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[[alternative]]Targeting the ST3 β-galactoside α-2,3-sialyltransferase 1 (ST3Gal1) as a potential therapeutic strategy to overcome anti-VEGF resistance in endometrial cancer
No full text[[abstract]]ObjectiveTo investigate the role of ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) in endometrial cancer (EC) progression and its potential as a therapeutic target to enhance the efficacy of antiangiogenic treatment.MethodsST3Gal1 expression and its clinical relevance were analyzed in EC tissues. Functional assays evaluated its effects on vascular endothelial growth factor-A (VEGF-A) expression, epithelial-mesenchymal transition (EMT), and cell invasiveness. Mechanistic studies, including Duolink proximity ligation assays and co-immunoprecipitation, examined ST3Gal1-VEGF-A interactions. ST3Gal1 was inhibited genetically or pharmacologically using soyasaponin I (SsaI), both in vitro and in xenograft models, alone or combined with bevacizumab. Angiogenic and EMT marker expression and focal adhesion kinase (FAK)/paxillin pathway activation were assessed.ResultsST3Gal1 was amplified and overexpressed in EC and correlated with advanced stage, deep myometrial invasion, and poor prognosis. It directly glycosylated VEGF-A and activated FAK/paxillin signaling, promoting VEGF-A expression and EMT. ST3Gal1 inhibition via SsaI reduced VEGF-A signaling, reversed EMT marker expression, and suppressed cell migration and invasion, particularly in RL95-2 cells. In vivo, SsaI significantly inhibited tumor growth and angiogenesis, with the most pronounced effect observed in combination with bevacizumab. Dual treatment disrupted ST3Gal1-VEGF-A interactions and downregulated angiogenic and EMT markers.ConclusionST3Gal1 promotes EC progression by enhancing VEGF-A signaling and EMT via the FAK/paxillin pathway. Its inhibition improves the efficacy of antiangiogenic therapy, supporting ST3Gal1 as a promising therapeutic target to overcome anti-VEGF-A resistance in advanced EC
Noncontact monitoring of the peripheral microcirculation using laser speckle contrast imaging to evaluate the skin perfusion pressure
No full text[[abstract]]The skin perfusion pressure (SPP) is traditionally measured with laser Doppler flowmetry (LDF), but this technique is limited by its single-point fiber optic probe, the need to contact the skin, and susceptibility to various factors, resulting in poor data consistency. Therefore, we developed a noncontact system for measuring the SPP over a large area based on laser speckle contrast imaging (LSCI). When it was paired with a pressure cuff device, the system accurately recorded blood flow changes during various pressure interventions, and the reperfusion pressure point could be calibrated to overcome traditional measurement limitations. Cross-comparison experiments revealed that the measurements obtained with the LSCI and LDF systems were highly correlated (r > 0.7), confirming the reliability of LSCI in assessing microcirculatory function. Since supine measurements are not always suitable in clinical environments, such as in space-constrained clinics or when the patient cannot lie flat, we compared SPP measurements obtained from individuals in sitting versus supine positions, revealing minimal differences (Cohen's d = 0.1, p > 0.05), which demonstrates the system's stability over different patient postures. Under cold water stimulation, which induces microvascular contraction, simulating poor circulation, the measured SPP was significantly lower than that measured under normal conditions (Cohen's d = 2.6, p < 0.05), verifying the system's potential applicability under different pathological conditions. According to our results, the LSCI system not only obtains SPP measurements that are correlated with the LDF-measured SPP but also overcomes the limitations of the latter system, providing noncontact, instant, and large-scale microcirculation monitoring. This study offers a reliable microcirculatory assessment tool based on LSCI technology, and the results support the future application of this tool in the early diagnosis and monitoring of diabetic foot neuropathy and peripheral arterial disease
[[alternative]]青少年族群的二手酒害：危險因子與生活品質影響
No full text[[abstract]]Objectives: The study aimed to investigate the prevalence of alcohol’s harm to others (AHTO), its risk factors, and its relationship with quality of life in adolescents in Taiwan. Methods: Data came from the 2018 National Survey of Substance Use in Taiwan. A total of 3,598 respondents aged 12-17 with national representativeness were included. Sociodemographic characteristics at both family and individual levels, eight forms of AHTO, and five-dimensional quality of life (as assessed by the EQ-5D-5L) were obtained in the survey. Logistic and Tobit regressions with complex survey analyses were used. Results: The lifetime prevalence of AHTO in adolescents was estimated at 0.92%. Parents’ drinking emerged as the strongest risk factor for AHTO experience (adjusted odds ratio [aOR]=14.1). Running away from home and monthly drinking were found to increase the odds of AHTO by 478% and 475%, respectively. Having AHTO experience appeared to be a significant predictor for deteriorated quality of life (adjusted β=-0.17), with that deterioration manifested primarily in the dimension of anxiety/depression. Among all AHTO victims, fewer than one in six ever reached out for help. Conclusions: AHTO provides a vital perspective to help tackle alcohol harm in Taiwan, particularly in the vulnerable underage population. To prevent AHTO-related deterioration in mental health and quality of life among young people in the community, policies and interventions should involve strategies targeting harm to young children in families
