, behavioral weight loss), we compared response magnitude between nominated and adequately-instrumented non-nominated features using rank-based Cliff's δ ; methylation was baseline-variance-matched and directional analyses exploratory. Results Here we show genetic nomination is not consistently associated with larger observed response magnitude: estimates are small (|δ| < 0.08 in all 13; median |δ| = 0.03), near zero (descriptive pooled δ = +0.001, 95% CI −0.013 to +0.015; I ² = 0%), none significant by label-permutation, though smaller proteomic and transcriptomic analyses remain compatible with modest differences. Nominated proteins and metabolites frequently changed (48—71% were responsive), at rates similar to comparison features; the null is not one of universal non-response. Nominated CpG sites have lower baseline inter-individual variance (Mann–Whitney P = 1.7 × 10 ⁻⁶ to 4 × 10 ⁻³ at the primary nomination tiers), and apparent methylation persistence attenuates after variance-matching. Conclusions Under the definitions and datasets studied, genetic target support does not consistently predict pharmacodynamic responsiveness and should not be read as a treatment-response or reversibility biomarker; baseline dynamic range should be assessed and controlled when comparing molecular change across selected features. Nominated features are not shown unchanged or to explain residual risk; same-subject longitudinal studies are needed to test prognostic or therapeutic value.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder among the elderly. Although pharmacological therapies can alleviate symptoms, they often fail to provide sustained or complete symptom control, underscoring the need for alternative therapeutic strategies. Neuromodulation techniques, particularly cortical electrical stimulation (CES), have shown promise in modulating cortical plasticity. However, the therapeutic efficacy of CES in PD remains to be fully elucidated. In this study we investigated the long-term therapeutic potential of a novel CES protocol in a transgenic MitoPark mouse model of PD. Methods: MitoPark mice received CES beginning at 8 weeks of age (one session per day, 2 days per week) for a total of 12 weeks. Motor function was assessed using a comprehensive behavioral battery, including beam walking, open-field, and gait performance tests. Neuroprotective effects were evaluated by quantifying dopaminergic neuronal survival and striatal fiber density using tyrosine hydroxylase (TH) immunohistochemistry. Results: Long-term CES treatment significantly ameliorated motor impairments in MitoPark mice, improving locomotor activity, gait coordination, and beam walking performance compared with sham controls. Immunohistochemical analyses further revealed enhanced survival of nigrostriatal dopaminergic neurons and fibers in the CES-treated group, indicating pronounced neuroprotective effects. Conclusions: These findings demonstrate that early and sustained CES intervention mitigates motor deficits and enhances dopaminergic neuron survival in the MitoPark PD model. The results provide compelling preclinical evidence supporting CES as a potential adjunctive neuromodulatory therapy for Parkinson’s disease.

BACKGROUND AND OBJECTIVES: Combining focused ultrasound (FUS)–induced blood-brain barrier opening with bevacizumab (BEV) has demonstrated survival benefits in preclinical models. This study aimed to evaluate the safety and feasibility of repeated FUS-BEV treatments in patients with recurrent glioblastoma and to explore imaging and serum biomarkers in relation to disease status. METHODS: This was a prospective, single-arm, open-label pilot trial. The primary end point was 6-month progression-free survival (PFS). Disease progression was assessed according to the Response Assessment in Neuro-Oncology criteria by independent radiological review. Radiological response was evaluated using fluid-attenuated inversion-recovery sequences to compare FUS-exposed vs nonexposed regions. Plasma cell–free DNA (cfDNA) concentrations were measured before and after FUS treatment. RESULTS: Between July 2020 and August 2023, 6 patients received a median of 14.5 sessions of biweekly FUS-BEV (10 mg/kg). The median PFS was 11 months, with a 6-month PFS rate of 66.7%. The only FUS-related adverse event was transient scalp heating (grade 1; 1.9%). A fluid-attenuated inversion recovery normalization effect emerged within 1 month after treatment. Plasma cfDNA increased significantly post-FUS, with total cfDNA rising 2.03 ± 0.76-fold, EGFR cfDNA 1.77 ± 0.76-fold, and HMBS cfDNA 1.68 ± 0.66-fold. CONCLUSION: Repeated FUS-BEV treatment is safe and feasible in patients with recurrent glioblastoma. Randomized controlled trials are warranted to confirm its therapeutic efficacy and validate imaging and liquid biopsy biomarkers.

Supplementary Table 2. Patient demographics of CGGA cohorts.

Supplementary Figure 9. Hypoxia induced SSAT expression in glioma cells and the intracellular GSH levels.

Supplementary Table 3. Cox regression analysis of TCGA cohorts.

Supplementary Table 1. Patient demographics of TCGA cohorts.

Glioblastoma (GBM), a highly aggressive brain tumor, thrives in hypoxic environments. Tumor-derived exosomes are key drivers of glioma progression, facilitating tumor growth, immune evasion, angiogenesis, and therapy resistance. Acrolein, a toxic byproduct produced under hypoxic conditions, causes DNA damage, inflammation, and mitochondrial dysfunction and potentiates oxidative stress. Elevated acrolein levels and associated DNA damage are linked to poor GBM prognosis. This study aims to uncover the role of acrolein in GBM progression through exosome-mediated pathways and the associated molecular mechanisms. We found that acrolein production under hypoxia promotes GBM cell malignant behaviors, such as migration and spheroid formation, by downregulating NCAM1 via autocrine and paracrine signaling of miR-30a-5p. Inhibiting the miR-30a-5p/NCAM1 axis reverses the tumor-promoting effects of acrolein treatment. Analysis of tumor samples from GL261 tumor–bearing mice and patients with glioma showed that decreased NCAM1 levels in glioma tissues correlate with elevated acrolein expression. In samples of patients with GBM, lower NCAM1 levels are associated with a worse prognosis. This study suggests that targeting the miR-30a-5p/NCAM1 axis could be a potential therapeutic strategy for GBM.