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Intraflagellar transport 140 mutations in Taiwan polycystic kidney disease
No full text[[abstract]]Background: Autosomal dominant polycystic kidney disease (ADPKD) is primarily caused by PKD1 and PKD2, followed by a small portion of cases caused by GANAB and DNAJB11. Other genes, including ALG8, ALG9, PKHD1, and COL4A can cause similar cystic ab-normality and mimic ADPKD. We previously performed the genetic analysis in a total of 920 ADPKD families and identified nearly 70% of the genetic causes. However, many families remained undiagnosed or had only a variant of uncertain significance identified. We performed exome sequencing in a total of 286 families aiming to identify their disease-causing genes. Methods: A total of 286 probands from 286 families were included in this study. The study was approved by the institutional review boards of the Kaohsiung Medical University Hospital. Nextera Flex for Enrichment and Exome panel (CEX V2, Illumina) was used for exome library creation. The resulting fastq data were aligned to the reference human genome sequence and performed nucleotide variant calling using the DRAGEN Bio-IT platform (Illumina). The VCF file was analyzed in CLC Genomics Workbench (Qiagen). FastreeR was used to calculate distances, build phylogenetic trees, and perform hierarchical clustering between the samples. Results: A total of 11 families were identified to have 6 different heterozygous IFT140 truncation or obligatory splicing variants, including p.Glu51*, p.Leu540*, p.Gln667*, p.Asp738fs, p.Tyr923fs, and p.Gln1162* in the Taiwan ADPKD cohort. Two recurrent mutations, p.Glu51* and p.Leu540* were identified. Phylogenetic analysis showed that the two families with the p.Leu540* variant should be close relatives, while the 5 families with p.Glu51* have various degrees of kinship. Most affected individuals have relatively fewer and larger kidney cysts than classical ADPKD individuals. Their kidney function deterioration rate differs significantly in these 11 affected individuals. Conclusions: Our data showed that heterozygous IFT140 pathogenic mutations represented a small but significant 1.2 percent of ADPKD in Taiwan. All our IFT140 pathogenic mutations are different from the report by Senum et. al. in 2022, although 4 of them existed in the GnomAD database. Missense variants of IFT140, as well as variants in the other intraflagellar proteins, were also identified. However, their role in the pathogenicity of ADPKD needs further evidence and functional analysis
Air pollution associated with mortality among chronic hepatitis B patients treated with nucleotide/nucleoside analogues
No full text[[abstract]]Background and Aims: Air pollution is associated with advanced liver fibrosis in patients with chronic liver diseases, including chronic hepatitis B (CHB). This study aimed to investigate the association between air pollution and mortality in patients with CHB treated with nucleotide/nucleoside analogues. Methods: We enrolled 697 patients with CHB treated with nucleotide/nucleoside analogues and analysed the incidence and risk factors for mortality. Daily air pollutant concentrations were estimated from the year before enrolment. Results: All-cause mortality showed an annual incidence of 1.1/100 person-years after a follow-up period of 3798.1 person-years. Factors with the strongest association with all-cause mortality were liver cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 3.95/1.69-9.23; p = 0.02), age ([HR]/CI: 1.07/1.03-1.17, p 25.5 ppb were associated with a higher incidence of mortality in patients with cirrhosis (HR/CI:2.49/1.03-6.02; p = 0.04). Conclusions: Air pollution influences all-cause mortality in patients with CHB receiving nucleotide/nucleoside analogue therapy. Long-term NOx exposure may increase liver-related mortality in patients with chronic hepatitis B and cirrhosis receiving nucleotide/nucleoside analogue treatment
Higher nonunion rates with locking plates compared to dynamic compression plates in forearm diaphyseal fractures: A multicenter study
