Association of metastatic nodal size with survival in non-surgical non-small cell lung cancer patients: Recommendations for clinical N staging.

Background: This study aims to analyze the prognostic significance of the metastatic lymph node (mLN) size in non-small cell lung cancer (NSCLC) patients receiving chemoradiotherapy (CRT) to provide some information for the optimization of clinical nodal (cN) staging. Methods: A retrospective study with 325 NSCLC patients was conducted between January 2011 and December 2018 at two participating institutes. We evaluated the potential relationship between the mLN size and the survival to propose a potential revised nodal (rN) staging. Results: Kaplan-Meier analyses showed significant differences in the overall survival (OS) based on the cN staging and the size of mLNs (N0, ≤2 cm, and >2 cm). We found that the nodal size correlated statistically with the response to CRT. The HRs of OS for patients with bulky mLNs increase significantly compared with patients in the non-bulky mLNs group in the cN2-3 group. Interestingly, the HRs of patients with bulky cN2 disease and non-bulky cN3 disease were similar to each other. We classified the patients into five subsets: N0, rN1(cN1), rN2(non-bulky cN2), rN3a(bulky cN2, and non-bulky cN3), and rN3b(bulky cN3). In our study, the rN stage showed better prognostic discrimination than the 8th IASLC cN staging and was an independent prognostic factor for survival. Conclusions: In addition to the anatomic location, the size of mLNs correlated statistically with the response to CRT and should be incorporated into the cN staging system to predict survival more accurately.

Insights into POT1 structural dynamics revealed by cryo-EM.

Telomeres are protein-DNA complexes that protect the ends of linear eukaryotic chromosomes. Mammalian telomeric DNA consists of 5'-(TTAGGG)n-3' double-stranded repeats, followed by up to several hundred bases of a 3' single-stranded G-rich overhang. The G-rich overhang is bound by the shelterin component POT1 which interacts with TPP1, the component involved in telomerase recruitment. A previously published crystal structure of the POT1 N-terminal half bound to the high affinity telomeric ligand 5'-TTAGGGTTAG-3' showed that the first six nucleotides, TTAGGG, are bound by the OB1 fold, while the adjacent OB2 binds the last four, TTAG. Here, we report two cryo-EM structures of full-length POT1 bound by the POT1-binding domain of TPP1. The structures differ in the relative orientation of the POT1 OB1 and OB2, suggesting that these two DNA-binding OB folds take up alternative conformations. Supporting DNA binding studies using telomeric ligands in which the OB1 and OB2 binding sites were spaced apart, show that POT1 binds with similar affinities to spaced or contiguous binding sites, suggesting plasticity in DNA binding and a role for the alternative conformations observed. A likely explanation is that the structural flexibility of POT1 enhances binding to the tandemly arranged telomeric repeats and hence increases telomere protection.

Linker histone defines structure and self-association behaviour of the 177 bp human chromatosome.

Linker histones play essential roles in the regulation and maintenance of the dynamic chromatin structure of higher eukaryotes. The influence of human histone H1.0 on the nucleosome structure and biophysical properties of the resulting chromatosome were investigated and compared with the 177-bp nucleosome using Cryo-EM and SAXS. The 4.5 Å Cryo-EM chromatosome structure showed that the linker histone binds at the nucleosome dyad interacting with both linker DNA arms but in a tilted manner leaning towards one of the linker sides. The chromatosome is laterally compacted and rigid in the dyad and linker DNA area, in comparison with the nucleosome where linker DNA region is more flexible and displays structural variability. In solution, the chromatosomes appear slightly larger than the nucleosomes, with the volume increase compared to the bound linker histone, according to solution SAXS measurements. SAXS X-ray diffraction characterisation of Mg-precipitated samples showed that the different shapes of the 177 chromatosome enabled the formation of a highly ordered lamello-columnar phase when precipitated by Mg2+, indicating the influence of linker histone on the nucleosome stacking. The biological significance of linker histone, therefore, may be affected by the change in the polyelectrolyte and DNA conformation properties of the chromatosomes, in comparison to nucleosomes.

Automated Vulnerability Discovery and Exploitation in the Internet of Things.

