Kuang Tien General Hospital

Angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is critical for viral entry and pulmonary homeostasis, yet its regulation during infection remains unclear. Using SARS-CoV-2 single-round infectious particles (SRIPs), we found that ACE2 protein and mRNA were markedly reduced in human alveolar (A549) and bronchial (Calu-3) cells. This effect was reproduced by expression of the viral main protease (Mpro). Notably, ACE2 suppression was independent of Mpro enzymatic activity, as the catalytically inactive mutant (Mpro_C145A) downregulated ACE2 comparably to wild-type Mpro, and inhibition with nirmatrelvir or MG132 failed to restore expression. Mechanistically, Mpro enhanced STAT1 phosphorylation while suppressing STAT3 Tyr705 phosphorylation, impairing STAT3 nuclear localization and transcriptional activity. Overexpression of STAT3, but not STAT1, restored ACE2 expression in both Mpro-expressing and SARS-CoV-2-infected cells. Moreover, Mpro activated ERK1/2 through TRAF6-TAK1 signaling, which facilitated STAT3 interaction with the tyrosine phosphatase MEG2, leading to dephosphorylation of STAT3 at Tyr705. ERK1/2 inhibition restored STAT3 activity and ACE2 expression, while JNK inhibition had no effect. In infected cells, ERK1/2 inhibition increased ACE2 but also enhanced viral replication. These findings identify a non-enzymatic role of Mpro in suppressing ACE2 through the ERK1/2-MEG2-STAT3 axis, highlighting a mechanism that regulates host receptor availability and influences SARS-CoV-2 pathogenesis.

This study aimed to evaluate the prognostic implications and optimal timing for assessing left ventricular ejection fraction (LVEF) trajectory in patients with heart failure (HF) and an LVEF < 50%. The Taiwan Society of Cardiology HF Registry 2020 is a prospective, multicenter registry of hospitalized HF patients in Taiwan. This study included patients with an LVEF < 50% during their index HF hospitalization, and at least one follow-up echocardiogram within 2 years. HF with improved EF (HFimpEF) was defined as an absolute increase in LVEF > 10% from baseline. The primary endpoints were all-cause mortality and HF hospitalization at 2 years. Predictors of an improvement in LVEF trajectory were also evaluated. A total of 1478 patients were enrolled, with 873 in the HFimpEF group and 605 in the non-HFimpEF group. HFimpEF was associated with a lower risk of mortality (hazard ratio: 0.41 [0.27-0.62], p < 0.001) and reduced HF hospitalizations (8.6% vs. 24.4%, p < 0.001) at 2 years follow-up. Subgroup analysis showed that survival benefits diverged at an LVEF improvement > 10%, emerging as early as 6 months and persisting beyond 12 months. Lower baseline LVEF was paradoxically associated with better survival. Neither maximal guideline-directed medical therapy (GDMT) score nor revascularization correlated with LVEF trajectory. However, HFimpEF patients received higher doses of renin-angiotensin system inhibitors and beta-blockers in the first year. LVEF trajectory at 6 months appears to be a valuable prognostic tool, and higher-dose fundamental HF therapy was more important than achieving a higher overall GDMT score.