Comparative outcomes of adding SGLT2 inhibitors versus incretin-based therapies to insulin in type 2 diabetes
No full text[[abstract]]Aims: To compare the risks of cardiovascular events and major microvascular complications associated with adding sodium-glucose cotransporter-2 (SGLT2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to insulin therapy in patients with type 2 diabetes (T2D). Methods: Using Taiwan's National Health Insurance Research Database (2008–2021), we identified 20,655 propensity score–matched pairs of SGLT2 inhibitor and DPP-4 inhibitor users, and 10,445 matched pairs of SGLT2 inhibitor and GLP-1 RA users, all receiving concurrent insulin therapy. Cox proportional hazards models were applied to assess outcome risks. Results: SGLT2 inhibitor use was associated with significantly lower risks of major microvascular complications compared to both DPP-4 inhibitors (adjusted hazard ratio [aHR] 0.37, 95% CI: 0.33–0.41) and GLP-1 RAs (aHR 0.57, 95% CI: 0.49–0.66). Compared with DPP-4 inhibitors, SGLT2 inhibitors also conferred a lower risk of major adverse cardiovascular events (aHR 0.57, 95% CI: 0.53–0.61) and all-cause mortality (aHR 0.42, 95% CI: 0.39–0.45). Conclusions: In patients with T2D on insulin, adding SGLT2 inhibitors was associated with lower risks of cardiovascular events, major microvascular complications, and mortality compared to DPP-4 inhibitors, and lower risk of major microvascular complications compared to GLP-1 RAs
Marine-derived STING inhibitors, excavatolide B promote wound repair in full-thickness-incision rats
No full text[[abstract]]The process of wound healing encompasses both inflammatory and proliferative stages. Excessive inflammation is known to impede the healing of chronic wounds. Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway causes inflammation during cellular stress and tissue damage. Herein, we examined the anti-inflammatory effects of the marinederived STING antagonist excavatolide B (EXCB) and its derivatives, EXCB-61 and EXCB-79, in full-thicknessincision rats. Wound area measurements, histopathological observations, and immunohistochemical analyses were performed to evaluate the roles of these compounds in wound healing. These three compounds were found to have low toxicity, with EXCB promoting Hs68 human dermal fibroblast migration and proliferation. EXCB and EXCB61 treatments, but not EXCB79, reduced the wound area. The histopathological results showed a significant decrease in immune cell infiltration and mast cell accumulation in all compound-treated groups. Immunohistochemical analysis revealed that EXCB and its derivatives reduced cGAS-STING pathway factors such as STING, phosphorylated TANK-binding kinase 1, nuclear factor kappa-light-chain-enhancer of activated B cells, and M1 macrophages while increasing the expression of angiogenic factors vascular endothelial growth factor and CD31, as well as M2 macrophages and collagen I/III deposition. We conclude that marine-derived STING antagonists can attenuate inflammatory responses by inhibiting the cGAS-STING pathway and promoting angiogenesis, thereby aiding wound healing
Integrating DCPR-R and DSM-5 into clinical psychosomatic practice in Taiwan: Their relationship with psychopathologies and quality of life
No full text[[abstract]]INTRODUCTION: This study aimed to assess the benefit of integrating the Diagnostic Criteria for Psychosomatic Research-Revised (DCPR-R) into the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5). Specifically, it examined whether this integration enhances the understanding of psychopathologies and quality of life (QOL) in psychosomatic medicine. METHODS: In this cross-sectional study conducted in Taiwan, 277 patients from psychosomatic clinics and 225 community participants were included. Standardized interview tools based on DCPR-R and DSM-5 were used to assess the presence of various diagnoses. Participants also completed several scales related to persistent somatic symptoms, negative emotions, and QOL. Latent class analysis was used to explore the clustering of diagnoses, and multiple linear regression analysis was employed to investigate the relationship between diagnoses, psychopathologies, and QOL under conditions of possible comorbidity. RESULTS: Three classes were identified via latent class analysis: somatic symptoms, demoralization and stress, and insomnia. In the multivariate analysis considering multiple diagnoses simultaneously, the number of diagnoses significantly associated with psychopathologies and QOL was greatly reduced compared to the univariate analysis. Persistent somatization was more strongly associated with somatic distress than somatic symptom disorder. Several DCPR-R constructs showed significant associations with illness-related anxiety. The DCPR-R diagnoses with broader influences on QOL were demoralization, demoralization with hopelessness, and irritable mood. CONCLUSIONS: The results suggest the potential clinical significance of integrating DCPR-R and DSM-5 in Eastern societies. The DCPR-R diagnoses with significant findings mentioned above may contribute to the personalized treatment plans for patients in psychosomatic medicine