Recently, automated software vulnerability detection and exploitation in Internet of Things (IoT) has attracted more and more attention, due to IoT's fast adoption and high social impact. However, the task is challenging and the solutions are non-trivial: the existing methods have limited effectiveness at discovering vulnerabilities capable of compromising IoT systems. To address this, we propose an Automated Vulnerability Discovery and Exploitation framework with a Scheduling strategy, AutoDES that aims to improve the efficiency and effectiveness of vulnerability discovery and exploitation. In the vulnerability discovery stage, we use our Anti-Driller technique to mitigate the "path explosion" problem. This approach first generates a specific input proceeding from symbolic execution based on a Control Flow Graph (CFG). It then leverages a mutation-based fuzzer to find vulnerabilities while avoiding invalid mutations. In the vulnerability exploitation stage, we analyze the characteristics of vulnerabilities and then propose to generate exploits, via the use of several proposed attack techniques that can produce a shell based on the detected vulnerabilities. We also propose a genetic algorithm (GA)-based scheduling strategy (AutoS) that helps with assigning the computing resources dynamically and efficiently. The extensive experimental results on the RHG 2018 challenge dataset and the BCTF-RHG 2019 challenge dataset clearly demonstrate the effectiveness and efficiency of the proposed framework.

MiR-592 inhibited cell proliferation of human colorectal cancer cells by suppressing of CCND3 expression.

Accumulating evidence shows that microRNA (miRNA) is frequently associated with multiple kinds of human cancers, including colorectal cancer (CRC). Previous studies have shown that miR-592 play critical roles in cancer cell biological processes. However, the function of miR-592 in CRC remains largely unknown. In the present study, we investigated the miR-592's role in cell proliferation of colorectal cancer. MiR-592 expression was markedly down-regulated in CRC tissues and CRC cells. Overexpression of miR-592 reduced the proliferation and anchorage-independent growth of CRC cells. Furthermore, bioinformatics analysis further revealed CCND3, a putative tumor promoter, was found to be a potential target of miR-592 in CRC. The dual-luciferase reporter gene assay results showed that CCND3 was a direct target of miR-592. Ectopic expression of miR-592 led to down-regulation of CCND3 protein, which resulted in the down-regulation of phosphorylated retinoblastoma (p-Rb). In functional assays, CCND3-silenced in miR-592-in-transfected SW48 cells have positive effect to suppress cell proliferation, suggesting that direct CCND3 suppression is required for miR-592-induced cell proliferation of CRC. We conclude that miR-592 can regulate CCND3 and function as a tumor suppressor in CRC. Therefore, miR-592 represents a potential anti-onco-miR and serves as a useful therapeutic agent for miRNA-based CRC therapy.

Boswellic acid attenuates asthma phenotypes by downregulation of GATA3 via pSTAT6 inhibition in a murine model of asthma.

Asthma is a serious global health problem characterised by airway inflammation, airway epithelial wall shedding, enhanced mucus production, increased IgE levels and airway hyperresponsiveness. The pathophysiology of asthma is mediated by Th2 cells which produce Th2 cytokines like interleukin-4, interleukin-5, interleukin-13 and interleukin-9. The differentiation of Th2 cells is induced by the transcription factor GATA3 which is activated by pSTAT6 via IL-4 signalling. To investigate the anti-asthmatic potential of Boswellic acid, as well as the underlying mechanism involved, we studied its anti-asthmatic potential in a murine model of asthma. In this study, BALB/c mice were systemically sensitized by ovalbumin (OVA) followed by aerosol allergen challenges. We investigated the effect of Boswellic acid on airway hyperresponsiveness, inflammatory cell infiltration, Th2 cytokine and OVA-specific IgE production in a mouse model of asthma. We found that Boswellic acid treated groups suppressed allergic airway inflammation, AHR, OVA-specific IgE and Th2 cytokines secretion. It also suppressed the expression of pSTAT6 and GATA3 in a dose dependent manner. Our data suggest that the mechanism by which Boswellic acid effectively treats asthma is based on reductions of Th2 cytokines via inhibition of pSTAT6 and GATA-3 expression.