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

a byte-based guess and determine attack on sosemanuk

International Association for Cryptologic Research (IACR); National Research Foundation of Singapore; Lee Foundation; IBM Singapore Ltd.; OConnors Singapore Ltd.SOSEMANUK is a software-oriented stream cipher proposed by C. Berbain et al for the eSTREAM project and has been selected into the final portfolio. It is noticed that most components of SOSEMANUK can be calculated byte-oriented. Hence an attacker can observe SOSEMANUK from the view of byte units instead of the original 32-bit word units. Based on the above idea, in this work we present a new byte-based guess and determine attack on SOSEMANUK, where we view a byte as a basic data unit and guess some certain bytes of the internal states instead of the whole 32-bit words during the execution of the attack. Surprisingly, our attack only needs a few words of known key stream to recover all the internal states of SOSEMANUK, and the time complexity can be dramatically reduced to O(2176). Since SOSEMANUK has a key with the length varying from 128 to 256 bits, our results show that when the length of an encryption key is larger than 176 bits, our guess and determine attack is more efficient than an exhaustive key search. © 2010 International Association for Cryptologic Research

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

Effects of InAlAs strain reducing layer on the photoluminescence properties of InAs quantum dots embedded in InGaAs/GaAs quantum wells

Two kinds of self-assembled quantum dots (QDs) embedded within InGaAs/GaAs quantum wells were grown by molecular beam epitaxy: one was capped with an InAlAs strain reducing (SR) layer, while the other was not. Their emission dynamics was investigated by time-resolved and temperature dependent (TD) photoluminescence (PL) measurements. A significant redshift can be observed in the emission peak position of InAs QDs with thin InAlAs SR cap layer, which results from SR effects. Different behaviors of the integrated PL intensity for the samples with or without InAlAs layer may be ascribed to the reduced carrier transition at higher temperature for the higher energy barrier of the InAlAs layer, and the TD mode of carrier migration. The PL decay time of quantum dots grown with InAlAs layer was much longer than that without the layer, which implies that the InAlAs layer with higher energy barrier may enhance the quantum restriction of carriers in InAs QDs. These observations are discussed from the viewpoint of strain compensation and potential barrier variation with SR layers. Our experiments also demonstrate that the main mode of carrier migration is quantum tunneling effect at lower temperature, while it is quantum transition at higher temperature. The results demonstrate the importance of InAlAs SR layer for the optical quality of InAs QDs. ? 2014 Elsevier B.V