OBJECTIVES: To investigate the effect of interferon-λ1 (IFN-λ1) on glucocorticoid (GC) resistance in human bronchial epithelial cells (HBECs) stimulated by respiratory syncytial virus (RSV). METHODS: HBECs were divided into five groups: control, dexamethasone, IFN-λ1, RSV, and RSV+IFN-λ1. CCK-8 assay was used to measure the effect of different concentrations of IFN-λ1 on the viability of HBECs, and the sensitivity of HBECs to dexamethasone was measured in each group. Quantitative real-time PCR was used to measure the mRNA expression levels of p38 mitogen-activated protein kinase (p38 MAPK), glucocorticoid receptor (GR), and MAPK phosphatase-1 (MKP-1). Western blot was used to measure the protein expression level of GR in cell nucleus and cytoplasm, and the nuclear/cytoplasmic ratio of GR was calculated. RESULTS: At 24 and 72 hours, the proliferation activity of HBECs increased with the increase in IFN-λ1 concentration in a dose- and time-dependent manner (P˂0.05). Compared with the RSV group, the RSV+IFN-λ1 group had significant reductions in the half-maximal inhibitory concentration of dexamethasone and the mRNA expression level of p38 MAPK (P<0.05), as well as significant increases in the mRNA expression levels of GR and MKP-1, the level of GR in cell nucleus and cytoplasm, and the nuclear/cytoplasmic GR ratio (P<0.05). CONCLUSIONS IFN-λ1 can inhibit the p38 MAPK pathway by upregulating MKP-1, promote the nuclear translocation of GR, and thus ameliorate GC resistance in HBECs.
Humans ; p38 Mitogen-Activated Protein Kinases/genetics* ; Glucocorticoids/pharmacology* ; Receptors, Glucocorticoid/analysis* ; Dual Specificity Phosphatase 1/physiology* ; Dexamethasone/pharmacology* ; Drug Resistance/drug effects* ; Respiratory Syncytial Viruses ; Interferons/pharmacology* ; MAP Kinase Signaling System/drug effects* ; Epithelial Cells/drug effects* ; Signal Transduction/drug effects* ; Cells, Cultured

OBJECTIVE: To explore the efficacy and apoptosis of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of acute myeloid leukemia (AML) with ASXL1 mutation. METHODS: The clinical data of 80 AML patients with ASXL1 mutation treated in our hospital from January 2019 to December 2021 were retrospectively analyzed. The clinical characteristics of the patients were summarized, and the therapeutic effect and prognostic factors of allo-HSCT for the patients were analyzed. RESULTS: Among the 80 patients, 38 were males and 42 were females, and the median age was 39(14-65) years. There were 17 patients in low-risk group, 25 patients in medium-risk group and 38 patients in high-risk group. ASXL1 mutation co-occurred with many other gene mutations, and the frequent mutated genes were TET2 (71.25%), NRAS (18.75%), DNMT3A (16.25%), NPM1 (15.00%), CEBPA (13.75%). Among medium and high-risk patients, 29 underwent allo-HSCT, while 34 received chemotherapy. The 2-year overall survival (OS) rate and disease-free survival (DFS) rate of the allo-HSCT group were 72.4% and 70.2%, while those of the chemotherapy group were 44.1% and 34.0%, respectively. The statistical analysis showed significant differences between the two groups (both P < 0.01). Multivariate analysis showed that age at transplantation >50- years and occurrence of acute graft-versus-host disease after transplantation were poor prognostic factors for OS and DFS in transplantation patients. CONCLUSION Allo-HSCT can improve the prognosis of AML patients with ASXL1 mutation.
Humans ; Leukemia, Myeloid, Acute/therapy* ; Hematopoietic Stem Cell Transplantation ; Female ; Male ; Middle Aged ; Mutation ; Adult ; Repressor Proteins/genetics* ; Adolescent ; Retrospective Studies ; Aged ; Nucleophosmin ; Young Adult ; Transplantation, Homologous ; Prognosis ; Survival Rate

Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

Disrupted bone morphogenetic protein type 2 receptor (BMPR2) signaling in endothelial cells drives pulmonary arterial hypertension (PAH). However, targeted recovery of this signaling pathway by lipid nanoparticles (LNPs) has not been explored as a therapy. Here, we employed Design of Experiments to optimize the delivery efficiency of LNPs targeting pulmonary endothelial cells developed by our laboratory, resulting in a remarkable 35-fold increase in a simplified three-component formulation without helper lipids. Administration of BMPR2 mRNA LNPs effectively reversed established PAH in two experimental rat models (monocrotaline or SU5416-hypoxia) by reversing pulmonary vascular remodeling. Specifically, BMPR2 mRNA LNPs replenished the expression of BMPR2 protein and subsequently activated downstream pathways, as confirmed by elevated levels of p-SMAD1/5/9 and ID1 proteins. The relief of pulmonary arterial occlusion was demonstrated by thinned pulmonary arterial media and decreased proportion of full muscularized vessels. Alleviation of right ventricular hypertrophy was indicated by declined Fulton index, the cross-sectional area of right ventricular cardiomyocytes as well as collagen deposition. Effective recovery of right ventricular function was evidenced by increased pulmonary artery flow acceleration time/pulmonary artery flow ejection time ratio. These findings underscore the potential of restoring BMPR2 signaling through pulmonary endothelial cell-specific LNPs for treating PAH.

Patients with periodontal disease often require combined periodontal-orthodontic interventions to restore periodontal health, function, and aesthetics, ensuring both patient satisfaction and long-term stability. Managing these patients involving orthodontic tooth movement can be particularly challenging due to compromised periodontal soft and hard tissues, especially in severe cases. Therefore, close collaboration between orthodontists and periodontists for comprehensive diagnosis and sequential treatment, along with diligent patient compliance throughout the entire process, is crucial for achieving favorable treatment outcomes. Moreover, long-term orthodontic retention and periodontal follow-up are essential to sustain treatment success. This expert consensus, informed by the latest clinical research and practical experience, addresses clinical considerations for orthodontic treatment of periodontal patients, delineating indications, objectives, procedures, and principles with the aim of providing clear and practical guidance for clinical practitioners.
Humans ; Consensus ; Orthodontics, Corrective/standards* ; Periodontal Diseases/complications* ; Tooth Movement Techniques/methods* ; Practice Guidelines as Topic

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*