Abstract Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to ...distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei , Albatrellus confluens , Cordyceps militaris , Ganoderma lucidum , Poria cocos and Silybum marianum , together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.
Global satellite observations of temperature and geopotential height (GPH) from the Microwave Limb Sounder (MLS) on the EOS Aura spacecraft are discussed. The precision, resolution, and accuracy of ...the data produced by the MLS version 2.2 processing algorithms are quantified, and recommendations for data screening are made. Temperature precision is 1 K or better from 316 hPa to 3.16 hPa, degrading to ∼3 K at 0.001 hPa. The vertical resolution is 3 km at 31.6 hPa, degrading to 6 km at 316 hPa and to ∼13 km at 0.001 hPa. Comparisons with analyses (Goddard Earth Observing System version 5.0.1 (GEOS‐5), European Centre for Medium‐range Weather Forecasts (ECMWF), Met Office (MetO)) and other observations (CHAllenging Minisatellite Payload (CHAMP), Atmospheric Infrared Sounder/Advanced Microwave Sounder Unit (AIRS/AMSU), Sounding of the Atmosphere using Broadband Radiometry (SABER), Halogen Occultation Experiment (HALOE), Atmospheric Chemistry Experiment (ACE), radiosondes) indicate that MLS temperature has persistent, pressure‐dependent biases which are between −2.5 K and +1 K between 316 hPa and 10 hPa. The 100‐hPa MLS v2.2 GPH surface has a bias of ∼150 m relative to the GEOS‐5 values. These biases are compared to modeled systematic uncertainties. GPH biases relative to correlative measurements generally increase with height owing to an overall cold bias in MLS temperature relative to correlative temperature measurements in the upper stratosphere and mesosphere.
It is known that metal parts can be made stronger, tougher and better wear resistance by introducing gradient microstructure. This work reports the cooling rate of melt pool induced discrepancy in ...microstructural gradient and element distribution during selective laser melting (SLM), thereby resulting in decrease in microhardness and wear resistance from surface to inside with a range of ∼100 μm of SLM- manufactured AlSi10Mg alloy. The cooling rate in the top surface of melt pool reaches ∼1.44 × 106 K/s, which is much higher than that at the bottom (≤1 × 103 K/s). Such a difference in cooling rate of melt pool is the main cause for forming gradient microstructure in terms of the distribution of Si particles, dendrite size, sub-grains and sub-boundaries. The variation in microstructure of SLM-produced AlSi10Mg alloy, as a result of gradient cooling rate, has a significant impact on its mechanical properties. Compared with core area, the surface area with a higher cooling rate is composed of finer Si particles, dendritic structure and more sub-boundaries, resulting in higher microhardness and greater wear resistance. The mechanism for formation of gradient microstructure and its influence on the mechanical properties are discussed, which provide new and deep insight into fabricating SLM-produced components with gradient microstructure.
•Gradient in microstructure and mechanical property of selective laser melted parts was reported.•The cooling rate of the melt pool was simulated.•The top surface area has a lower degree of crystallinity of Al matrix than that of core area.•Obvious massive sub-boundaries and finer dendrites were found in surface area.•The hardness and wear resistance of the surface is better than the core area.
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is expressed in the epithelial cells of a wide range of organs/tissues from which most cancers are derived. Although accumulating ...reports have indicated the association of cancer incidence with genetic variations in CFTR gene, the exact role of CFTR in cancer development and the possible underlying mechanism have not been elucidated. Here, we report that CFTR expression is significantly decreased in both prostate cancer cell lines and human prostate cancer tissue samples. Overexpression of CFTR in prostate cancer cell lines suppresses tumor progression (cell growth, adhesion and migration), whereas knockdown of CFTR leads to enhanced malignancies both in vitro and in vivo. In addition, we demonstrate that CFTR knockdown-enhanced cell proliferation, cell invasion and migration are significantly reversed by antibodies against either urokinase plasminogen activator (uPA) or uPA receptor (uPAR), which are known to be involved in various malignant traits of cancer development. More interestingly, overexpression of CFTR suppresses uPA by upregulating the recently described tumor suppressor microRNA-193b (miR-193b), and overexpression of pre-miR-193b significantly reverses CFTR knockdown-enhanced malignant phenotype and abrogates elevated uPA activity in prostate cancer cell line. Finally, we show that CFTR gene transfer results in significant tumor repression in prostate cancer xenografts in vivo. Taken together, the present study has demonstrated a previously undefined tumor-suppressing role of CFTR and its involvement in regulation of miR-193b in prostate cancer development.
