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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.

A case report involving incessant multi‐types of supraventricular tachycardia and acute decompensated heart failure required a rescuing electrophysiology study and ablation. Ventricular fibrillation occurred due to coronary spasm, complicating the deteriorating heart. However, aggressive therapies, including extracorporeal support and the timely elimination of the culprit accessory pathway, successfully resolved the patient's condition.

Because hydrogen sulfide (H2S) is classified as a gaseous signaling molecule, protein S-sulfhydration is known to be one of the mechanisms by which H2S signals are conducted. PTP1B, a negative regulator in insulin signaling, has been found to be S-sulfhydrated at Cys215-SH to form Cys215-SSH in response to endoplasmic reticulum (ER) stress. Therefore, we aimed to understand the change in PTP1B S-sulfhydration and cellular redox homeostasis in response to insulin stimulation. We demonstrated a feasible PEG-switch method to determine the levels of PTP1B S-sulfhydration. According to the results obtained from HEK293T and MDA-MB-231 cells, insulin induced a change in PTP1B S-sulfhydration that was similar to the change in Insulin receptor substrate 1 (IRS1) phosphorylation in both cell lines. However, insulin-induced PTP1B S-sulfhydration and IRS1 phosphorylation were only significantly affected by metformin in HEK293T cells. Insulin also induced an increase in reactive oxygen species (ROS) in both cell lines. However, the level of H2S, GSH, and GSSG was only significantly affected by insulin and metformin in HEK293T cells. HEK293T cells maintained high levels of H2S and cysteine, but low levels of GSSG and GSH in general compared to MDA-MB-231 cells. From these findings, we suggest that PTP1B activity is modulated by H2S and redox-regulated S-sulfhydration during insulin signaling.

Background The aim of this study was to assess the impact of diabetic retinopathy (DR) severity on the risk of DR progression to proliferative DR (PDR) or clinically significant macular edema (CSME) in patients with diabetes mellitus (DM). Methods This is a prospective, longitudinal, non-interventional, and observational cohort study of patients with DM in the United States based on a database of 7-field color fundus photograph images from primary care visits. Study participants were adults aged ≥ 18 years who underwent DR screening in either eye between January 1999 and December 2016. DR severity was graded according to the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale (ETDRS-DRSS) on 7-field color fundus photographs. The main outcomes were ≥ 2-step DR worsening and development of CSME, PDR, or CSME and PDR together. Results For all 41,977 eyes evaluated, the proportion of eyes with ≥ 2-step DR worsening was 2.7% at year 2 and 9.6% at year 5. Rate of ≥ 2-step DR worsening was greatest among eyes with moderate-to-severe NPDR with baseline DRSS 43–53 (36.5% at year 5). Analysis of PDR and CSME outcomes showed the presence of 3 distinct clinical phenotypes: 1 subset progressed to CSME (1.24% at year 5), another to PDR (0.49% at year 5), and only a small subset progressed to both vision-threatening forms of DR (0.10% at year 5). The clinical phenotype did not appear to be dependent on baseline DRSS. Conclusions Overall, the risk of progression to vision-threatening forms of DR was more pronounced in eyes with moderate-to-severe non-proliferative DR at baseline. In addition, we found that distinct DR clinical subtypes progressing to either PDR and/or CSME over a 5-year period are not driven by baseline DR severity, suggesting other factors may contribute.

