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Tumor cells have significant heterogeneity in metabolism and are closely related to prognosis, gene mutation, and subtype. However, this association has not been demonstrated in reports of gastrointestinal tumors. In this study, we constructed four metabolic subtypes and identified four gene signatures using the expression data and clinical information of 252 metabolism-related genes from TCGA and NCBI databases for gastric adenocarcinoma (STAD) and colorectal cancer (COAD and READ). MC1 had the worst prognosis compared to other classifications. GSig1 was mainly related to drug metabolism and was the highest in MC1 with the worst prognosis, while the other subtypes were mainly related to glucose metabolism pathways. This difference also existed in other different malignant tumors. In addition, metabolic typing was associated with chemotherapeutic drug response and tumor heterogeneity, which indicated that monitoring metabolic typing could contribute to drug efficacy and gene-targeted therapy. In conclusion, we identified differences among subtypes in clinical characteristics such as prognosis and revealed the potential function of metabolic subtype in response to chemotherapeutic agents and oncogene mutations. This work highlighted the potential clinical meaning of metabolic subtype and characteristics in drug therapy and prognosis assessment of malignant tumors. [ABSTRACT FROM AUTHOR]

Visual tracking is a fundamental task and has many applications in computer vision. We incorporate local dictionary and L0 regularized low-rank features into the particle filter framework to address this problem. Specifically, by developing an efficient L0 regularized sparse coding model to incrementally learn low-rank features for the tracking target and incorporating a local dictionary into low-rank features to build the observation model, we establish a robust online object tracking system. As a nontrivial byproduct, we also develop numerical algorithms to efficiently solve the resulting nonconvex optimization problems. Compared with conventional methods, which often directly use corrupted observations to form the dictionary, our low-rank feature-based dictionary successfully removes occlusions and exactly represents the intrinsic structure of the object. Furthermore, in contrast to the traditional holistic methods, the local strategy contains abundant partial and spatial information, thus enhancing the discrimination of our observation model. More importantly, the L0 norm-based hard sparse coding can successfully reduce the redundant information while preserving the intrinsic low-rank features of the target object, leading to a better appearance subspace updating scheme. Experimental results on challenging sequences show that our method consistently outperforms several state-of-the-art methods. [ABSTRACT FROM AUTHOR]

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer-associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC. [ABSTRACT FROM AUTHOR]

The high mortality rate of patients with diabetic foot ulcers is urging the appearance of an effective biomedical drug. Senescence is one of the major reasons of aginginduced decline in the diabetic wound. Our previous studies have demonstrated the anti-senescence effect of secretomes derived from human fetal mesenchymal stem cells (hfMSC). The present study tends to explore the potential role of hfMSC secretome (HFS) in wound healing through anti-aging. Meanwhile, we try to overcome several obstacles in the clinical application of stem cell secretome. A verticle bioreactor and microcarriers are employed to expand hfMSC and produce the HFS on a large scale. The HFS was then subjected to lyophilization (L-HFS). The PLGA (poly lacticco-glycolic acid) particles were used to encapsulate and protect L-HFS from degradation in the streptozotocin (STZ)-induced diabetic rat model. Results showed that HFS-PLGA significantly enhanced wound healing by promoting vascularization and inhibiting inflammation in the skin wound bed. We further analyzed the contents of HFS. Isobaric tag for relative and absolute quantitation (ITRAQ) and label-free methods were used to identify peptides in the secretome. Bioinformatics analysis indicated that exosome production-related singling pathways and heat-shock protein family could be used as bio-functional markers and quality control for stem cell secretome production. [ABSTRACT FROM AUTHOR]

Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase of VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations. [ABSTRACT FROM AUTHOR]

Constitutively active androgen receptor splice variants (AR-V) lacking the ligand-binding domain have been implicated in the pathogenesis of castration-resistant prostate cancer and in mediating resistance to newer drugs that target the androgen axis. AR-V regulates expression of both canonical AR targets and a unique set of cancer-specific targets that are enriched for cell-cycle functions. However, little is known about how AR-V controls gene expression. Here, we report that two major AR-Vs, termed AR-V7 and ARv567es, not only homodimerize and heterodimerize with each other but also heterodimerize with full-length androgen receptor (AR-FL) in an androgen-independent manner. We found that heterodimerization of AR-V and AR-FL was mediated by N- and C-terminal interactions and by the DNA-binding domain of each molecule, whereas AR-V homodimerization was mediated only by DNA-binding domain interactions. Notably, AR-V dimerization was required to transactivate target genes and to confer castrationresistant cell growth. Our results clarify the mechanism by which AR-Vs mediate gene regulation and provide a pivotal pathway for rational drug design to disrupt AR-V signaling as a rational strategy for the effective treatment of advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Phase pure and clean MgB2 films have been fabricated on different types of single-crystal substrate, including SiC, sapphire, MgO, LaAlO3, SrTiO3, and yttrium-stabilized ZrO2 (YSZ), via the hybrid physical-chemical vapor deposition (HPCVD) technique. Pure MgB2 films with different structural textures are obtained by selecting the substrate and its orientation, such as off-axis epitaxial MgB2 on MgO(211) or textured MgB2 on YSZ(110) substrates. Films show Tc(0) in the range 37-41 K, and residual resistivity r(42 K) between 0.3 and 5 µO cm as the substrate and film thickness are varied. The crystal structures and film morphologies are presented and discussed. Further investigations are focused on c-axis epitaxial films. Epitaxial MgB2 films with thickness about 300 nm manifest Tc(0) = 41.2 K and residual resistivity r(42 K) = 0.35 µO cm on SiC(0001) while Tc(0) = 39.5 K and r(42 K) = 0.27 µO cm on c-cut sapphire, reflecting that the films are of high quality and in the 'clean limit'. Low upper critical field H_{\mathrm {c}2}^{ \parallel ab}(0) and large anisotropy of the upper critical field g comparable to the results from MgB2 single crystals are also revealed. The smooth surface of the epitaxial films, with root-mean-square (RMS) roughness less than 5 nm, makes them well qualified for device applications. Microwave performance measurements are carried out using a coplanar resonator on a 300 nm thick film on sapphire substrate and no power dependence of unloaded quality factor in the output power range of [?]10-25 dB is found. [ABSTRACT FROM AUTHOR]