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Orally bioavailable and site-selective covalent STING inhibitor derived from a macrocyclic marine diterpenoid
No full text[[abstract]]Pharmacological inhibition of the cGAS-STING-controlled innate immune pathway is an emerging therapeutic strategy for a myriad of inflammatory diseases. Here, we report GHN105 as an orally bioavailable covalent STING inhibitor. Late-stage diversification of the briarane-type diterpenoid excavatolide B allowed the installation of solubility-enhancing functional groups while enhancing its activity as a covalent STING inhibitor against multiple human STING variants, including the S154 variant responsible for a genetic autoimmune disease. Selectively engaging the membrane-proximal Cys91 residue of STING, GHN105 dose-dependently inhibited cGAS-STING signaling and type I interferon responses in cells and in vivo. Moreover, orally administered GHN105 exhibited on-target engagement in vivo and markedly reversed key pathological features in a delayed treatment of the acute colitis mouse model. Our study provided proof of concept that the synthetic briarane analog GHN105 serves as a safe, site-selective, and orally active covalent STING inhibitor and devises a regimen that allows long-term systemic administration
Large language models may struggle to detect culturally embedded filicide-suicide risks
No full text[[abstract]]This study examines the capacity of six large language models (LLMs)—GPT-4o, GPT-o1, DeepSeek-R1, Claude 3.5 Sonnet, Sonar Large (LLaMA-3.1), and Gemma-2-2b—to detect risks of domestic violence, suicide, and filicide-suicide in the Taiwanese flash fiction “Barbecue”. The story, narrated by a six-year-old girl, depicts family tension and subtle cues of potential filicide-suicide through charcoal-burning, a culturally recognized method in Taiwan. Each model was tasked with interpreting the story's risks, with roles simulating different mental health expertise levels. Results showed that all models detected domestic violence; however, only GPT-o1, Claude 3.5 Sonnet and Sonar Large identified the risk of suicide based on cultural cues. GPT-4o, DeepSeek-R1 and Gemma-2-2b missed the suicide risk, interpreting the mother's isolation as merely a psychological response. Notably, none of the models comprehended the cultural context behind the mother sparing her daughter, reflecting a gap in LLMs' understanding of non-Western sociocultural nuances. These findings highlight the limitations of LLMs in addressing culturally embedded risks, essential for effective mental health assessment
A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies
No full text[[abstract]]Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis
Selective photothermal eradication of glioblastoma cells coexisting with astrocytes by anti-EGFR-coated raman tags
No full text[[abstract]]Glioblastoma (GBM) is an aggressive and fatal tumor. The infiltrative spread of GBM cells hinders gross total resection. The residual GBM cells are significantly associated with survival and recurrence. Therefore, a theranostic method that can enhance the contrast between residual GBM and normal astrocyte (AS) cells and selectively eradicate GBM cells is highly desired. In this report, GBM and normal astrocyte cells are both cultured in the same microplate well to imitate a coexistence environment and treated with Raman tags functionalized by anti-EGFR. Compared to AS cells, GBM cells show 25% higher Raman emission, and their cell death rate increases by a factor of 2. These results demonstrate the potential for selective eradication of the residual GBM cells guided by robust Raman signals after the primary GBM surgery
Policy spotlight effects on critical time-sensitive diseases: Nationwide retrospective cohort study on Taiwan's hospital emergency capability categorization policy
