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治疗C型肝炎病毒感染的医药组合物
No full text[[abstract]]本发明涉及一种治疗C型肝炎病毒的医药组合物，包括(a)有效剂量的至少一HCV抑制剂，其选自由HCV NS3抑制剂、HCV NS5B抑制剂、雷巴威林、以及干扰素‑α(IFN‑α)所组成的组；以及(b)有效剂量的如式(I)所示的抗HCV化合物
Oral squamous cell carcinoma-derived ISG15 enforces fibroblast recruitment via CD11a-dependent glycolysis reprogramming
No full text[[abstract]]The mechanisms underlying the crosstalk of oral squamous cell carcinoma (OSCC) cells and fibroblasts remain poorly investigated. We identified that ectopic expression of interferon stimulated gene 15 (ISG15) enhanced expression of collagen and alpha-smooth muscle actin (alpha-SMA) in ISG15-expressing tumors. The in vivo experiments confirmed fibroblast recruitment in ISG15-expressing OSCC tissues. And, exogenous ISG15 induced fibroblast migration, morphological changes and vimentin expression. Using geneset enrichment analysis (GSEA), the glycolysis pathway was enriched in ISG15-treated fibroblasts. The glucose consumption and lactate production were amplified in ISG15-treated fibroblast. Also, lactate release and fibroblast migration were blocked by 2-deoxy-d-glucose (2-DG), a competitive inhibitor of glucose metabolism. Furthermore, CD11a, a subunit of ISG15 receptor, lymphocyte function-associated antigen-1 (LFA-1), was involved in ISG15-meidated glycolysis and fibroblast migration. Our findings uncovered that OSCC-derived ISG15 bond to its receptors, LFA-1 on fibroblasts to activate glycolysis reprogramming and finally promote fibroblast movement
Adverse effects of tyrosine kinase inhibitors on glucose and lipid metabolism in patients with chronic myeloid leukemia
No full text[[abstract]]Background: The development of tyrosine kinase inhibitors (TKIs) significantly improved the prognosis of chronic myeloid leukemia (CML) patients. Adverse effects following long-term treatment are of concern; especially, cardiovascular events associated abnormal glucose-lipid metabolism. Objectives: This retrospective cohort study investigates the onset of high hemoglobin A1C (HbA1C), hypercholesterolemia, hypertriglyceridemia, and hyper-low density lipoprotein (LDL)-cholesterolemia in the patients treated with first-line TKI. Methods: CML patients aged over 20 years who had related laboratory data in the 6 months prior to the first-line TKI and within one year after TKI were selected. We extracted information from Taiwan National Health Insurance Database and laboratory data (2015–2020). Patients with other cancers history at baseline were excluded, and they were further grouped by the first-line TKI including imatinib, dasatinib and nilotinib. Time-to-event analysis and multivariable Cox regression was performed to analyze the probability of laboratory data over high cut-off values, including high HbA1C (≥ 6.5 %), hypercholesterolemia (≥ 240 mg/dL), hypertriglyceridemia (≥ 200 mg/dL), and hyper-LDL-cholesterolemia (≥ 160 mg/dL). Death, treatment discontinuation, switched to another TKI or the end of 1-year follow-up period were considered censored. Results: Nilotinib (N) users had higher risk than dasatinib (D) and imatinib (I) users in terms of hypercholesterolemia (N vs. I, hazard ratio, HR, [95% CI] = 3.90 [1.71–8.88]; N vs. D, HR = 2.60 [1.50–4.53]), hyper-LDL-cholesterolemia (N vs. I, HR = 2.91 [1.16–7.31]; N vs. D, HR = 2.15 [1.14–4.05]) and high HbA1C level (N vs. I, HR = 2.38 [1.50–3.78]; N vs. D, HR = 2.14 [1.39–3.28]). In patients without history of hyperlipidemia (N vs. I, HR = 7.61 [1.61–35.98]; N vs. D, HR = 4.33 [1.96–9.59]), without history of ischemic heart disease (N vs. I, HR = 4.36 [1.74–10.90]; N vs. D, HR = 2.76 [2.53–4.99]) or without diabetes (N vs. I, HR = 5.38 [1.87–15.47]; N vs. D, HR = 3.09 [1.67–5.71]), significantly higher risks of hypercholesterolemia were found in the nilotinib group. There was no significant difference for hypercholesterolemia onset in those with histories mentioned above. In patients with history of diabetes (N vs. I, HR = 2.3 [1.43–3.69]; N vs. D, HR = 2.18 [1.39–3.41]), significantly higher risks of high HbA1C level were found in the nilotinib group. No significant difference for high HbA1C level was found in those without diabetes history. Conclusions: Compared with imatinib and dasatinib, nilotinib is more likely to present adverse effects on blood glucose and lipids profile. Therefore, the selection of TKIs would need to consider patient's baseline comorbidity history
Association between early retirement and risk of frailty in later life: A population-based longitudinal study
