A phase 1 study of dimdazenil to evaluate the pharmacokinetics, food effect and safety in Chinese healthy subjects

Background and objective: As a partial positive allosteric modulator of the gamma-aminobutyric acid A (GABAA) receptor, dimdazenil was used for the treatment of insomnia with the potential to alleviate associated side effects compared to full agonists. The objective of this trial is to assess the safety, tolerability, food effect and pharmacokinetics following single and multiple doses of dimdazenil in Chinese healthy subjects.Methods: In this phase 1 trial, 36 healthy subjects aged ≥18 years were assigned to receive a single dose of 1.5, 2.5, or 5 mg dimdazenil, with each dose cohort consisting of 12 subjects, and 14 subjects were assigned to receive a multiple 2.5 mg daily dose of dimdazenil for 5 days. Safety, tolerability, and pharmacokinetic characteristics were evaluated.Results: Of the 50 subjects enrolled and 49 completed the trial, the incidences of treatment-emergent adverse events (AEs) in the single-dose groups of 1.5, 2.5, and 5 mg were 16.7%, 58.3% and 66.7% respectively, while 61.5% in the multiple-dose group. There were no serious AEs, deaths, AEs leading to discontinuation or AEs of requiring clinical intervention in any treatment groups. The most treatment-emergent AEs were dizziness (n = 4, 8.2%), hyperuricemia (n = 2, 6.1%), upper respiratory tract infection (n = 2, 6.1%), diastolic blood pressure decreased (n = 2, 6.1%), blood TG increased (n = 2, 6.1%) and RBC urine positive (n = 2, 6.1%). All AEs were mild-to-moderate and transient, and no severe AEs were documented in any study phase. The PK profile of dimdazenil and its active metabolite Ro46-1927 was linear across 1.5–5 mg oral doses in humans. The median Tmax for dimdazenil was in the range of 0.5–1.5 h, and the apparent terminal t1/2z ranged from 3.50 to 4.32 h. Taking Dimdazenil with food may delay Tmax and decrease Cmax, without affecting the total exposure (AUC). No relevant accumulations of dimdazenil and Ro 46–1927 were observed in multiple-dose group.Conclusion: Dimdazenil was generally well tolerated in healthy Chinese subjects after single and 5 days-multiple dosing. The pharmacokinetic properties of dimdazenil are compatible with a drug for the treatment of insomnia.Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR2020197

A miR-155–Peli1–c-Rel pathway controls the generation and function of T follicular helper cells

MicroRNA (miRNA) deficiency impairs the generation of T follicular helper (Tfh) cells, but the contribution of individual miRNAs to this phenotype remains poorly understood. In this study, we performed deep sequencing analysis of miRNAs expressed in Tfh cells and identified a five-miRNA signature. Analyses of mutant mice deficient of these miRNAs revealed that miR-22 and miR-183/96/182 are dispensable, but miR-155 is essential for the generation and function of Tfh cells. miR-155 deficiency led to decreased proliferation specifically at the late stage of Tfh cell differentiation and reduced CD40 ligand (CD40L) expression on antigen-specific CD4+T cells. Mechanistically, miR-155 repressed the expression of Peli1, a ubiquitin ligase that promotes the degradation of the NF-κB family transcription factor c-Rel, which controls cellular proliferation and CD40L expression. Therefore, our study identifies a novel miR-155-Peli1-c-Rel pathway that specifically regulates Tfh cell generation and functionC. Xiao is a Pew Scholar in Biomedical Sciences. This study is supported by the PEW Charitable Trusts, Cancer Research Institute, Lupus Research Institute, National Institutes of Health (grants R01AI087634, R01AI089854, R56AI110403, and R56AI121155 to C. Xiao and grants R01AI103646 and R01AI108651 to L.-F. Lu), National Natural Science Foundation of China (grant 31570882 to W.-H. Liu, grant 31570883 to N. Xiao, and grant 31570911 to G. Fu), 1000 Young Talents Program of China (grant K08008 to N. Xiao), the Fundamental Research Funds for the Central Universities of the People’s Republic of China (grant 20720150065 to N. Xiao and G. Fu), the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, Information and Communications Technology, and Future Planning (grant NRF-2015R1C1A1A01052387 to S.G. Kang), and a 2016 research grant from Kangwon National University (to S.G. Kang

Comparative observations on the squamous-columnar junction of Von Ebner’s glandular duct at the bottom of vallate papillae in dogs, rats, mice and human

Background: This paper aims to comparatively observe similarities of squamous-columnar junction (SCJ) at the opening of Von Ebner's glandular ducts at the vallate papillae in dogs, mice, rats and humans, lay a foundation for the selection of the model in future study of the carcinogenesis in SCJ at vallate papillae. Materials and methods: The localization of the vallate papillae in three laboratory animals and humans was comparatively observed. The differences of SCJ at vallate papillae were comparatively observed by Alcian blue, immunohistochemistry and HE staining. Results: Anatomically, the canine vallate papillae were most similar to those of humans in location, whereas mice and rats only had a single, Ω-shaped, vallate papilla lying directly anterior to the posterior border of the intermolar eminence. In histology, the SCJ of dogs lacked a transition zone similar to that of the human SCJ, and there was glandular epithelium secreting acidic mucus at the opening of the rats’ Von Ebner's glandular ducts. All of this suggested that the histological structure of SCJ in rats and dogs is more distinct from that of humans, whereas the histological structure of SCJ at vallate papilla in mice was more similar. Conclusions: The structure of SCJ at vallate papilla in mice is most similar to that of humans, so we conclude that mouse is the most suitable model for studying tumorigenesis in SCJ at vallate papillae in these three common laboratory animals