No full text[[abstract]]BACKGROUND: Taiwan's categorization of hospital emergency capability (CHEC) policy is designed to regionalize and dispatch critical patients. The policy was designed in 2009 to improve the quality of emergency care for critical time-sensitive diseases (CTSDs). The CHEC policy primarily uses time-based quality surveillance indicators. OBJECTIVE: We aimed to investigate the impact of Taiwan's CHEC policy on CTSDs. METHODS: Using Taiwan's 2005 Longitudinal Health Insurance Database, this nationwide retrospective cohort study examined the CHEC policy's impact from 2005 to 2011. Propensity score matching and difference-in-differences analysis within a generalized estimating equation framework were used to compare pre- and postimplementation periods. The study focused on acute ischemic stroke (AIS), ST-segment elevation myocardial infarction (STEMI), septic shock, and major trauma. AIS and STEMI cases, monitored with time-based indicators, were evaluated for adherence to diagnostic and treatment guidelines as process quality measures. Mortality and medical use served as outcome indicators. Major trauma, with evolving guidelines and no time-based monitoring, acted as a control to test for policy spotlight effects. RESULTS: In our cohort of 9923 patients, refined through 1:1 propensity score matching, 5566 (56.09%) were male and were mostly older adults. Our analysis revealed that the CHEC policy effectively improved system efficiency and patient outcomes, resulting in significant reductions in medical orders (-7.29 items, 95% CI -10.09 to -4.48; P<.001), short-term mortality rates (-0.09%, 95% CI -0.17% to -0.02%; P=.01) and long-term mortality rates (-0.09%, 95% CI -0.15% to -0.04%; P=.001), and total medical expenses (-5328.35 points per case, 95% CI -10,387.10 to -269.60; P=.04), despite a modest increase in diagnostic fees (376.37 points, 95% CI 92.42-660.33; P=.01). The CHEC policy led to notable increases in diagnostic fees, major treatments, and medical orders for AIS and STEMI cases. For AIS cases, significant increases were observed in major treatments (β=0.77; 95% CI 0.21-1.33; P=.007) and medical orders (β=15.20; 95% CI 5.28-25.11; P=.003) compared to major trauma. In STEMI cases, diagnostic fees significantly increased (β=1983.75; 95% CI 84.28-3883.21; P=.04), while upward transfer rates significantly decreased (β=-0.59; 95% CI -1.18 to -0.001; P=.049). There were also trends toward increased major treatments (β=0.30; 95% CI -0.03 to 0.62, P=.07), medical orders (β=11.92; 95% CI -0.90 to 24.73; P=.07), and medical expenses (β=24,275.54; 95% CI -640.71 to 4,991,991.78; P=.06), although these were not statistically significant. In contrast, no significant changes were identified in process or outcome quality indicators for septic shock. These findings suggest policy spotlight effects, reflecting a greater emphasis on diseases directly prioritized under the CHEC policy. CONCLUSIONS: The CHEC policy demonstrated the dual benefits of reducing costs and improving patient outcomes. We observed unintended consequences of policy spotlight effects, which led to a disproportionate improvement in guideline adherence and process quality for CTSDs with time-based surveillance indicators
Differential regulation of calcium-NFAT signaling pathway by Akt isoforms: unraveling effector dynamics and exhaustion of cytotoxic T lymphocytes in tumor microenvironment
No full text[[abstract]]BACKGROUND: Impairment of Akt signaling has been observed in antigen-specific cytotoxic T lymphocytes (CTLs) during chronic viral infections or tumor progression. Despite numerous studies emphasizing Akt's role in driving CTL effector functions, there is limited exploration of using Akt molecules in T-cell engineering to enhance their antiviral or antitumor capabilities for therapeutic purposes. Some studies even conclude that inhibiting Akt activation during the in vitro expansion process can prevent T-cell exhaustion and boost the antitumor effector functions of chimeric antigen receptor-T cells in vivo. Given the unique expression patterns and functions of the three Akt isoforms in immune cells, we proposed that Akt isoforms in CTLs may regulate effector functions and T-cell exhaustion distinctly. METHODS: In this study, we genetically modified tumor/virus-antigen-specific T-cell receptor tg CTLs to ectopically express Akt isoforms via retroviral transduction. We subsequently conducted western blotting, flow cytometry, and RNA sequencing analysis to assess their Akt expression, expression of immune checkpoints, antitumor/antivirus functionalities, and transcriptome. Additionally, we employed a persistent Hepatitis B Virus mouse model and a syngeneic hepatocellular carcinoma mouse model for further evaluation of their antivirus/antitumor efficacies. RESULTS: We found that both Akt1 and Akt2 overexpression enhanced the cytotoxic capabilities of mouse CTLs, although with