Non-small-cell lung cancer (NSCLC) constitutes 85% of all lung cancers, and is the leading cause of cancer-related death worldwide. The poor prognosis and resistance to both radiation and chemotherapy warrant further investigation into the molecular mechanisms of NSCLC and the development of new, more efficacious therapeutics. The processes of autophagy and apoptosis, which induce degradation of proteins and organelles or cell death upon cellular stress, are crucial in the pathophysiology of NSCLC. The close interplay between autophagy and apoptosis through shared signaling pathways complicates our understanding of how NSCLC pathophysiology is regulated. The apoptotic effect of autophagy is controversial as both inhibitory and stimulatory effects have been reported in NSCLC. In addition, crosstalk of proteins regulating both autophagy and apoptosis exists. Here, we review the recent advances of the relationship between autophagy and apoptosis in NSCLC, aiming to provide few insights into the discovery of novel pathogenic factors and the development of new cancer therapeutics.
Magnetic, durable, and superhydrophobic polyurethane (PU) sponges were fabricated by chemical vapor deposition (CVD) of tetraethoxysilane (TEOS) to bind the Fe3O4 nanoparticles tightly on the sponge and then dip-coating in a fluoropolymer (FP) aqueous solution. The sponges were characterized using scanning electron microscopy and other analytical techniques. The effects of CVD time of TEOS and FP concentration on wettability, mechanical properties, oil absorbency, and oil/water selectivity of the sponges were also investigated. The sponges exhibit fast magnetic responsivity and excellent superhydrophobicity/superoleophilicity (CAwater = 157° and CAoil ≈ 0°). The sponges also show very high efficiency in oil/water separation and could, driven by a magnet, quickly absorb floating oils on the water surface and heavy oils under water. Moreover, the PU@Fe3O4@SiO2@FP sponges could be used as membranes for oil/water separation and for continuous separation of large amounts of oil pollutants from the water surface with the help of a pump. The in turn binding of Fe3O4 nanoparticles, SiO2, and FP can also improve mechanical properties of the PU sponge. The sponges maintain the superhydrophobicity even when they are stretched with 200% strain or compressed with 50% strain. The sponges also show excellent mechanical stability, oil stability, and reusability in terms of superhydrophobicity and oil absorbency. The magnetic, durable, and superhydrophobic PU sponges are very promising materials for practical oil absorption and oil/water separation.
Fitting geometric primitives to 3D point cloud data bridges a gap between low-level digitized 3D data and highlevel structural information on the underlying 3D shapes. As such, it enables many downstream applications in 3D data processing. For a long time, RANSAC-based methods have been the gold standard for such primitive fitting problems, but they require careful per-input parameter tuning and thus do not scale well for large datasets with diverse shapes. In this work, we introduce Supervised Primitive Fitting Network (SPFN), an end-to-end neural network that can robustly detect a varying number of primitives at different scales without any user control. The network is supervised using ground truth primitive surfaces and primitive membership for the input points. Instead of directly predicting the primitives, our architecture first predicts per-point properties and then uses a differential model estimation module to compute the primitive type and parameters. We evaluate our approach on a novel benchmark of ANSI 3D mechanical component models and demonstrate a significant improvement over both the state-of-the-art RANSACbased methods and the direct neural prediction.
A facile method for preparing porous polydimethylsiloxane (PDMS) sponges is reported. The PDMS sponges are fabricated by the polymerization of the PDMS prepolymer and a curing agent in dimethicone using NaCl microparticles as the hard templates. The porous structure of the PDMS sponges is controllable simply by regulating the weight ratio of prepolymer to dimethicone and the size of the NaCl microparticles. The PDMS sponges feature high compressibility and stretchability, excellent superhydrophobicity/superoleophilicity, as well as high chemical and thermal stability. The PDMS sponge can completely recover its original shape even after 50 cycles of 90% strain. The elongation at breaking the sponge is as high as 97%. The PDMS sponge is superhydrophobic with a water contact angle of 151.5 but can be easily wetted by oils.The sponge also exhibits excellent repellency to corrosive aqueous liquids. The flexibility and superhydrophobicity of the sponge remain unchanged even after keeping in liquid nitrogen or at 250 C for 24 h. Long-term immersion in various organics has no obvious influence on superhydrophobicity, oil absorbency, or weight of the sponge. The PDMS sponge can selectively absorb a large amount of floating oils on the water surface and heavy oils under the water, and furthermore, is reusable. Moreover, the PDMS sponge swells quickly after the adsorption of oils, which makes it a promising material for plugging oil leakages.
Additional Sex Combs-Like 1 () is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a promoter-driven transgenic mouse model, Tg, to express a truncated FLAG-ASXL1 protein in the hematopoietic system. The Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1 truncating protein expression results in more open chromatin in cKit cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Tg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the truncation mutations in myeloid malignancies.
The roles of silanes and silicones in forming superhydrophobic and superoleophobic materials are summarized, and the challenges are also listed.
Rational design of nanoparticulate drug delivery systems (nano-DDS) for efficient cancer therapy is still a challenge, restricted by poor drug loading, poor stability, and poor tumor selectivity. Here, we report that simple insertion of a trisulfide bond can turn doxorubicin homodimeric prodrugs into self-assembled nanoparticles with three benefits: high drug loading (67.24%, w/w), high self-assembly stability, and high tumor selectivity. Compared with disulfide and thioether bonds, the trisulfide bond effectively promotes the self-assembly ability of doxorubicin homodimeric prodrugs, thereby improving the colloidal stability and in vivo fate of prodrug nanoassemblies. The trisulfide bond also shows higher glutathione sensitivity compared to the conventional disulfide bond, and this sensitivity enables efficient tumor-specific drug release. Therefore, trisulfide bond–bridged prodrug nanoassemblies exhibit high selective cytotoxicity on tumor cells compared with normal cells, notably reducing the systemic toxicity of doxorubicin. Our findings provide new insights into the design of advanced redox-sensitive nano-DDS for cancer therapy.
Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning anti-apoptotic proteins BCL2 and MCL1 are frequently expressed. Here, we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find clinical samples have frequent co-expression of MCL1 and BCL2, suggesting therapeutic strategies targeting only one will lead to treatment failures due to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest anti-tumor activity against most DLBCL lines and resulted in compensatory up-regulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent anti-tumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients.
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