Abstract Background. To test the hypothesis that the genomic alterations of HMGB1, ROS1, IL6, FGFR1, FGFR2, and TLR4 would be associated with long-term outcomes in patients with ESCC through disrupting normal immune surveillance and promote mechanisms that allow tumor cells to evade immune detection and destruction. These genes were also variously involved in the RTK-Ras pathway (ROS1, FGFR1, FGFR2), PI3K-Akt signaling (FGFR1, FGFR2, IL6 and TLR4), TLR signaling (TLR4 and IL6) and the SHP2 signaling (FGFR2 and IL6). Methods. This study merged five datasets and sorted out pure squamous cell carcinoma for analysis. GSE53624 was used for gene expression correlating to survival analysis on the genes of interest. Disease-free survival (DFS) and overall survival (OS) were calculated in patients whose survival times were available for Kaplan-Meier analysis. The log-rank test was used for comparison. Only patients with available survival data were put into the survival modes. Hazard ratios (HR) with 95% confidence interval (CI) were derived from the log-rank test. The research was conducted via the KEGG.jp, cBioPortal (accessed November 2024), and ESCCdb/Sichuan. Results. A total of 437 patients with 437 samples were selected. Male accounted for 78.5%. The altered and unaltered group comprises 66 (15%) and 371 (85%) patients. The top 10 mutated genes in this cohort are TP53, TTN, KMT2D, MUC16, CSMD3, PKHD1L1, ZNF804B, SYNE1, NOTCH1 and PCLO. Patients were assigned to either altered group (any alteration in the six genes of interest) or unaltered group. Compared with the unaltered group, the altered group has a higher nonsynonymous tumor mutational burden (TMB) [(median (IQR), 3.37 (2.07-5.23) vs 5.33 (4.32-6.3), p = 5.22e-8 by Wilcoxon test)] and higher mutation count [(median (IQR), 56 (13-117) vs 158.5 (125-187), p &amp;lt; 10e-10)]. DFS can be calculated in 76 patients. The altered group has a nonsignificant worse DFS with an HR of 1.171 (95% CI, 0.512-2.681). With more than 85 months of follow-up in 288 patients, compared with the altered group, the altered group shows significantly worse overall survival: median and 95% CI, 40.93 mo. (28.42 mo. - not reached) vs. 18.63 mo. (18.17 mo. - 28.13 mo.), HR = 2.16 (1.33 - 3.52)]. Gene expression versus survival analyses revealed that higher HMGB1 expression harbors a significantly worse prognosis (p &amp;lt; 0.008). Conclusions. These in silico and dataset experiments leveraging the genomic data from ESCC demonstrate that despite having a higher mutation count and TMB, which might elicit more tumor neoantigens for immune recognition and eradication, the altered group with genomic alterations in any of the six genes might still have a significantly worse long-term survival prognosis. The novelty of the study findings needs further investigation. Citation Format: Victor C. Kok. Impact of genomic alterations in HMGB1, ROS1, IL6, FGFR1, FGFR2, and TLR4 on long-term survival outcomes in esophageal squamous cell carcinoma (ESCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3390.

Mitochondrial Ca2+ uniporter (MCU) provides a Ca2+ influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca2+ rise stimulates ATP production and cell growth. MCU is highly expressed in various cancer cells including breast cancer cells, thereby increasing the capacity of mitochondrial Ca2+ uptake, ATP production, and cancer cell proliferation. The objective of this study was to examine MCU inhibition as an anti-cancer mechanism. The effects of MCU-i4, a newly developed MCU inhibitor, on cell viability, apoptosis, cytosolic Ca2+, mitochondrial Ca2+ and potential, glycolytic rate, generation of ATP, and reactive oxygen species, were examined in breast cancer BT474 cells. MCU-i4 caused apoptotic cell death, and it decreased and increased, respectively, mitochondrial and cytosolic Ca2+ concentration. Inhibition of MCU by MCU-i4 revealed that cytosolic Ca2+ elevation resulted from endoplasmic reticulum (ER) Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RYR). Unexpectedly, MCU-i4 enhanced glycolysis and ATP production; it also triggered a large production of reactive oxygen species (ROS) and mitochondrial membrane potential collapse. Cytotoxic mechanisms of MCU-i4 in cancer cells involved enhanced glycolysis and heightened formation of ATP and ROS. It is conventionally believed that cancer cell death could be caused by inhibition of glycolysis. Our observations suggest cancer cell death could also be induced by increased glycolytic metabolism.

Family caregivers have a vital role to play in palliative care for chronically ill patients. In Taiwan, caregiver demographics are evolving, with the number of male caregivers increasing. Gender differences influence psychosocial behaviours, thought processes and communication styles. In healthcare, acknowledgement of gender differences facilitates effective delivery of high-quality care. The aim of this study is to explore male caregivers' decision-making process for palliative care for chronically ill family members. This study employed grounded theory to generate a substantive theory of male caregivers' decision-making process for palliative care for chronically ill family members. We recruited 22 male participants from three inner-city teaching hospitals in Taiwan. Regarding the decision-making process of palliative care of chronic ill family, where male caregivers do not want their loved ones suffering anymore, the male caregivers' decision-making process was impacted, first, by caregivers' views on the last stage of life; second, by their wish for good care during the end of life; and third, by their conviction that the patients' wishes should be respected. Furthermore, caregivers' philosophy of life and death is also a supportive ground for decision-making. This philosophy was influenced by their education in palliative care, financial status and religious beliefs and practices. The core category emerging from this study is encapsulated by a participant's assertion, 'How difficult is it? There are no male and female differences'. We found that palliative care experiences of male caregivers are important for the decision-making process for palliative care for their chronically ill family members. Caregivers want their loved ones to receive good care as the last step in life, to respect their wishes and no more suffering for the patient. Therefore, health professionals should be familiar with the palliative care process that caregivers go through to offer updated information when needed.