different dynamics. Specifically, Akt2 signaling in CTLs accelerated effector functions, leading to a rapid attack on tumor cells. Conversely, Akt1 signaling triggered calcium influx and subsequent nuclear factor of activated T cells (NFAT) activation, while Akt2 signaling suppressed calcium influx, preventing excessive NFAT expression and nuclear translocation. This repression of NFAT transcriptional activity by Akt2 signaling during prolonged antigen stimulation subsequently led to reduced expression of transcription factors associated with T-cell exhaustion, such as Egr2, Nr4a, Tox, and immune checkpoints. Consequently, Akt2-overexpressed CTLs displayed reduced T-cell exhaustion within the tumor microenvironment and efficiently eradicated tumors. CONCLUSION: These findings highlight the essential role of Akt signaling in enabling tumor-specific CTLs to eliminate cancer cells in the solid TME, with Akt isoforms differentially regulating the calcium-calcineurin-NFAT signaling pathway. This discovery suggests the potential of AKT2 in T-cell engineering technology to enhance the survival and effector functions of adoptively transferred T cells for treating liver malignancies or chronic viral infections
[[alternative]]Author Correction: Crosstalk between FTH1 and PYCR1 dysregulates proline metabolism and mediates cell growth in KRAS-mutant pancreatic cancer cells
No full text[[abstract]]After online publication of this article, the authors noticed an error in the results section and supplementary information. The correct statement of this article should have read as below. Modification of language around FTH1 and PYCR1 interaction in the paragraph of Result, under the title of “FTH1-PYCR1 crosstalk mediates pancreatic cancer progression” on pages 2071-2073. We would like to clarify of experimental findings supporting the feedback mechanism between FTH1 and PYCR1
[[alternative]]Lack of IFN-γ response of human uterine myometrium-derived MSCs significantly improve multiple IBD parameters compared to bone marrow MSCs: Implications for anti-TNFα-refractory patients
No full text[[abstract]]The clinical efficacy of mesenchymal stem cell (MSC) therapy for inflammatory bowel disease (IBD) is inconsistent and often fails to match promising preclinical findings. To improve outcome, we compared MSCs isolated from human uterine myometrium (Ut), a readily-available tissue source from a unique immune niche, to bone marrow (BM) MSCs, the most common source, in a murine IBD model with mechanisms underlying differential effects. In this study, human BMMSCs and UtMSCs were intravenously administered to mice with dextran sulfate sodium-induced colitis and evaluated for disease activity, microbiome composition, and cellular immunity. Bioinformatics analyses including patient data were performed to further specify involved mechanisms with subsequent functional validation performed. We found that UtMSC but not BMMSC treatment significantly reversed disease parameters by improving microbiome and reducing mesenteric lymph node IFN-γ and IL-17A-secreting T cells. Transcriptomic analysis revealed UtMSCs had reduced MHC II pathway activation compared to BMMSCs. Functional validation confirmed UtMSCs compared to BMMSCs expressed lower IFN-γ receptors, prevent MHC II-mediated human unstimulated T cell activation, and modulated stimulated T helper (Th) cells away from effector phenotypes while increasing regulatory T cells (Tregs) and IL-10 levels. Bioinformatics from IBD patients resistant to non-T cell-specific therapies implicated persistent MHC II-mediated Th1/Th17 activation as key drivers of disease. Overall, UtMSCs outperformed BMMSCs in improving microbiota, avoiding IFN-γ responses, and modulating overall Th responses, suggesting this MSC source may offer more significant effectiveness for IBD and Th1/Th17-mediated conditions. Our findings also highlight that understanding MSC source-specific therapeutic mechanisms is crucial for optimizing clinical therapies
Impact of rapid temperature fluctuations on acute stroke risk: A nationwide case-crossover study from 2001 to 2020