Chemotherapy and EGFR tyrosine kinase inhibitors for treatment of brain metastases from non-small-cell lung cancer: survival analysis in 210 patients

BACKGROUND: Chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are controversial in the treatment of patients with brain metastases from non-small-cell lung cancer (NSCLC). METHODS: We retrospectively studied the effects of solely localized treatment or localized treatment in combination with chemotherapy and/or EGFR tyrosine kinase inhibitors on outcomes in 210 NSCLC patients with brain metastases. The effects of treatment modality, Karnofsky performance status, age, primary tumor histology, number of brain metastases, and other factors on survival time were analyzed, and the robustness of two prognostic indices, ie, recursive partitioning analysis and graded prognostic assessment, was evaluated. RESULTS: The median survival time in patients with systemic medication and localized treatments was higher than in those with localized treatments alone (11 versus 3 months, P=0.000). Within the systemic medication group, median survival time was significantly longer for EGFR tyrosine kinase inhibitors than for other types of chemotherapy (12 versus 9 months, P=0.002). In the EGFR tyrosine kinase inhibitor group, median survival time for patients with EGFR gene mutation was 20 months versus 8 months for those with the wild-type EGFR gene. The median survival time with pemetrexed was significantly higher than with other chemotherapies (13 versus 7 months, P=0.006). In multivariate analysis, the prognosis was significantly correlated with treatment modality (P=0.000), Karnofsky performance status (P=0.000), number of brain metastases (P=0.001), and histologic tumor type (P=0.007). In the graded prognostic assessment model, survival curves for the subgroups showed clear separations. CONCLUSION: NSCLC patients with brain metastasis benefited from pemetrexed and/or tyrosine kinase inhibitors along with localized treatments, and the graded prognostic assessment index is a robust model for prognostic evaluation

Abstract PO-057: Targeting ErbB2 degradation via the ubiquitin–proteasome pathway to inhibit the metastasis of pancreatic cancer

Abstract Objective: Pancreatic cancer is currently one of the most lethal human cancers and continues to be a major unsolved health problem in the 21st century. Since pancreatic cancer has a high metastatic potential, chemotherapy is inevitable for most pancreatic cancer patients, whereas the clinical responses to anticancer agents are not satisfied. In this work, we designed and synthesized a novel compound, termed as 6-MPA, and found that 6-MPA could improve the proteasomal degradation of ErbB2 pancreatic cancer cells. Methods: The inhibitory effects of 6-MPA on migration and invasion was measured by scratch experiment, wound healing assay and transwell experiment. Clone formation and CCK-8 assay was used to determine the cytotoxicity of 6-MPA. Real-time PCR and western blotting was used to determine the expression of indicated genes or proteins respectively. Immunoprecipitation was used to characterize protein–protein interactions. Results: 4, 8, and 16 μM of 6-MPA exhibited an inhibitory effects on the migration of SW1990 cells and the inhibition rates reached 40.2±10.1%, 58.2±11.2%, and 65.2±9.9% in vitro, respectively. RNA-seq showed that 6-MPA treatment manipulated ErbB2 level and its downstream PI3K/AKT/mTOR signaling pathways, which was verified by western blotting assay. Treatment with 6-MPA could enhance the interaction between ErbB2 and ubiquitin, and thus promote the proteasomal degradation of ErbB2. Conclusion: In this study, we obtained a novel small molecule 6-MPA, which could specifically degrade ErbB2 through the activation of protein ubiquitinination. And we found that 6-MPA possessed potent inhibitory effects on migration and invasion of pancreatic cancer cells. Therefore, our work illustrated a novel structure skeleton that could be used to target ErbB2, and potentially suppressed the metastasis of pancreatic cancer. Citation Format: Bo Zhang, Fei Teng, Nengming Lin. Targeting ErbB2 degradation via the ubiquitin–proteasome pathway to inhibit the metastasis of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-057.</jats:p

Recent nanotechnology-based strategies for interfering with the life cycle of bacterial biofilms

This review provides a comprehensive overview of the state-of-the-art progress in nanotechnology-based strategies for interfering with the biofilm life cycle according to the requirements of different stages.</jats:p

N-Glycosylation on Asn50 of SND1 Is Required for Glioma U87 Cell Proliferation and Metastasis

Staphylococcal nuclease domain-containing protein 1 (SND1) is an evolutionarily conserved multidomain protein, which has gained attention recently due to its positive regulation in several cancer progression and metastatic spread. However, the specific contribution of SND1 glycosylation in glioma remains uncertain. In the current study, we confirmed that SND1 was highly expressed in human glioma. Using site-directed mutagenesis, we created four predicted N-glycosylation site mutants for SND1 and provided the first evidence that SND1 undergoes N-glycosylation on its Asn50, Asn168, Asn283, and Asn416 residues in human glioma U87 cells. In addition, we found that removing the N-glycans on the Asn50 site destabilized SND1 and led to its endoplasmic reticulum-associated degradation. Furthermore, destabilized SND1 inhibits the glioma cell proliferation and metastasis. Collectively, our results reveal that N-glycosylation at Asn50 is essential for SND1 folding and trafficking, thus essential for the glioma process, providing new insights for SND1 as a potential disease biomarker for glioma