Emerging evidence suggests that air pollution exposure may increase the risk of Parkinson's disease (PD). We aimed to investigate the association between exposure to fine particulate matter (PM2.5) and the risk of incident PD nationwide. We utilized data from the Taiwan National Health Insurance Research Database, which is spatiotemporally linked with air quality data from the Taiwan Environmental Protection Administration website. The study population consisted of participants who were followed from the index date (January 1, 2005) until the occurrence of PD or the end of the study period (December 31, 2017). Participants who were diagnosed with PD before the index date were excluded. To evaluate the association between exposure to PM2.5 and incident PD risk, we employed Cox regression to estimate the hazard ratio and 95% confidence interval (CI). A total of 454,583 participants were included, with a mean (standard deviation) age of 63.1 (9.9) years and a male proportion of 50%. Over a mean follow-up period of 11.1 (3.6) years, 4% of the participants (n = 18,862) developed PD. We observed a significant positive association between PM2.5 exposure and the risk of PD, with a hazard ratio of 1.22 (95% CI, 1.20-1.23) per interquartile range increase in exposure (10.17 μg/m3) when adjusting for both SO2 and NO2. We provide further evidence of an association between PM2.5 exposure and the risk of PD. These findings underscore the urgent need for public health policies aimed at reducing ambient air pollution and its potential impact on PD.

This study assessed the effects of electroacupuncture (EA) stimulation at different frequencies at the Dazhui and Baihui acupoints in the subacute phase after transient global cerebral ischemia (GCI). Rats were subjected to GCI for 25 min, followed by reperfusion for 7 days. EA at acupoints was performed at 10, 30, or 50 Hz, 1 day after reperfusion and then once daily for 6 consecutive days. EA at acupoints at 10 and 50 Hz effectively down-regulated apoptosis in the hippocampal cornu ammonis 1(CA1) area and ameliorated memory deficits. Moreover, EA treatment at 10 and 50 Hz markedly increased phospho (p)-extracellular signal-regulated protein kinase 1/2 (ERK1/2), p-ERK1/2/neuronal nuclei (NeuN), p-cAMP response element-binding protein (CREB)/p-ERK1/2, B-cell lymphoma-2 (Bcl-2)/p-CREB, and X-linked inhibitor of apoptosis protein/NeuN expression levels and decreased Bcl-2 homologous antagonist/killer, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI, cytochrome c, cleaved caspase-3, and apoptosis-inducing factor expression levels. Furthermore, 10-Hz EA treatment effectively increased p-p38 mitogen-activated protein kinase (MAPK), p-p38 MAPK/NeuN, and p-CREB/p-p38 MAPK expression levels. Pretreatment with U0126 (ERK1/2 inhibitor) completely abrogated the effects of 10- and 50-Hz EA treatments on the aforementioned protein expression levels. Similarly, pretreatment with SB203580 (p38 MAPK inhibitor) completely abrogated the effects of 10-Hz treatment on the aforementioned protein expression levels. The effects of 10- and 50-Hz EA treatments on mitochondria-related apoptosis can be attributed to the activation of ERK1/2/p38 MAPK/CREB/Bcl-2- and ERK1/2/CREB/Bcl-2-mediated signaling, respectively, in the hippocampal CA1 area at 7 days after transient GCI.

Head and neck mucosal melanoma is a rare but highly aggressive malignant tumor that usually has a poor prognosis. We describe a 53-year-old male patient, having no any medical history, with left maxillary sinus mucosal melanoma causing bilateral lung metastasis. Rapid tumor regrowth was observed on the 49th day after radical tumor resection. Subsequent pembrolizumab immunotherapy initially elicited pseudoprogression, for which add-on radiation therapy was carried out during maintenance pembrolizumab. A gradual decrease in tumor volume and complete remission were observed by a series of magnetic resonance imaging scans and lung windows of a computer tomography scan of chest. At the 29-month follow-up, the patient was rendered disease-free. In conclusion, head and neck mucosal melanoma may regrow rapidly after surgical resection and pseudoprogression could be frightening during immunotherapy. Subsequent single-agent pembrolizumab plus localized radiation therapy aiming to release more tumor antigens may offer the possibility of long-term remission.