No full text[[abstract]]Background Climate factors greatly affect cardiovascular health, with stroke ranking among serious global concerns. However, the impact of rapid temperature fluctuations on stroke risk remains underexplored. Given Taiwan's aging population and the intensifying effects of climate change, understanding influence of ambient temperatures on stroke risk is crucial for public health protection. This study aimed to explore the link between ambient temperature, sudden day-to-day temperature changes, and stroke onset in Taiwan, taking air pollutants into consideration. Methods We conducted a time-stratified case-crossover study from 2001 to 2020 using Distributed Lag Nonlinear Models (DLNM) within conditional logistic regression to examine lagged associations between temperature parameters and stroke risk. We analyzed associations separately for total stroke, ischemic stroke, and hemorrhagic stroke to identify potential differences in risk patterns, using odds ratios (ORs) relative to the temperature associated with the lowest stroke risk. Data from the National Health Insurance Research Database (NHIRD) identified the study population, including 1,100,074 first-time stroke emergency events and self-matched with 2,200,148 non-stroke onset dates as controls. The primary exposure assessments included daily temperatures (mean, maximum, and minimum) and temperature fluctuations (diurnal temperature range (DTR), sudden dayto-day temperature increases (TDI), and sudden day-to-day temperature decrease (TDD)), adjusted for air pollutants (PM2.5, O3, SO2, and NO2), and rainfall. Lag periods up to 13 days prior to the corresponding event or control days were used to examine the lag effect of stroke risk. Findings Through DLNM exposure-lag-response effect analysis after adjustment for PM2.5, O3, SO2, NO2, and rainfall, the study revealed that when TDI exceeded 6 degrees C, the risk of ischemic stroke more than doubled compared to the lowest risk temperature (OR: 2.173, 95% CI: 1.887, 2.501). The risk continued to rise until 9 degrees C, with a second peak observed when TDI exceeded 16 degrees C (OR: 2.096, 95% CI: 1.733, 2.535). Conversely, TDD exceeding 14 degrees C was linked to heightened hemorrhagic stroke risk (OR: 2.187, 95% CI: 2.055, 2.326). Additionally, daily maximum temperature exceeding 35 degrees C was associated with an increased stroke risk, primarily affecting ischemic stroke, while daily minimum temperature below 16 degrees C was strongly associated with a doubled risk of hemorrhagic stroke. Interpretation Our findings indicate that sudden day-to-day temperature increases and decreases are significant predictors of stroke onset. These results emphasize a noteworthy relationship between temperature and stroke risk over consecutive days, supporting interventions aimed at reducing stroke incidence
Endotypic traits characterizing obesity and sleep-related hypoventilation in patients with obstructive sleep apnea
No full text[[abstract]]Rationale: Sleep-related hypoventilation disorder (SHD) is common among obese patients with obstructive sleep apnea (OSA), but the pathological endotypes associated with obesity and SHD remain unclear. Objectives: To investigate the relationship between endotypes with body mass index (BMI) among patients with OSA and to explore endotypic traits of patients with comorbid SHD. Methods: We prospectively collected polysomnographic studies of 1,364 patients with OSA and overnight transcutaneous CO(2) measurements among 420 obese patients. Endotypic traits were estimated using polysomnographic signals. SHD was determined using transcutaneous CO(2) > 55 mm Hg for ⩾10 minutes. We illustrated the nonlinear relationship between BMI and endotypic traits. Differences in endotypic traits between nonobese patients with OSA, obese patients with simple OSA, and obese patients with comorbid OSA and SHD were examined using Kruskal-Wallis tests and multiple regression analysis. Results: A unit increase in BMI was associated with a 1.02%eupnea increase in arousal threshold, 1.16%eupnea increase in collapsibility, 0.01 increase in loop gain, and 0.48%eupnea increase in compensation, with a ceiling effect. SHD was observed in 18-36% of obese patients with OSA, depending on the criteria. Among obese patients with OSA, those with SHD exhibited a 0.06 higher loop gain than those with simple OSA, after adjusting for BMI. Conclusions: A ceiling effect of upper airway compensation function coupled with worse collapsibility and high loop gain characterizes pathological endotypes of obese patients with OSA. Patients with SHD exhibited a more sensitive respiratory pattern, indicated by increased loop gain