No full text[[abstract]]Background Dynamic compression plate (DCP) osteosynthesis is the gold standard for treating forearm diaphyseal fractures, providing stability and promoting healing. Locking plates (LPs) are increasingly used in modern fracture management but may increase the risk of nonunion if applied with excessive rigidity and without proper fracture site compression. The purpose of this study is to compare the nonunion rate between LPs and DCPs. Materials and methods We conducted a retrospective study by reviewing the medical records and radiographs of 515 patients diagnosed with radial and/or ulnar shaft fractures at three trauma centers between 2014 and 2019. Inclusion criteria were patients treated with locking plates (LPs), locking compression plates (LCPs), or dynamic compression plates (DCPs) who had at least 9 months of outpatient follow-up and imaging assessments. Exclusion criteria included treatment with other methods, hospitalization for pathological fractures or implant removal, or incomplete surgical records. Data on patient demographics, injury details, and surgical outcomes were collected to compare nonunion rates, as well as early and late complications, between the LP and DCP groups. Results A total of 368 patients were included in the analysis. Among them, 132 (35.9%) had isolated radial shaft fractures, 116 (31.5%) had isolated ulnar shaft fractures, and 120 (32.6%) had both-bone fractures. Of these, 124 patients received LP implants, 98 were treated with LCPs, and 146 were treated with DCPs. Early complications were comparable among the groups; however, the nonunion rate was significantly higher in the LP group (18.5% versus 11.2% versus 6.2%, p < 0.007). Logistic regression identified LP use [odds ratio (OR): 3.05, 95% confidence interval (CI) 1.24-7.53] as a significant predictor of nonunion. Notably, LPs lacking dynamic compression functionality were associated with markedly higher odds of nonunion in radial shaft fractures (OR: 26.94, 95% CI 3.52-206.15). These findings collectively indicate that LPs increase the nonunion rate in forearm fractures. Conclusions Using LPs without compression functionality to treat forearm diaphyseal fractures increases the nonunion rate, particularly in radial shaft fractures. Therefore, we recommend using LCPs or DCPs for forearm diaphyseal fractures to ensure adequate compression at the fracture site during fixation, thereby promoting optimal bone healing rates. Level of evidence: Level III: retrospective comparative therapeutic study
Enhanced construction of a bivalent adenovirus-based vaccine for preventing childhood pathogens: Human respiratory syncytial virus and norovirus
No full text[[abstract]]To impede the spread of respiratory syncytial virus (RSV) and norovirus (NoV) in children, we developed novel recombinant adenoviruses expressing RSV fusion (F) and NoV VP1 proteins driven by different promoter elements (EF1 alpha, SV40, and CMV), resulting in Ad-F/E/NoV, Ad-F/S/NoV, and Ad-F/C/NoV, respectively. The expressed F can be recognized by postfusion-specific antibody targeting to site II and prefusion-specific antibodies targeting to sites V and & Oslash; in the Ad-F-infected cells. However, NoV VP1 is only expressed in Ad-F/E/NoV and Ad-F/C/NoV-infected cells. Intraperitoneal two-dose with monovalent Ad-F and all three bicistronic Ads individually in rodents induced anti-F neutralizing antibodies similarly. Ad-F/C/NoV and Ad-F/E/NoV but not Ad-F/S/NoV significantly induced NoV VP1-specific IgG. The serum from Ad-F/C/NoV-immunized subjects elicited superior anti-NoV activity, as evidenced by reduced binding of NoV VLPs to histo-blood group antigens. Ad-F/C/NoV and Ad-F/E/NoV-immunized mice exhibited elevated cellular immune-mediated splenic IFN-gamma and IL-4 secretions. In the RSV challenge study, pulmonary virions were significantly decreased during the vaccination with each of the three bicistronic Ads, confirming their efficacy in preventing RSV infection. Finally, the mucosal (intranasal) immunization in mice with Ad-F/C/NoV induced superior anti-RSV and NoV IgA in both serum and vaginal washes specific to RSV and NoV were highly induced. These findings highlight the optimization of an Ad vaccine targeting two pathogens prevalent in childhood. Additionally, the results underscore the utility of mucosal delivery of Ad vaccines as a valuable strategy for public vaccination efforts
EndoMT cells stimulate the stemness of colorectal cancer cells through the secretion of JAG1
No full text[[abstract]]Cancer stem cells are believed to contribute to drug resistance and poor prognosis. Previously, we demonstrated that OPN can induce the differentiation of EndoMT cells, a type of Cancer-associated fibroblast (CAF) derived from endothelial cells, constituting approximately 40-60% of CAFs in the tumor microenvironment. Our current study observed that the conditioned medium of EndoMT cells could stimulate colorectal cancer cells to express stemness markers such as CD133, ALDH, and CD326 and form cell spheroids. Moreover, we found that the conditioned medium of EndoMT cells contained higher levels of soluble JAG1, an extra cellular domain of JAG1 cleaved by ADAM17, which is known to induce stemness in colorectal cancer (CRC) cells. When CRC cells were treated with recombinant JAG1, the expression of stemness markers mentioned above, along with related transcription factors such as Nanog, Oct4, and KLF4, were upregulated. Additionally, the rate of cell spheroid formation increased following recombinant JAG1 treatment. These data suggest that EndoMT cells secrete soluble JAG1 to stimulate CRC cells to gain cell stemness
