The Marine-Derived Oligosaccharide Sulfate (MdOS), a Novel Multiple Tyrosine Kinase Inhibitor, Combats Tumor Angiogenesis both In Vitro and In Vivo

Despite the emerging success of multi-targeted protein tyrosine kinase (PTK) inhibitors in cancer therapy, significant side effects and resistance concerns seems to be avoided unlikely. The aim of the present study was to identify novel multi-targeting PTK inhibitors. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay (ELISA). The antiproliferative activities in human microvascular endothelial cells (HMECs) were evaluated by sulforhodamine (SRB) assay. The phosphorylation of kinases and their downstream molecules was probed by western blot analysis. The binding mode between MdOS and PTKs was profiled by surface plasmon resonance (SPR) approach and molecular simulation. Tube formation assay, rat aortic ring method and chicken chorioallantoic membrane assay were combined to illustrate the in vitro and in vivo anti-angiogenic effects. Results indicated that MdOS, a novel marine-derived oligosaccharide sulfate, exhibited a broad-spectrum PTK inhibitory action. At an enzymatic level, MdOS inhibited HER2, EGFR, VEGFR, PDGFR, c-Kit, FGFR1 and c-Src, with little impact on FGFR2. In cellular settings, MdOS inhibited phosphorylation of PTKs, exemplified by HER2, EGFR and VEGFR2, and downstream molecules of Erk1/2 and AKT. Further studies demonstrated that MdOS acted as an ATP-competitive inhibitor via directly binding to the residues of entrance rather than those of the ATP-binding pocket. Furthermore, MdOS inhibited proliferation and tube formation of HMECs, arrested microvessel outgrowth of rat aortic rings and hindered the neovascularization of chick allantoic membrane. Taken together, results presented here indicated that MdOS exhibited anti-angiogenic activity in a PTK-dependent manner and make it a promising agent for further evaluation in PTK-associated cancer therapy

A nomogram based on CT intratumoral and peritumoral radiomics features preoperatively predicts poorly differentiated invasive pulmonary adenocarcinoma manifesting as subsolid or solid lesions: a double-center study

BackgroundThe novel International Association for the Study of Lung Cancer (IASLC) grading system suggests that poorly differentiated invasive pulmonary adenocarcinoma (IPA) has a worse prognosis. Therefore, prediction of poorly differentiated IPA before treatment can provide an essential reference for therapeutic modality and personalized follow-up strategy. This study intended to train a nomogram based on CT intratumoral and peritumoral radiomics features combined with clinical semantic features, which predicted poorly differentiated IPA and was tested in independent data cohorts regarding models’ generalization ability.MethodsWe retrospectively recruited 480 patients with IPA appearing as subsolid or solid lesions, confirmed by surgical pathology from two medical centers and collected their CT images and clinical information. Patients from the first center (n =363) were randomly assigned to the development cohort (n = 254) and internal testing cohort (n = 109) in a 7:3 ratio; patients (n = 117) from the second center served as the external testing cohort. Feature selection was performed by univariate analysis, multivariate analysis, Spearman correlation analysis, minimum redundancy maximum relevance, and least absolute shrinkage and selection operator. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the model performance.ResultsThe AUCs of the combined model based on intratumoral and peritumoral radiomics signatures in internal testing cohort and external testing cohort were 0.906 and 0.886, respectively. The AUCs of the nomogram that integrated clinical semantic features and combined radiomics signatures in internal testing cohort and external testing cohort were 0.921 and 0.887, respectively. The Delong test showed that the AUCs of the nomogram were significantly higher than that of the clinical semantic model in both the internal testing cohort(0.921 vs 0.789, p< 0.05) and external testing cohort(0.887 vs 0.829, p< 0.05).ConclusionThe nomogram based on CT intratumoral and peritumoral radiomics signatures with clinical semantic features has the potential to predict poorly differentiated IPA manifesting as subsolid or solid lesions preoperatively

Trapping virtual pores by crystal retro-engineering

Stable guest-free porous molecular crystals are uncommon. By contrast, organic molecular crystals with guest-occupied cavities are frequently observed, but these cavities tend to be unstable and collapse on removal of the guests—this feature has been referred to as ‘virtual porosity’. Here, we show how we have trapped the virtual porosity in an unstable low-density organic molecular crystal by introducing a second molecule that matches the size and shape of the unstable voids. We call this strategy ‘retro-engineering’ because it parallels organic retrosynthetic analysis, and it allows the metastable two-dimensional hexagonal pore structure in an organic solvate to be trapped in a binary cocrystal. Unlike the crystal with virtual porosity, the cocrystal material remains single crystalline and porous after removal of guests by heating

AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo

Despite the initial response to the reversible, ATP-competitive quinazoline inhibitors that target ErbB-family, such a subset of cancer patients almost invariably develop resistance. Recent studies have provided compelling evidence that irreversible ErbB inhibitors have the potential to override this resistance. Here, we found that AST1306, a novel anilino-quinazoline compound, inhibited the enzymatic activities of wild-type epidermal growth factor receptor (EGFR) and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. Importantly, AST1306 functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that AST1306 inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to AST1306, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to AST1306 antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to AST1306. In vivo, AST1306 potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/Nneu transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of AST1306 in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h) and sustained (≥24 h) inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish AST1306 as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2-overexpressing cells