Abstract
Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. ...The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion.
MGMT
promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries
MGMT
genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these
MGMT
rearrangements in glioma cells and demonstrated that the
MGMT
genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.
Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). ...Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.
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•Tetramerization of PKM2 reverses the LPS-induced Warburg effect•PKM2 plays a key role in stabilizing Hif-1α and regulates Hif-1α-dependent genes•Tetramerization of PKM2 attenuates LPS-induced M1 macrophage traits•PKM2 is a critical determinant of glycolytic reprogramming in macrophages
TLR4-activated macrophages switch their metabolism from oxidative phosphorylation to glycolysis to rapidly provide for the high energy and biosynthetic demands of infection or injury response. Palsson-McDermott identify PKM2 as a critical modulator of IL-1β production and the Warburg effect in LPS-activated macrophages, highlighting it as a target in cancer and inflammation.
Investigations of the effect of size on the tensile strength of composite laminates containing circular holes show that there is a large difference both in failure stress and mechanism due to changes ...in test configuration. This is particularly true of the ply and laminate thickness, and hole diameter. Interrupted tests have been performed on open hole tensile specimens at different load levels to determine the progressive damage development, evaluated through non-destructive testing (X-ray and C-scanning). The tests were also analysed using a novel Finite Element Modelling technique. This was able to accurately predict the wide range of ultimate strengths measured with variation in test parameters, principally through incorporation of the sub-critical damage in the analysis. A significant damage mechanism was seen to be delamination at the hole edge which generally occurred at a lower stress for a smaller hole diameter to ply block thickness ratio. Delaminations allowed damage to join up through the thickness of the laminate and propagate. In ply-level scaled specimens, the delamination propagation was the ultimate failure mode of most of the specimens. In sub-laminate level scaled specimens, localised damage relieved stress in the 0° fibres at the hole edge, delaying the onset of fibre failure. Less damage was seen for larger holes, thus leading to a decreasing failure stress with increasing hole diameter.
To understand how genomic heterogeneity of glioblastoma (GBM) contributes to poor therapy response, we performed DNA and RNA sequencing on GBM samples and the neurospheres and orthotopic xenograft ...models derived from them. We used the resulting dataset to show that somatic driver alterations including single-nucleotide variants, focal DNA alterations and oncogene amplification on extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, ecDNAs and chromosomal alterations demonstrated divergent inheritance patterns and clonal selection dynamics during cell culture and xenografting. We infer that ecDNA was unevenly inherited by offspring cells, a characteristic that affects the oncogenic potential of cells with more or fewer ecDNAs. Longitudinal patient tumor profiling found that oncogenic ecDNAs are frequently retained throughout the course of disease. Our analysis shows that extrachromosomal elements allow rapid increase of genomic heterogeneity during GBM evolution, independently of chromosomal DNA alterations.
Ovarian cancer is the most lethal of all gynecological malignancies, and the identification of novel prognostic and therapeutic targets for ovarian cancer is crucial. It is believed that only a small ...subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. NANOG is one of the key transcription factors essential for maintaining self-renewal and pluripotency in stem cells. This study investigated the role of NANOG in ovarian carcinogenesis and showed overexpression of NANOG mRNA and protein in the nucleus of ovarian cancers compared with benign ovarian lesions. Increased nuclear NANOG expression was significantly associated with high-grade cancers, serous histological subtypes, reduced chemosensitivity, and poor overall and disease-free survival. Further analysis showed NANOG is an independent prognostic factor for overall and disease-free survival. Moreover, NANOG was highly expressed in ovarian cancer cell lines with metastasis-associated property and in clinical samples of metastatic foci. Stable knockdown of NANOG impeded ovarian cancer cell proliferation, migration and invasion, which was accompanied by an increase in mRNA expression of E-cadherin, caveolin-1, FOXO1, FOXO3a, FOXJ1 and FOXB1. Conversely, ectopic NANOG overexpression enhanced ovarian cancer cell migration and invasion along with decreased E-cadherin, caveolin-1, FOXO1, FOXO3a, FOXJ1 and FOXB1 mRNA expression. Importantly, we found Nanog-mediated cell migration and invasion involved its regulation of E-cadherin and FOXJ1. This is the first report revealing the association between NANOG expression and clinical outcome of patients with ovarian cancers, suggesting NANOG to be a potential prognostic marker and therapeutic molecular target in ovarian cancer.
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