Utilizing radioactive gold nanoparticles in simultaneous chemoradiotherapy of glioblastoma
No full text[[abstract]]This research showcases a single-step method for synthesizing radioactive gold nanoparticles (RGNP) without using radioactive precursors or reducing agents. Trivalent gold ions undergo reduction to yield gold nanoparticles, with a specific fraction of 197Auatoms concurrently transmuting into 198Au atoms, thereby rendering the nanoparticles with radioactivity. This study proposes the viability of leveraging nuclear energy for gold nanoparticles to propel advancements in nanotechnology for cancer therapy. Employing RGNP via convection-enhanced delivery (CED) in conjunction with temozolomide (TMZ) administered orally demonstrates synergistic effects in treating glioblastoma-bearing mice. The mean survival duration for RGNP/TMZ treatment stands at 68.9 days, surpassing those of standalone RGNP (38.4 days) or TMZ (42.8 days) therapies. Through verification via bioluminescence imaging, positron emission tomography, and immunohistochemistry analysis, the combined treatment regimen exhibits the ability to impede glioblastoma proliferation, underscoring the potential of concurrent chemoradiotherapy facilitated by RGNP and TMZ.[Disclosure of COI by Responsible researcher] Lead presenter is the Responsible researcher
Prevotella intermedia protease interpain A promotes human cancer cell lines proliferation and migration
No full text[[abstract]]Oral squamous cell carcinoma (OSCC) is one of the prevalent cancers worldwide, and oral microbiota dysbiosis is considered a risk factor for causing OSCC. It was reported that the abundance of Prevotella intermedia was increased in the saliva samples of OSCC patients compared to healthy controls. The relation between P. intermedia and OSCC still needed to be clarified. Therefore, we hypothesized that P. intermedia plays a crucial role in OSCC development. In the cell culture assays, including trans-well and wound-healing assays, of SG, SCC-15, and SAS cells, P. intermedia ATCC 25611 and its conditioned medium enhanced cell proliferation and migration, and this activity was higher than in clinical strains. The activity has been linked to P. intermedia interpain A, a cysteine protease, and cellular protease-activated receptor 2 (PAR-2) with proteomic analysis, the cell culture assays with protease inhibiter E64 and PAR-2 antagonist FSLLRY-NH2. In the AOM/DSS colorectal cancer mouse model, the P. intermedia ATCC 25611 was also demonstrated to increase colon tumor number. In conclusion, P. intermedia protease InpA may affect human cancer cells
Phospholipid remodeling and its derivatives as associated with pulmonary inflammation
No full text[[abstract]]Rationale: Lipid metabolism dysregulation, particularly Lysophosphatidylethanolamines (LPEs), is involved in a dynamic process leading to airway inflammation. Researchers have considered the association between airway inflammation and phospholipid remodeling, LPEs, in individuals with asthma and its mechanistic impact on epithelial and inflammatory cells as a model in-vitro and in-vivo. Methods: Study samples were plasma analyzed using LCMS. Of the 60 subjects, 40 had a clinical diagnosis of stable asthma; 20 were healthy controls. Various cells were stimulated for intracellular calcium measurement and inflammation assay. Results: Examination of changes in subgroups of lipids found that asthmatic children had significant elevation in LPE (22:6/18:2/18:1/16:0) but not in LPC – Lysophosphatidylcholine (22:6/20:4/18:2/18:1/18:0/16:0) and SM–Sphingomyelin (24:0/22:0/20:0/18:1/18:0/16:0) compared to controls. Experimental observations further showed LPE18:1 and LPE22:6 to be able to activate mast cells, macrophages and airway epithelial cells via their ability to cause membrane perturbation, and increase intracellular calcium, cytokines and, to an extent, apoptosis. Moreover, in a mouse model of airway inflammation, following antigen (OVA) or IP sensitization and challenge, significant levels of inflammatory cells (eosinophils and neutrophils) were found in lung lavages, concomitant with an elevated level of CCL1 chemokine. Interestingly, a significant elevation of LPE22:6 was noted in mice challenged with IP(indeno[1,2,3-cd]pyrene) alone and in OVA-sensitized and challenged mice following co-exposure with IP. Conclusions: LPE in the serum of asthmatic children was significantly higher than that of controls as measured by LCMS. Bioactive LPEs with cell type-selective regulatory mechanisms and environmental pollutant exposure play a critical role in pulmonary inflammation