Background CD24 plays a crucial role not only in promoting tumor progression and metastasis but also in modulating macrophage-mediated anti-tumor immunity. However, its impact on the immune landscape of the tumor microenvironment (TME) remains unexplored. Here, we investigated the role of CD24a, the murine CD24 gene, in tumor progression and TME immune dynamics in a murine triple-negative breast cancer (TNBC) model. Methods Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 knockout technology was employed to generate CD24a knockout in the murine TNBC cell line 4T1. Flow cytometry was utilized to analyze the immune cell populations, including myeloid-derived suppressor cells (MDSCs), natural killer cells, T cells, and macrophages, within tumors, spleens, and bone marrow in the orthotopic mouse 4T1 breast cancer model. Immunofluorescence (IF) staining was used to detect the immune cells in tumor sections. High-speed confocal was used to perform three-dimensional (3D) mapping of immune cells in the 4T1 orthotopic tumors. Results Knocking out CD24a significantly reduced tumor growth kinetics and prolonged mouse survival in vivo. Flow cytometry and IF analysis of tumor samples revealed that CD24a loss significantly promoted the infiltration of M1 macrophages and cytotoxic CD8 + T cells into the TME while reducing the recruitment and expansion of granulocytic MDSCs (gMDSCs). In vitro coculture experiments showed that CD24a deficiency significantly enhanced macrophage‐mediated phagocytosis and CD8⁺ T cell-mediated cytotoxicity, effects that were partially reversed by re‐expression of CD24a. Moreover, in vivo depletion of macrophages and CD8 + T cells reverted the delayed tumor growth caused by CD24a knockout, underscoring their critical role in tumor growth suppression associated with CD24a knockout. 3D mapping of immune cells in the TME confirmed the anti-tumor immune landscape in the CD24a knockout 4T1 tumors. Furthermore, in vitro analysis showed that CD24a loss upregulated macrophage colony-stimulating factor expression while suppressed levels of CXCL1, CXCL5, and CXCL10, chemokines known to recruit gMDSCs, further providing a molecular basis for enhanced macrophage recruitment and diminished gMDSC accumulation. Conclusions Our findings suggest that CD24a may regulate immune suppression within the TNBC TME. Targeting CD24a enhances macrophage- and CD8⁺ T cell-mediated anti-tumor immune responses and is associated with a shift in the TME toward a more immunogenic state, thereby suppressing tumor growth. These results may support CD24 as a promising immunotherapeutic target for TNBC.

This case demonstrated the feasibility of administering emergent intravenous thrombolysis followed by Dabigatran reversal with idarucizumab in a patient who underwent atrial fibrillation ablation. The consideration of transitioning anticoagulant therapy to dabigatran for scheduled AF ablation in patients at high risk of stroke should be carefully evaluated.

Background To investigate the differences in body composition and metabolic syndrome (MS) under a daily 12,000-step strategy with or without moderate-intensity walking exercise in college students with obesity. Methods Thirty-two adults with obesity (mean (s.d.) age: 19.72 (0.80) years; height: 165.38 (3.99) cm; wt: 83.31 (4.66) kg; body mass index: 30.38 (0.83) kg m − 2 ) were recruited and randomly assigned to the walking step goal group (WSG; achieving 12,000 steps per day), walking exercise group (WEG; achieving 12,000 steps per day, including 3 days per week on which walking at a step rate of over 103 steps min − 1 was required), or control group (CG; maintaining a free-living life style). Each participant’s accumulated daily steps from daily activities and walking exercises were monitored using a smartwatch for 8 weeks. The variables of body composition and MS were measured before and after intervention. Results Average daily steps over 8 weeks did not significantly differ between the WSG and WEG (11,677.67 (480.24) vs. 12,131.90 (527.14) steps per day, respectively, P >  .05). Although the CG and WSG showed no improvement in body composition, the WEG exhibited significant improvements in terms of hip circumference and visceral fat area (VFA) (∆ − 2.28 (3.27) cm and ∆ − 13.11 (9.83) cm 2 , respectively, P  < .05); high-density lipoprotein cholesterol (HDL-C), fasting glucose (FG), and triglycerides (TG) (∆ 16.36 (8.39), ∆ − 2.53 (3.73), and ∆ − 10.52 (36.26) mg dL − 1 , respectively, P  < .05). The WSG exhibited improvements only in HDL-C (∆ 14.24 (16.13) mg dL − 1 , P  < .05). Conclusion The combination of walking exercise program and daily step goal is a more time efficient strategy in improving body composition and MS than simply establishing a daily step goal. Furthermore, this strategy may also include a potential reduction effect on the risk factors of cardiovascular diseases. Trial registration Australian New Zealand Clinical Trials Registry, number ACTR N12618001237279 (Retrospectively registered).

