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

Genetic and phenotypic profiling of single living circulating tumour cells from patients with microfluidics

Accurate prediction of the efficacy of immunotherapy for cancer patients through the characterization of both genetic and phenotypic heterogeneity in individual patient cells holds great promise in informing targeted treatments, and ultimately in improving care pathways and clinical outcomes. Here, we describe the nanoplatform for interrogating living cell host-gene and (micro-)environment (NICHE) relationships, that integrates micro- and nanofluidics to enable highly efficient capture of circulating tumor cells (CTCs) from blood samples. The platform uses a unique nanopore-enhanced electrodelivery system that efficiently and rapidly integrates stable multichannel fluorescence probes into living CTCs for in situ quantification of target gene expression, while on-chip coculturing of CTCs with immune cells allows for the real-time correlative quantification of their phenotypic heterogeneities in response to immune checkpoint inhibitors (ICI). The NICHE microfluidic device provides a unique ability to perform both gene expression and phenotypic analysis on the same single cells in situ, allowing us to generate a predictive index for screening patients who could benefit from ICI. This index, which simultaneously integrates the heterogeneity of single cellular responses for both gene expression and phenotype, was validated by clinically tracing 80 non–small cell lung cancer patients, demonstrating significantly higher AUC (area under the curve) (0.906) than current clinical reference for immunotherapy prediction

Efficient and Extensive Search Linear Approximations with High for Precise Correlations of Full SNOW-V

SNOW-V is a stream cipher recently designed for 5G communication system. In this paper, we propose two efficient algorithms to evaluate the precise correlation of SNOW-V\u27s two main nonlinear components with linear hull effects fully considered. Based on these algorithms, we could efficiently and extensively search much more linear masks than before. The ideas of these algorithms can be generalized to other similar nonlinear components in symmetric cipher. We apply our algorithms to full SNOW-V to search different types of linear approximations with high correlations. Our results depict more linear approximations with higher correlations than those proposed for full SNOW-V and SNOW-$\text{V}_{\boxplus_{32},\boxplus_8}$ recently. The best linear approximation we found has absolute correlation $2^{-47.567}$. There are at least 8, 135 and 1092 linear approximations with absolute correlation greater than $2^{-47.851}$, $2^{-49}$ and $2^{-50}$ respectively, which would derive a fast correlation attack with time/memory/data complexities $2^{240.86}$, $2^{240.37}$ and $2^{236.87}$. It is better than all the previous results of fast correlation attack against full SNOW-V. Moreover, we propose some properties for linear trails with 3 active S-boxes, which give a theoretical explanation that automatic search method lacks of. Our work provides a more comprehensive description for the linear approximation properties of full SNOW-V

Vectorial Decoding Algorithm for Fast Correlation Attack and Its Applications to Stream Cipher Grain-128a

Fast correlation attack, pioneered by Meier and Staffelbach, is an important cryptanalysis tool for LFSR-based stream cipher, which exploits the correlation between the LFSR state and key stream and targets at recovering the initial state of LFSR via a decoding algorithm. In this paper, we develop a vectorial decoding algorithm for fast correlation attack, which is a natural generalization of the original binary approach. Our approach benefits from the contributions of all correlations in a subspace. We propose two novel criteria to improve the iterative decoding algorithm. We also give some cryptographic properties of the new FCA which allows us to estimate the efficiency and complexity bounds. Furthermore, we apply this technique to the well-analyzed stream cipher Grain-128a. Based on a hypothesis, an interesting result for its security bound is deduced from the perspective of iterative decoding. Our analysis reveals the potential vulnerability for LFSRs over matrix ring and also for nonlinear functions with biased multidimensional linear approximations such as Grain-128a

Comprehensive Disease Identification and 3D Geological Modeling of Rock Mass Based on Elastic Wave CT and GPR

Taking the rock slope of the subway deep foundation pit as the research object, elastic wave CT is used to preliminarily judge the type and spatial distribution of rock mass diseases in foundation pit, which is then verified by geological radar. Furtherly the a watershed algorithm is adopted to analyze the wave velocity distribution obtained by elastic wave CT in order to extract the detailed sound velocity change at the rock cave and delineate its range. On this basis, based on the coordinate information of elastic wave CT three-dimensional spatial wave velocity database, combined with the spatial coordinate information obtained by watershed algorithm, the modeling database is constructed, after imported into GOCAD software, the three-dimensional geological visualization model is established after processing and analysis. The rock mass disease model established in this paper is highly consistent with geological drilling, peephole imaging and field observation. The proposed rock disease identification method and modeling technology can not only provide an important reference for rock mass support but also provide a basis for water disaster prevention of urban underground engineering

Grape Seed Proanthocyanidin Extract Ameliorates Diabetic Bladder Dysfunction via the Activation of the Nrf2 Pathway.

Diabetes Mellitus (DM)-induced bladder dysfunction is predominantly due to the long-term oxidative stress caused by hyperglycemia. Grape seed proanthocyanidin extract (GSPE) has been reported to possess a broad spectrum of pharmacological and therapeutic properties against oxidative stress. However, its protective effects against diabetic bladder dysfunction have not been clarified. This study focuses on the effects of GSPE on bladder dysfunction in diabetic rats induced by streptozotocin. After 8 weeks of GSPE administration, the bladder function of the diabetic rats was improved significantly, as indicated by both urodynamics analysis and histopathological manifestation. Moreover, the disordered activities of antioxidant enzymes (SOD and GSH-Px) and abnormal oxidative stress levels were partly reversed by treatment with GSPE. Furthermore, the level of apoptosis in the bladder caused by DM was decreased following the administration of GSPE according to the Terminal Deoxynucleotidyl Transferase (TdT)-mediated dUTP Nick-End Labeling (TUNEL) assay. Additionally, GSPE affected the expression of apoptosis-related proteins such as Bax, Bcl-2 and cleaved caspase-3. Furthermore, GSPE showed neuroprotective effects on the bladder of diabetic rats, as shown by the increased expression of nerve growth factor (NGF) and decreased expression of the precursor of nerve growth factor (proNGF). GSPE also activated nuclear erythroid2-related factor2 (Nrf2), which is a key antioxidative transcription factor, with the concomitant elevation of downstream hemeoxygenase-1 (HO-1). These findings suggested that GSPE could ameliorate diabetic bladder dysfunction and decrease the apoptosis of the bladder in diabetic rats, a finding that may be associated with its antioxidant activity and ability to activate the Nrf2 defense pathway

Image_1_The association between the triglyceride–glucose index and prognosis in postoperative renal cell carcinoma patients: a retrospective cohort study.jpeg

BackgroundInsulin resistance has been proven to be associated with renal cell carcinoma (RCC). However, the prognostic value of the triglyceride–glucose (TyG) index, as a marker for insulin resistance (IR), is still unclear. Therefore, we conducted research to explore the prognostic value and the predictive performance of the TyG index in postoperative RCC patients.MethodsA total of 651 postoperative RCC patients from January 2016 to June 2018 were enrolled in the final study. Their clinical and laboratory parameters were collected from medical records and through follow-up by phone. The triglyceride–glucose (TyG) index was calculated as follows: TyG = Ln[TG (mg/dl) × FBG (mg/dL)/2]. The overall survival (OS) and disease-free survival (DFS) were identified as the main outcomes.ResultsThe TyG index is an independent prognostic factor for OS (HR = 2.340, 95% CI = 1.506 to 3.64, P ConclusionThe TyG index is significantly associated with RCC survival. The mechanisms responsible for these results may contribute toward the improvement of RCC prognosis and immunotherapy efficacy and the development of new immunotherapeutic targets.</p