Mediating effects of insulin resistance on lipid metabolism with elevated paraben exposure in the general Taiwan population
No full text[[abstract]]INTRODUCTION: Parabens are commonly used to prevent bacteria from growing in cosmetics and foodstuffs. Parabens have been reported to influence hormone regulation, potentially leading to metabolic anomalies, including insulin resistance and obesity. However, there is a paucity of knowledge regarding the relationship between urinary paraben levels and lipid metabolism in the general Taiwanese population. Therefore, the objective of this study was to determine whether the mediating role of insulin resistance exists between paraben exposure and lipid metabolism. METHODS: We selected the data of 264 adult participants from a representative survey in five major Taiwan area in 2013. UPLC tandem mass spectrometry was used to examine four urine parabens: methyl- (MeP), ethyl- (EtP), propyl- (PrP) and butyl- (BuP). Blood samples were analyzed for concentrations of glucose and lipid metabolic indices using the DxI 800 immunoassay analyzer and immunoradiometric assay kit. The relationship between urinary paraben levels and metabolism indices were evaluated through a multiple linear regression analysis. Finally, a mediation analysis was employed to understand the underlying mechanism by which paraben exposure influences lipid metabolism through insulin resistance. RESULTS: The significant positive association between MeP exposure and Castelli risk index I (CRI-I; β = 0.05, p = 0.049) was found, and also exhibited the similar associations between EtP exposure and low-density lipoprotein cholesterol (β = 0.10, p = 0.001), total cholesterol (β = 0.06, p = 0.003), and non-HDL cholesterol (NHC; β = 0.08, p = 0.005). EtP exhibited a significant positive association with triglyceride BMI (TyG-BMI; β = 0.02, p = 0.040). Additionally, TyG-BMI was positively associated with CRI-I (β = 0.98, p < 0.001), CRI-II (β = 1.03, p < 0.001) and NHC (β = 0.63, p < 0.001). Moreover, insulin resistance served as mediators for the effects of EtP exposure on lipid metabolism indices. DISCUSSION: The results indicate that changes in insulin resistance mediated the relationship between urinary paraben and lipid metabolism. Large-scale epidemiological and animal studies are warranted to identify biological mechanisms underlying validate these relationships
EFFResNet-ViT: A fusion-based convolutional and vision transformer model for explainable medical image classification
No full text[[abstract]]The rapid advancement of medical imaging technologies requires the development of advanced, automated, and interpretable diagnostic tools for clinical decision-making. Although convolutional neural networks (CNNs) have shown significant promise in medical image analysis, they have limitations in capturing the global context and lack interpretability, thereby hindering their clinical adoption. This study presents EFFResNet-ViT, a novel hybrid deep learning (DL) model designed to address these challenges by combining EfficientNet-B0 and ResNet-50 CNN backbones with a vision transformer (ViT) module. The proposed architecture employs a feature fusion strategy to integrate the local feature extraction strengths of CNNs with the global dependency modeling capabilities of transformers. The extracted features are further refined through a post-transformer CNN and a global average pooling layer to enhance the classification performance. To improve interpretability, EFFResNet-ViT incorporates Grad-CAM visualization techniques to highlight regions contributing to classification decisions and employs t-distributed stochastic neighbor embedding for feature space analysis, providing insights into class separability. The proposed model was evaluated on two benchmark datasets: brain tumor (BT) CE-MRI for BT classification and a retinal image dataset for ophthalmological diagnosis. EFFResNet-ViT achieved state-of-the-art performance, with accuracies of 99.31% and 92.54% on the BT CE-MRI and retinal datasets, respectively. Comparative analyses demonstrate the superior classification performance and interpretability of EFFResNet-ViT over existing ViT and CNN-based hybrid models. The explainable design of EFFResNet-ViT addresses the critical need for transparency in artificial intelligence-driven medical diagnostics, facilitating its potential integration into clinical workflows to improve decision-making and patient outcomes