No full text[[abstract]]AimEarly retirement is prevalent and can alter daily habits, potentially impacting health. This study aims to explore the association between early retirement and frailty and to examine the modifying effect of sociodemographic characteristics.MethodsWe conducted a population-based matched cohort study that included 1 779 628 early retirees aged 45-64 years and an equal number of employed individuals from Taiwan's National Health Insurance (2010-2021). Early retirement was defined as unemployment before age 65 years without reemployment. Frailty was assessed using the multimorbidity Frailty Index (mFI) based on the International Classification of Diseases, 10th Revision, Clinical Modification codes. Covariates such as demographics, socioeconomic status, and medical conditions were adjusted using propensity score weighting. Generalized estimating equations determined the association between early retirement and frailty. Subgroup analyses were conducted by age, sex, income and occupation.ResultsThe results showed that early retirees exhibited a significant increase in mFI score changes compared to their employed counterparts, with a coefficient rise of 0.372 (95% CI, 0.303-0.441). Early retirement was associated with higher mFI scores among younger individuals (aged 45-54 years); men; those with lower incomes; and individuals working as employers, private-sector employees, freelancers, farmers and fishers. Conversely, early retirement was linked to lower mFI scores among civil servants.ConclusionThese findings support the development of targeted retirement policies and occupational health programs. Further research on frailty mediators, such as physical activity, diet and social participation is crucial for improving clinical care and informing health policies to mitigate the negative impacts of early retirement on high-risk populations
A new hope for multiple system atrophy: A translational research of a novel nmdar receptor modulator from preclinical models to patients
No full text[[abstract]]Background: NMDA receptor (NMDAR) is an essential glutamate receptor and as a contributor to neurodegenerative disorder1,2. Until now, NMDAR (especially glycine modulatory site (GMS) of the NMDARs) has been proposed to be a potential therapeutic target for the treatment of neurological disorders, such as multiple system atrophy (MSA)3. MSA, an atypical parkinsonism, is a fatal and rapidly progressive neurodegenerative disease with autonomic dysfunction and cerebellar deficits4-6. Up to now, the etiology and pathogenesis of MSA remains unclear4. One potential mechanism in MSA is accumulation of α-synuclein aggregated in oligodendrocytes7,8, and aggregation of α-synuclein promotes the NMDAR internalization9,10, contributing to NMDAR dysfunction and LTP impairment11,12. Unfortunately, currently available medications have not been proven efficacious in treating symptoms of MSA13. The need to develop novel therapeutic agents for the “unmet medical needs” in patients with MSA is of upmost importance. Take advantage of virtual high-throughput screening and AI-based predicted assay, a novel NMDAR modulator, RS-D7, was discovered with safety and efficacy profile. It is urgent and imperative to evaluate the therapeutic potentials of RS-D7 in MSA from basics to clinical trials. Aims & Objectives: The aims of this study were to evaluation the therapeutic potential and mechanism of RS-D7 on the alleviation of MSA. Taking advantage of in vitro assays, in vivo efficacy tests, and proof- of-concept clinical trials in drug development, a series of experiments was conducted on RS-D7 in this study. Method: In Experiment 1, enzymatic inhibition and cell-based inhibition assay was performed to examine the inhibition effect of RS-D7 on D-amino acid oxidase (DAO). To further determine the mechanism of RS-D7 on NMDAR, surface dynamics of NMDAR with RS-D7 was analyzed in primary neurons using single- particle tracking in Experiment 2, and fEPSP and LTP were recorded in hippocampal slices in Experiment 3. In Experiment 4 to 6, a series of in vivo animal experiments were performed with RS-D7 treatment using wild-type (WT), pharmacological (MK-801, a NMDAR antagonist) and genetic (TgM83 mice overexpressing human A53T α-synuclein) mouse models mimicking ataxia/MSA, respectively. In Experiment 7, an open-labeled, proof-of-concept clinical trial in MSA patients was conducted with RS-D7 prodrug (RS-D7pro). Results: In the inhibition assay, RS-D7 acted as a potent DAO inhibitor (IC50 = 0.32 uM) with direct competitive inhibition. Then, surface dynamics of hippocampal NMDARs were decreased by MK-801but alleviated by RS-D7. Meanwhile, MK-801-induced NMDAR-mediated fEPSP and LTP deficits were also ameliorated after RS-D7 treatment. Next, RS-D7 demonstrated a high safety profile on WT mice and RS- D7 improved MK-801-induced ataxic behaviors in a dosage-dependent manner. Moreover, MSA-related behavioral deficits, reduction of membrane-bound NMDAR subunits, and abnormal inflammatory responses in TgM83 mice were also reversed by RS-D7. Final, the clinical rating results from MSA proof- of-concept clinical trial indicated that three ataxic scores (SARA, UMSARS and ICARS) were significantly improved in MSA patients after 12-week RS-D7pro treatment, and the symptoms rebounded and worsened 12 weeks after discontinuing RS-D7pro. Discussion & Conclusion: Collectively, these promising results support the therapeutic potential of RS-D7 in MSA and offer new hope for MSA patients