Linked read technology for assembling large complex and polyploid genomes

Background: Short read DNA sequencing technologies have revolutionized genome assembly by providing high accuracy and throughput data at low cost. But it remains challenging to assemble short read data, particularly for large, complex and polyploid genomes. The linked read strategy has the potential to enhance the value of short reads for genome assembly because all reads originating from a single long molecule of DNA share a common barcode. However, the majority of studies to date that have employed linked reads were focused on human haplotype phasing and genome assembly. Results: Here we describe a de novo maize B73 genome assembly generated via linked read technology which contains ~ 172,000 scaffolds with an N50 of 89 kb that cover 50% of the genome. Based on comparisons to the B73 reference genome, 91% of linked read contigs are accurately assembled. Because it was possible to identify errors with \u3e 76% accuracy using machine learning, it may be possible to identify and potentially correct systematic errors. Complex polyploids represent one of the last grand challenges in genome assembly. Linked read technology was able to successfully resolve the two subgenomes of the recent allopolyploid, proso millet (Panicum miliaceum). Our assembly covers ~ 83% of the 1 Gb genome and consists of 30,819 scaffolds with an N50 of 912 kb. Conclusions: Our analysis provides a framework for future de novo genome assemblies using linked reads, and we suggest computational strategies that if implemented have the potential to further improve linked read assemblies, particularly for repetitive genomes

Reconstructed covalent organic frameworks

Covalent organic frameworks (COFs) are distinguished from other organic polymers by their crystallinity1–3, but it remains challenging to obtain robust, highly crystalline COFs because the framework-forming reactions are poorly reversible4,5. More reversible chemistry can improve crystallinity6–9, but this typically yields COFs with poor physicochemical stability and limited application scope5. Here we report a general and scalable protocol to prepare robust, highly crystalline imine COFs, based on an unexpected framework reconstruction. In contrast to standard approaches in which monomers are initially randomly aligned, our method involves the pre-organization of monomers using a reversible and removable covalent tether, followed by confined polymerization. This reconstruction route produces reconstructed COFs with greatly enhanced crystallinity and much higher porosity by means of a simple vacuum-free synthetic procedure. The increased crystallinity in the reconstructed COFs improves charge carrier transport, leading to sacrificial photocatalytic hydrogen evolution rates of up to 27.98 mmol h−1 g−1. This nanoconfinement-assisted reconstruction strategy is a step towards programming function in organic materials through atomistic structural control

Functional materials discovery using energy–structure–function maps

Molecular crystals cannot be designed in the same manner as macroscopic objects, because they do not assemble according to simple, intuitive rules. Their structures result from the balance of many weak interactions, rather than from the strong and predictable bonding patterns found in metal–organic frameworks and covalent organic frameworks. Hence, design strategies that assume a topology or other structural blueprint will often fail. Here we combine computational crystal structure prediction and property prediction to build energy–structure–function maps that describe the possible structures and properties that are available to a candidate molecule. Using these maps, we identify a highly porous solid, which has the lowest density reported for a molecular crystal so far. Both the structure of the crystal and its physical properties, such as methane storage capacity and guest-molecule selectivity, are predicted using the molecular structure as the only input. More generally, energy–structure–function maps could be used to guide the experimental discovery of materials with any target function that can be calculated from predicted crystal structures, such as electronic structure or mechanical properties

Regional Actual Evapotranspiration Estimation with Land and Meteorological Variables Derived from Multi-Source Satellite Data

Evapotranspiration (ET) is one of the components in the water cycle and the surface energy balance systems. It is fundamental information for agriculture, water resource management, and climate change research. This study presents a scheme for regional actual evapotranspiration estimation using multi-source satellite data to compute key land and meteorological variables characterizing land surface, soil, vegetation, and the atmospheric boundary layer. The algorithms are validated using ground observations from the Heihe River Basin of northwest China. Monthly data estimates at a resolution of 1 km from the proposed algorithms compared well with ground observation data, with a root mean square error (RMSE) of 0.80 mm and a mean relative error (MRE) of −7.11%. The overall deviation between the average yearly ET derived from the proposed algorithms and ground-based water balance measurements was 9.44% for a small watershed and 1% for the entire basin. This study demonstrates that both accuracy and spatial depiction of actual evapotranspiration estimation can be significantly improved by using multi-source satellite data to measure the required land surface and meteorological variables. This reduces dependence on spatial interpolation of ground-derived meteorological variables which can be problematic, especially in data-sparse regions, and allows the production of region-wide ET datasets

Revealing the microstructures and seepage characteristics in the uncured rubber-cord composites using micro-computed tomography and lattice Boltzmann approach

The internal microstructure distribution of cord-rubber-air during the processing of uncured rubber-cord composites (URCs) determines the finished product's performance. For the first time, we used computed tomography (CT) and the lattice Boltzmann method (LBM) to establish a geometrical representation model of the real microscopic pore-fracture structures of URCs and investigate the seepage law of fluid in porous URCs, where the reinforced rubber formula was originally designed to reduce CT artifacts of cord. The results showed that the average porosity and pore radius of the original cord (0.2711 and 15.53 μm, respectively) were considerably larger than those of the URCs (0.0509 and 4.46 μm, respectively); the pore number of the cord was the largest when the pore radius was 5–10 μm, accounting for 29.36% of the total number; however, the pore number accounted for 31.36% of the total number of the URCs when the pore radius was 2–3 μm. Moreover, the characteristics of the pore/throat surface area and pore volume/throat length exhibited perfect consistent patterns with those of the pore radius. Furthermore, the fluid flow velocity increased in both cord and URCs as the displacement differential pressure increased, but decreased dramatically as the fluid kinematic viscosity increased. The critical values of displacement differential pressure and kinematic viscosity were different in the cord and URCs samples, presenting 11.1209 Pa/1.3696 × 10−3 m2/s and 14.2984 Pa/2.8869 × 10−4 m2/s, respectively. This phenomenon should be attributed that when the uncured rubber was injected into the original cord sample, its porosity decreased, its pore radius decreased, the number of micro-scale pores increased, and flow resistance became larger, resulting in a higher critical value of displacement differential pressure and a lower critical value of kinematic viscosity