Background Given the altered gait patterns and metabolic demands in obese individuals, population-specific cadence thresholds (steps per minute) are essential for accurate intensity classification and effective exercise prescription. This study examined the relationship between body composition and Moderate-to-Vigorous Physical Activity (MVPA) cadence in obese individuals and establish cadence thresholds for moderate-intensity physical activity (MPA) (3 metabolic equivalents [METs]), MPA young (moderate-intensity physical activity for young adults, 4.8 METs), and vigorous physical activity (VPA) (6 METs). Methods A total of 48 obese young adults participated in this study. The VO 2 was collected at rest in seated position for 10 min, followed by an incremental walking exercise at 3.2, 4.0, 4.8, 5.6, and 6.4 km/h with 5 min duration in each stage. Walking cadence and oxygen consumption were recorded and converted to steps per minute and METs. Results Body fat significantly related to 3 METs cadence in male ( R ² = 0.156, p  < .05). The receiver operating characteristic (ROC) models demonstrated a good discrimination (area under the curve [AUC] = 0.85–0.88 in males, 0.82–0.89 in females). The optimal cadence thresholds for males were 114 steps/min for MPA (positive predictive value [PPV]: 96.97%, negative predictive value [NPV]: 47.30%), 119 steps/min for MPA young (PPV: 50.94%, NPV: 95.40%), and 124 steps/min for VPA (PPV: 21.21%, NPV: 99.07%). In females, the optimal cadences were 115 steps/min for MPA (PPV: 98.08%, NPV: 36.96%), 125 steps/min for MPA young (PPV: 68.75%, NPV: 93.94%), and 131 steps/min for VPA (PPV: 38.10%, NPV: 98.70%). Conclusion The effect of body fat percentage on gait adjustment mechanisms during MPA are different between genders in Taiwanese young adults. A practical cadence target range is 119–124 steps/min for males and 125–131 steps/min for females, based on the 4.8- to 6-METs thresholds; cadences within these ranges increase the likelihood of exceeding 3 METs. Trial registration ClinicalTrials.gov, number NCT06883253 (Retrospectively registered on March 19, 2025, for a study conducted between November 15, 2017, and November 8, 2018).

Intervertebral disk (IVD) degeneration is often associated with severity of lower back pain. IVD core is an avascular, highly hydrated tissue composed of type II collagen, glycosaminoglycans, and proteoglycans. The disk degeneration is not only a destruction of IVD structure but also is related to a disorder of the turnover of the disk matrix, leading the jelly-like IVD core to be replaced by fibrous components. Here we present a disease-modifying strategy for IVD degenerative diseases by direct regulation of the cells in the IVD using mRNA medicine, to alter the misbalanced homeostasis during disk degeneration. When mRNA encoding a cartilage-anabolic transcription factor, runt-related transcription factor-1, was administered to a rat model of coccygeal disk degeneration using a polyplex nanomicelle composed of polyethylene glycol-polyamino acid block copolymers and mRNA, the disk height was maintained to a significantly higher extent (≈81%) compared to saline control (69%), with prevention of fibrosis in the disk tissue. In addition, the use of nanomicelles effectively prevented inflammation, which was observed by injection of naked mRNA into the disk. This proof-of-concept study revealed that mRNA medicine has a potential for treating IVD degenerative diseases by introducing a cartilage-anabolic factor into the host cells, proposing a new therapeutic strategy using mRNA medicine.

Amiodarone is commonly used during therapeutic hypothermia (TH) following cardiac arrest due to ventricular arrhythmias. However, electrophysiological changes and proarrhythmic risk after amiodarone treatment have not yet been explored in TH. Epicardial high-density bi-ventricular mapping was performed in pigs under baseline temperature (BT), TH (32-34°C), and amiodarone treatment during TH. The total activation time (TAT), conduction velocity (CV), local electrogram (LE) duration, and wavefront propagation from pre-specified segments were analyzed during sinus rhythm (SR) or right ventricular (RV) pacing (RVP), along with tissue expression of connexin 43. The vulnerability to ventricular arrhythmias was assessed. Compared to BT, TH increased the global TAT, decreased the CV, and generated heterogeneous electrical substrate during SR and RVP. During TH, the CV reduction and LE duration prolongation were greater in the anterior mid RV than in the other areas, which changed the wavefront propagation in all animals. Compared to TH alone, amiodarone treatment during TH further increased the TAT and LE duration and decreased the CV. Heterogeneous conduction was partially attenuated after amiodarone treatment. After TH and amiodarone treatment, the connexin 43 expression in the anterior mid RV was lower than that in the other areas, compatible with the heterogeneous CV reduction. The animals under TH and amiodarone treatment had a higher incidence of inducible ventricular arrhythmias than those under BT or TH without amiodarone. Electrical heterogeneity during amiodarone treatment and TH was associated with vulnerability to ventricular arrhythmias.