Betaine mitigates reinstatement of methamphetamine- induced conditioned place preference in rats: Involvement of camkk2/Ampk signaling
No full text[[abstract]]Background: Methamphetamine (MA) use represents a significant worldwide public health concern. Currently, no pharmacological therapy has established efficacy for treating MA use disorder. Betaine has been found to reduce MA-induced behavioral sensitization. In addition, betaine activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) which has been associated with reinstatement of cocaine seeking. Aims & Objectives: This study aimed to examine the effects of betaine on conditioning and reinstatement of MA-conditioned place preference (CPP). Additionally, it sought to explore the involvement of AMPK and its upstream activator, calcium/calmodulin-dependent protein kinase (CAMKK2), in the reducing effect of betaine on the reinstatement of MA CPP. Method: Male Sprague-Dawley rats underwent a three-compartment CPP paradigm. Betaine or saline was administered 30 minutes prior to each MA (2 mg/kg) conditioning session or 30 minutes before MA (1 mg/kg) priming-induced reinstatement. To determine the roles of AMPK and CAMKK2 in betaine's reducing effect on the reinstatement of MA CPP, rats received bilateral intra-NAc core infusions of the AMPK inhibitor dorsomorphin or STO-609, a selective inhibitor of CAMKK2, followed by betaine (100 μ g/μ l) before MA priming-induced reinstatement. Results: Betaine did not affect conditioning, but significantly reduced reinstatement of MA CPP at 100 mg/kg. Furthermore, acute intra-NAc core infusions of betaine effectively ameliorated the reinstatement of MA CPP, and this effect was abolished by co-treatment with dorsomorphin or STO- 609. Discussion & Conclusions: These findings suggest that betaine may be a novel therapeutic agent for the treatment of MA use disorder, and activation of the CAMKK2-AMPK pathway might be one of the mechanisms underlying the MA relapse-preventing effect of betaine
Brain neuronal integrity in Covid-19 patients in Taiwan
No full text[[abstract]]Background: COVID-19 has caused a global pandemic characterized by severe pneumonia. Brain structure abnormality has been confirmed in COVID-19 patients in the UK biobank [1]. However, it is not clear whether this abnormality is reversible nor if the abnormality could be detected in the early stage of the disease. Aims & Objectives: In this study, the pathological effect of COVID-19 on the brain integrity was monitored through the utilization of a brain injury bioindicator, neurofilament light chain (NFL) [2]. It can be released from the brain into the peripheral blood when the brain neuronal axon is injured [3]. The study aimed to assess the correlation between the discharge diagnoses and NFL levels in COVID-infected patients. Method: Plasma samples from the National Health Research Institutes (NHRI) Biobank of 400 COVID-19 patients recruited from 24 hospitals across Taiwan were used for NFL analyses by immunoassay. Results: Among the successfully analyzed 394 patients, 10 patients (2.5%) showed an NFL level above 200 pg/ml. The mean NFL levels were significantly higher in patients older than 50 years (P <0.0001). Male patients had a higher NFL level than females (P = 0.008). The increase in plasma levels of NFL was the highest in the first 1-7 days after the COVID-19 diagnosis was confirmed, then gradually decreased within a month. Significant higher NFL levels were observed in patients with hospitalization, respiratory or ICU treatment, and oxygen therapy (P <0.0001). Moreover, higher NFL levels were also correlated with discharge diagnoses of cardiovascular, lung, kidney, and other chronic diseases (P ≦ 0.008). Discussion & Conclusion: COVID-19 infection may cause brain neuronal injury especially in male patients older than 50 years. In addition, the plasma NFL level was associated with a number of clinical features. The results demonstrated that NFL could be an indicator for assessing the brain neuronal integrity following COVID- 19 infection
Trends in palliative care utilization among older adult decedents with and without cancer in Taiwan: A population-based comparative study
