OBJECTIVE: To evaluate the efficacy and safety of DCAG (decitabine, cytarabine, anthracyclines, and granulocyte colony-stimulating factor) regimen in the treatment of patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). METHODS: The clinical data of 64 R/R AML patients received treatment at Chinese PLA General Hospital from January 1st, 2012 to December 31st, 2022 were retrospectively analyzed. Primary endpoints included efficacy measured by overall response rate (ORR) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). The patients were followed from enrollment until death, or the end of last follow-up (June 1st, 2023), whichever occurred first. RESULTS: Sixty-four patients who failed prior therapy were enrolled and completed 1 cycle, and 26 and 5 patients completed 2 and 3 cycles, respectively. Objective response rate was 67.2% ［39: complete remission (CR)/CR with incomplete hematologic recovery (CRi), 4: partial remission (PR)］. With a median follow-up of 62.0 months (1.0-120.9), the median overall survival (OS) was 23.3 and event-free survival was 10.6 months. The median OS was 51.7 months (3.4-100.0) in responders (CR/CRi/PR) while it was 8.4 months (6.1-10.7) in nonresponders ( P <0.001). Grade 3-4 hematologic toxicities were observed in all patients. Four patients died from rapid disease progression within 8 weeks after chemotherapy. CONCLUSION The DCAG regimen represents a feasible and effective treatment for R/R AML.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Cytarabine/administration & dosage* ; Granulocyte Colony-Stimulating Factor/administration & dosage* ; Retrospective Studies ; Male ; Female ; Decitabine ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Anthracyclines/administration & dosage* ; Middle Aged ; Adult ; Treatment Outcome ; Aged ; Recurrence

The blood-brain barrier limits the brain delivery of most drugs and affects the treatment of central nervous system disorders. The transnasal drug delivery allows the drug to bypass the blood-brain barrier and reach the brain directly through pathways such as the olfactory and trigeminal nerves, thus improving the therapeutic efficacy of the drug while reducing drug degradation and avoiding hepatic first pass effect. With the rise of nanotechnology, the combination of nanoformulations with transnasal routes of administration is expected to achieve better brain targeting and treatment of brain diseases. On the basis of summarizing the characteristics of the various nose-to-brain pathways, this review summarizes the researches on novel transnasal nanopreparations such as exosomes and liquid crystals in recent years as well as new strategies to improve the efficiency of brain entry including focused ultrasound-mediated techniques. We also review the recent studies on transnasal brain entry nanopreparations in the treatment of various brain disorders and current research dilemmas, looking forward to the prospect of their future clinical applications.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates gene expression in a range of cells, including immune and epithelial cells. AhR signaling plays important roles in the immune system in both health and disease states. Tapinarof is a first-in-class small-molecule topical therapeutic AhR modulating agent launched for the treatment of psoriasis. To improve the activity and chemical stability of Tapinarof, a series of 2-phenylchromen-4-one derivatives were designed, synthesized and evaluated as novel AhR agonists. Compounds 5a, 5c, 5e and 5f potently activated AhR with an EC₅₀ value of 7, 9, 6 and 6 nmol·L^-1, respectively, which are 10-14 fold more potent than Tapinarof. Compounds 5a and 5e exhibit comparable inhibitory effects on IFN-γ production as Tapinarof. Furthermore, compounds 5a-5f exhibited favorable photochemical stability compared to Tapinarof. The compounds may eventually serve as lead compounds for the development of new AhR agonists.

Heart failure with preserved ejection fraction (HFpEF) accounts for about half of the number of patients with heart failure. In addition to the typical features of heart failure such as myocardial stiffness and diastolic function impairment, the key characteristic of HFpEF is the normal left ventricular ejection fraction, which increases the difficulty of clinical diagnosis. QiShenYiQi Dripping Pills (QSYQ) is a standardized traditional Chinese medicine approved by the China Food and Drug Administration (CFDA), and many clinical studies have demonstrated the efficacy and safety of QSYQ in the treatment of heart failure with reduced ejection fraction, but the role of QSYQ in HFpEF has not been clarified. In this paper, high fat diet (HFD) and drinking water containing N-nitro-L-arginine methyl ester (L-NAME, 0.5 g·L^-1, pH=7.4) were used in C57BL/6N male mice to construct the classical HFpEF model (the experiment was approved by the Animal Ethics Committee of Hefei University of Technology, the approval number is HFUT20220921002), and at the 8^th week, the mice were dosed with ① empagliflozin, ② low-dose QSYQ (LQ), ③ high-dose QSYQ (HQ), ④ empagliflozin plus low-dose QSYQ (ELQ) for 4 weeks, the body weight of the mice was recorded during the experiment, echocardiography, blood pressure and glucose tolerance were detected and the exercise capacity of mice was evaluated, and pathological and biochemical experiments were used to detect cardiac fibrosis, liver fibrosis and serum biochemical indexes in mice, RNAseq assay was performed with mice heart tissues. The results showed that QSYQ as well as QSYQ+empagliflozin could significantly reduce the body weight, improve diastolic function and hypertension, improve glucose tolerance and enhance exercise ability of HFpEF mice. At the biochemical and molecular levels, QSYQ and QSYQ+empagliflozin can reduce the cross-sectional area of cardiomyocytes and reduce cardiac collagen contents, thereby alleviating myocardial hypertrophy and fibrotic phenotypes, and improve metabolic disorders. The RNAseq results suggest that the function of QSYQ in improving HFpEF may be related to calsequestrin 1. In conclusion, this study shows that QSYQ and QSYQ+empagliflozin can significantly improve HFpEF-related cardiac dysfunction and metabolic disorders, which provides a theoretical basis for the clinical treatment of HFpEF.

This study was aimed at creating an engineered strain of Bacillus subtilis for efficient expression of biologically active type 2 toxin B(TcdB2)derived from a highly virulent strain of Clostridium difficile.The TcdB2 gene was cloned from ST1/RT027 strain genome DNA,incorporated into the PHT01 vector,and then transformed into B.subtilis strain WB800N for prokaryotic expression.Cell toxicity assays revealed that the recombinant TcdB2 exhibited cytotoxic effects in various cells.The engineered B.subtilis strain effectively expressed biologically active TcdB2,thus providing a basis for further exploration of the pathogenic mechanisms of highly virulent strains of C.difficile and establishing a foundation for potential vaccine can-didate targets.

Objective:To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST)in the treatment of patients with acute myeloid leukemia(AML).Methods:Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed.The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor(GPBSC),followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission(CR).The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated.Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype,including KIR ligand mismatch,2DS1,haplotype,and HLA-Cw ligands on survival prognosis of patients.Results:Forty-two patients received MST induction therapy,and the CR rate was 57.1％after 1 course and 73.7％after 2 courses.Multivariate analysis showed that,medium and high doses of NK cells was significantly associated with improved disease-free survival(DFS)of patients(HR=0.27,P=0.005;HR=0.21,P=0.001),and high doses of NK cells was significantly associated with improved overall survival(OS)of patients(HR=0.15,P=0.000).Donor 2DS1 positive significantly increases OS of patients(HR=0.25,P=0.011).For high-risk patients under 60 years old,patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group(P=0.036);donor 2DS1 positive significantly prolonged OS of patients(P=0.009).Conclusion:NK cell dose,KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST,improve the survival of AML patients.