Search volume of insomnia and suicide as digital footprints of global mental health during the COVID-19 pandemic: 3-year infodemiology study
No full text[[abstract]]BACKGROUND: The global COVID-19 pandemic's mental health impact was primarily studied in the initial year of lockdowns but remained underexplored in subsequent years despite evolving conditions. This study aimed to address this gap by investigating how COVID-19-related factors, including nationwide COVID-19 deaths and incidence rates, influenced mental health indicators over time. OBJECTIVE: This study aimed to examine the interplay among national COVID-19 pandemic deaths, incidence rates, stay-at-home behaviors, and mental health indicators across different income-level countries. Specifically, we assessed the mediating role of stay-at-home behaviors in the relationship between the COVID-19 pandemic deaths and mental health indicators. METHODS: We analyzed data from 45 countries spanning March 2020 to October 2022. COVID-19-related factors included national COVID-19 pandemic deaths and incidence rates, obtained from publicly available datasets. Stay-at-home behaviors were assessed using Google Location History data, which captured residence-based cell phone activity as a proxy for mobility patterns. Mental health indicators were evaluated through Google Trends data, measuring changes in search volumes for "insomnia" and "suicide." The interplay among these variables was assessed using mediation analysis to quantify the proportion mediated by stay-at-home behaviors in the association between COVID-19 deaths and mental health indicators. RESULTS: In high-income countries, during the first pandemic year (March 2020 to February 2021), a higher monthly COVID-19 death count was associated with increased searches for "insomnia," with a total effect estimate of 2.1×10(-4) (95% CI 4.3×10(-5) to 3.9×10(-4); P=.01). Stay-at-home behaviors mediated 31.9% of this effect (95% CI 9.8% to 127.5%, P=.02). This association weakened and became nonsignificant in the second and third years (P=.25 and P=.54, respectively). For middle-income countries, a different pattern emerged regarding "suicide" searches. Higher COVID-19 death counts were linked to a decline in "suicide" searches in the first (estimate: -3.5×10(-4), 95% CI -6.1×10(-4) to -9.8×10(-5); P=.006) and second years (P=.01). Mediation analysis indicated that this effect was not significantly explained by stay-at-home behaviors, suggesting the influence of other societal factors. In high-income countries, no significant association between COVID-19 deaths and "suicide" searches was observed in the first year (P=.86). However, a positive association emerged in the second year, approaching statistical significance (estimate: 2.2×10(-4), 95% CI -9.5×10(-7) to 4.2×10(-4); P=.05), and became significant in the third year (estimate: 5.0×10(-4), 95% CI 5.0×10(-5) to 1.0×10(-3); P=.03,), independent of stay-at-home behaviors. CONCLUSIONS: Our findings highlight how the mental health impact of the pandemic varied across income groups and evolved over time. The mediating effect of stay-at-home behaviors was significant in the early phases but diminished in later stages, particularly in high-income countries. Meanwhile, middle-income countries exhibited unique patterns that suggest alternative protective factors. These insights can inform tailored mental health interventions and policy strategies in future public health crises
The efficacy and safety of anti-amyloid monoclonal antibody versus acetylcholinesterase inhibitor with an in-depth analysis across genotypes and disease stages: A systematic review and meta-analysis
No full text[[abstract]]BACKGROUND: To date, studies have not compared the efficacy and safety of monoclonal antibodies (mABs) with acetylcholinesterase inhibitors (AChEIs). METHODS: Five electronic databases were systemic searched from inception to 10 November 2024 for double-blinded randomized controlled trial (RCT) of patients diagnosed with MCI or mild AD treated with mABs or AChEIs for at least 6 months. The primary outcome was change in cognitive function, measured by the Alzheimer's Disease Assessment Scale-cognitive subscale 14-item (ADAS-Cog) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB). The secondary outcomes were acceptability, tolerability, serious adverse events (SAE), and all -cause mortality. For mABs, amyloid-related imaging abnormalities-edema (ARIA-E), and amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were also assessed. Subgroup analyses included (i) MCI versus mild AD; (ii) with versus without concomitant AD medications; and (iii) Apolipoprotein E (ApoE4) carriers versus non-carriers. Data were pooled using a random effects model within a Bayesian framework. RESULTS: There were 8010 participants (mean age: 71.5 years) across seven mAB trials, and 4993 participants (mean age:70.7 years) in nine AChEI trials. When compared to placebo, only mABs, not AChEIs, were associated with a slower progression of cognitive decline on CDR-SOB (mean difference -0.41 (95 % credible interval -0.61 to -0.22); minimally important difference (MID) -1) and ADAS-Cog (-1.35 (-2.36 to -0.36), MID -2); however, these benefits of mABs did not reach MID across the two cognitive measurements. Besides, mABs were associated with a slower progression of cognitive decline on CDR-SOB (-0.30 (-0.60 to -0.001)) than AChEIs, although mABs and AChEIs did not differ across safety outcomes, including acceptability, tolerability, SAE, and all-cause mortality. Further analysis of mABs indicated that their efficacy did not differ by disease stage, concomitant AD medications, or APOE4 carrier status. However, APOE4 homozygotes carriers were associated with a 5.53-fold (2.48 to 13.07) increased odds of developing ARIA-E compared to non-carriers. Finally, lecanemab demonstrated relatively better efficacy and a more favorable profile on ARIA-E compared to aducanumab and donanemab. CONCLUSIONS: mABs were associated with a slower progression of cognitive decline than AChEIs; however, this effect did not reach the MID. The incidence of ARIA-E with mABs was associated with APOE4 carrier status and was not indicative of treatment efficacy
Brain network changes in the harmaline induced tremor rat model
No full text[[abstract]]Patients with essential tremor suffer from involuntary and rhythmic movements of heads, hands, and legs. In addition to motor-related symptoms, non-motor features such as mild cognitive deficits have been discovered, implying the alterations in both cerebellar circuits and cerebral functions. As a disorder with a wide spectrum of clinical features, the underlying mechanisms of essential tremor and its alteration to the brain are not well recognized. Investigation to the animal models of essential tremor can provide more insights into its brain circuitry. This study utilized harmaline injection on rat model to mimic tremor features and characterized its brain networks by using resting-state functional MRI. The tremor movements were monitored by a customized platform combined with an accelerometer. The resting-state networks and the functional connectivity among several brain hubs were identified. Aside from regular movement of the rat, excessive movement frequency within 13–15 Hz was detected in the harmaline-injected rats. The fMRI results reveal the alteration of default mode network in the harmaline-induced tremor rat, particularly the lower connectivity in hippocampus and higher connectivity in primary somatosensory cortex. Furthermore, comparing with control rats, the harmaline-induced rats exhibited significantly higher functional connectivity among several region-pairs, including the connectivity between left hippocampus and left striatum, left hippocampus and right motor, left hippocampus and left somatosensory, and bilateral somatosensory cortex. Although the rat models were scanned under anesthesia, the consequences of the harmaline injection can be probed by using the resting-state fMRI, showing that the alteration is not only on the olivocerebellar circuit but also on other cerebral hubs. Besides, a low-price detection module for tremor measurement was developed by combining the accelerometer. The concept has the potential to be implemented to wearable devices for longitudinal recording in the future. In summary, the alteration in the resting-state brain networks of harmaline-induced tremor rat model has been identified in this study, highlighting specific regions that are associated with harmaline-induced tremor. The brain networks in this rat model can be further examined after various therapeutic approaches in the future
The accuracy of polygenic score models for BMI and Type II diabetes in the Native Hawaiian population
No full text[[abstract]]Polygenic scores (PGS) are promising in stratifying individuals based on the genetic susceptibility to complex diseases or traits. However, the accuracy of PGS models, typically trained in European- or East Asian-ancestry populations, tend to perform poorly in other ethnic minority populations and their accuracies have not been evaluated for Native Hawaiians. In particular, for body mass index (BMI) and type-2 diabetes (T2D), Polynesian-ancestry individuals such as Native Hawaiians or Samoans exhibit varied distribution from other continental populations, but are understudied, particularly in the context of PGS. Using BMI and T2D as examples of metabolic traits of importance to Polynesian populations (along with height as a comparison of a similarly highly polygenic trait), here we examine the prediction accuracies of PGS models in a large Native Hawaiian sample from the Multiethnic Cohort with up to 5300 individuals. We find evidence of lowered prediction accuracies for the PGS models in some cases, particularly for height. We also find that using the Native Hawaiian samples as an optimization cohort during training does not consistently improve PGS performance. Moreover, even the best-performing PGS models among Native Hawaiians have lowered prediction accuracy among the subset of individuals most enriched with Polynesian ancestry. Our findings indicate that factors such as admixture histories, sample size, and diversity in GWAS can influence PGS performance for complex traits among Native Hawaiian samples. This study provides an initial survey of PGS performance among Native Hawaiians and exposes the current gaps and challenges associated with improving polygenic prediction models for underrepresented minority populations