No full text[[abstract]]Background The leading causes of death among the older adults have shifted from cancer to non-cancer conditions such as ischemia heart diseases, stroke, and dementia, affecting end-of-life care needs. This study examined the difference in the proportion of palliative care utilization in relation to specific causes of death and compared the trends in palliative care utilization between older adult decedents with and without cancer in Taiwan from 2010 to 2020. Methods The study utilized data from the Health and Welfare Data Science Center in Taiwan, covering demographic and healthcare variables for 588,010 decedents aged 65+ years who died between 2010 and 2020. We used Poisson regression to investigate the temporal trends in palliative care utilization during the last six months of life. Multi- variable logistic regression models were constructed to analyze cancer, and non-cancer causes of death associated with palliative care utilization. Findings The proportion of palliative utilization in cancer deaths started at 21.7% in 2010 and increased to 63.2% by 2020 with the beta coefficient of 0.09 (95% CI: 0.09-0.09). The proportion of palliative utilization in non-cancer deaths started at 0.8% in 2010 and increased to 23.5% by 2020, with the beta coefficient of 0.26 (95% CI: 0.26-0.26). Compared to deceased cancer patients, deceased non-cancer individuals were less likely to have received palliative care (OR = 0.12, 95% CI: 0.12-0.13). Interpretation Efforts to ensure equitable access to palliative care for non-cancer individuals should focus on expanding services, enhancing provider education, and promoting cultural sensitivity to meet the growing need for palliative care integration
A non-structural protein 1 substitution of dengue virus enhances viral replication by interfering with the antiviral signaling pathway
No full text[[abstract]]BackgroundThe largest dengue virus 2 (DENV2) outbreak occurred in Taiwan in 2015, resulting in many fatalities. We therefore aim to identify crucial genetic variations which determine the virulence of the 2015 Taiwan outbreak strains.MethodsWe compared the 2015 Taiwan DENV2 sequences to the pre-2015 sequences. Reverse genetics (rg) viruses with substitutions were produced and the viral growth kinetics were investigated. We treated A549 cells with interferon (IFN) to determine the interferon-stimulated genes (ISGs) expression and STAT1 phosphorylation in the rg viral infection and plasmid transfection systems. IFN and pro-inflammatory cytokines levels were measured upon DENV infection using ELISA.ResultsThe rgNS1-K272R mutant showed faster replication in IFN-I producing cells compared to wildtype (WT) virus. Results revealed that NS1-K272R substitution contributed to higher soluble NS1 secretion and evade the antiviral response by suppressing the expression of ISGs and STAT1 phosphorylation compared to NS1-WT. Infection with rgNS1-K272R induced higher secretion of pro-inflammatory cytokines through the activation of canonical nuclear factor-kappa B (NF-kappa B) signaling pathway.ConclusionsOur results revealed that the DENV NS1 amino acid substitution affects the NS1 ability in immune evasion, which may contribute to the largest dengue outbreak in Taiwan since the 1990s
[[alternative]]Author Correction: Burdens of type 2 diabetes and cardiovascular disease attributable to sugar-sweetened beverages in 184 countries (Nature Medicine, (2025), 10.1038/s41591-024-03345-4)
No full text[[abstract]]Correction to: Nature Medicinehttps://doi.org/10.1038/s41591-024-03345-4, published online 6 January 2025. In the version of the article initially published, in the eighth paragraph of the Discussion, the text “Among large nations, the largest increases in SSB-related T2D burdens were in Mexico, Thailand and the United Kingdom, and in CVD burdens, Colombia, Nigeria, Thailand and Russia. These changes align with rises in SSB consumption in these nations12. Similarly, declining SSB-related cardiometabolic burdens in Brazil, the United States and the United Kingdom (for CVD) are consistent with their decreasing SSB consumption from 1990 to 202012” was incorrect and has now been updated to “Among largely populated nations, the largest increases in SSB-related T2D incidence was in Colombia, USA and Argentina; and in CVD incidence, Nigeria, Russia, Colombia and Thailand. These changes generally align with rises in SSB consumption in these nations, except in the US where slight declines in SSB consumption were offset by increased burdens of diabetes 12. Similarly, declining SSB-related cardiometabolic burdens in Turkey, Brazil, and the United States and the United Kingdom for CVD are consistent with their decreasing SSB consumption from 1990 to 202012.” Additionally, Supplementary Data 1 and 2 have been updated to remove decimals in values greater than 100. These corrections have been made to the HTML and PDF versions of the article