Taipei Medical University Hospital (TMUH; Chinese: 臺北醫學大學附設醫院) is a healthcare facility in Taipei, Taiwan established in 1976.
Heterozygous (G603R) LRP10 mutation causes autosomal dominant Parkinson's disease (PD). Heterozygous Lrp10G603R/+ mice were prepared to unravel pathomechanisms underlying (G603R) Lrp10-induced death of substantia nigra (SN) dopaminergic neurons. Lrp10G603R/+ mouse exhibited PD movement deficits, neurodegeneration of SN dopaminergic cells and existence of SN phospho-α-synuclein-containing aggregates. Lrp10 was expressed in mouse SN dopaminergic neurons, and WT LRP10 exerted neuroprotection function on dopaminergic cells by repressing α-synuclein gene transcription and downregulating α-synuclein mRNA. (G603R) LRP10 failed to negatively regulate α-synuclein mRNA of dopaminergic neurons, and heterozygous (G603R) Lrp10 mutation elevated protein and mRNA of pathological α-synuclein or α-synuclein oligomers in SN dopaminergic cells of Lrp10G603R/+ mouse. Macroautophagy activator rapamycin reversed (G603R) Lrp10-induced increment of α-synuclein, death of SN dopaminergic cells and PD locomotor disability in Lrp10G603R/+ mouse. (G603R) Lrp10 upregulation of α-synuclein increased ER α-synuclein and activated ER stress and UPR, resulting in excitation of ER stress pro-apoptotic pathway in SN of Lrp10G603R/+ mouse. Upregulated α-synuclein within SN dopaminergic cells increased mitochondrial α-synuclein and induced mitochondrial detriment and oxidative insult in SN of Lrp10G603R/+ mouse. (G603R) Lrp10-evoked overexpression of Puma, Noxa or Bim and mitochondrial abnormality excited mitochondrial apoptotic process in SN of Lrp10G603R/+ mouse. Elevated α-synuclein oligomers excited NLRP3 inflammasome and microglia in SN of Lrp10G603R/+ mouse, leading to incremented IL-1β-, IL-18- or TNF-α-triggered MKK4-JNK-c-Jun/ATF-2 degeneration and RIPK1-RIPK3-MLKL necroptotic pathways. Our data propose that heterozygous loss-of-function (G603R) mutation of LRP10 debilitates WT LRP10-mediated downregulation of α-synuclein mRNA, leading to elevated α-synuclein-evoked neurodegeneration of SN dopaminergic cells and autosomal dominant PD.
Heterozygous missense mutations of TAU cause frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). FTDP-17T neurodegeneration of hippocampal and substantia nigra dopaminergic cells causes dementia and parkinsonism motor deficits. FTDP-17T cellular model of mutant TAU-expressing differentiated dopaminergic or hippocampal neurons was utilized to test hypothesis that FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs located in different domains of TAU cause neurodegeneration with the same pathomechanism. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs caused degeneration of dopaminergic or hippocampal neurons via mutation-induced gain-of-neurotoxicity. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations promoted Ser202/Ser396/Ser404 phosphorylations of TAU and formation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers in dopaminergic or hippocampal neurons. GSK-3β inhibitor AR-A014418 completely blocked (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity by preventing (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations-augmented Ser202/Ser396/Ser404 phosphorylations and genesis of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers. Phospho-(R5H), phospho-(N279K), phospho-(K298E), phospho-(P301S), phospho-(K317M) or phospho-(G389R) TAUSer202/Ser396/Ser404 oligomers were found in ER of dopaminergic or hippocampal neurons and activated ER stress, UPR and ER stress apoptotic signaling. Overexpression of mitochondrial phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers caused mitochondrial malfunction via depolarizing mitochondrial membrane potential and oxidative damage by increasing ROS. Phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers-evoked upregulation of Noxa, Bim or Puma and mitochondrial defect and oxidative stress excited mitochondrial pro-apoptotic pathway. Our results suggest that shared pathomechanism underlying FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity is mutation-augmented GSK-3β-mediated Ser202/Ser396/Ser404 phosphorylations and generation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers, which cause neurodegeneration by stimulating ER stress and mitochondrial pro-apoptotic cascades.
Hypoxia in tumor niche is one of important factors to start regeneration of blood vessels, leading to increase survival, proliferation, and invasion in cancer cells. Under hypoxia microenvironment, furthermore, steadily increased hypoxia-inducible factor-1α (HIF-1α) is observed, and can increase vascular endothelial growth factor (VEGF) expression and promote angiogenesis. Zinc protoporphyrin (ZnPP), a heme oxygenase-1 (HO-1) inhibitor, is potential to inhibit tumor proliferation and progression. However, the mechanism of ZnPP in inhibition of tumor is not completely clear. We hypothesize that ZnPP may modulate HIF-1α through inhibiting HO-1, and then inhibit angiogenesis and tumor progression. This study aimed to dissect the mechanism of ZnPP in tumor suppression.
Glioblastoma Multiforme (GBM) is an aggressive and highly heterogeneous brain tumor with poor survival outcomes. While conventional radiomic analyses focus on tumor-centric regions, emerging surgical strategies, such as GTR and supratotal resection (SupTR), highlight the importance of the peritumoral zone. Moreover, due to intratumoral heterogeneity, MGMTpm, a key molecular biomarker guiding chemotherapeutic decisions, is assessed invasively and remains prone to sampling bias. Therefore, this study examined the prognostic and predictive utility of deep radiomic features from tumor and peritumoral regions in preoperative MRI to improve OS prediction and enable non-invasive MGMTpm classification. Multi-parametric structural MRI scans (T1, T1-Gd, T2, and T2-FLAIR) from 520 to 200 GBM patients were analyzed for OS and MGMTpm prediction, respectively. Tumor and peritumoral masks were segmented and expanded using morphological dilation from 2 to 12 mm. 11,000 deep features per patient were extracted using ResNet50 and ViT-B16 models, capturing patterns that may reflect tumor infiltration and microenvironmental changes. Hybrid feature selection using variance thresholding and Recursive Feature Elimination (RFE) was applied, including age and gender. Support Vector Machine (SVM) classifiers were trained using 10-fold cross-validation. In OS prediction, the inclusion of an 8 mm peritumoral margin improved AUC from 0.74 (95
Radiation-induced oral mucositis requires predictive biomarkers for personalized therapy. We evaluated salivary IL-6 for predicting severe mucositis and response to food-grade bee products. Secondary analysis of 51 head/neck cancer patients randomized to honey (n = 15), Taiwanese green propolis (TGP, n = 17), or usual-care (n = 19). Both interventions used standardized preparations (10 g in 20 mL water, 10 mL TID). Salivary cytokines were analyzed using ELISA at baseline and during early radiotherapy. Salivary IL-6 at week 3 of radiotherapy demonstrated superior predictive performance (AUC = 0.780, 95
