Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca 2þ , or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/ tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy.
By tuning the processing variables and solution properties using four different solvents (dimethylformamide, o-dichlorobeneze, tetrahydrofuran, and chloroform), polystyrene (PS) fibers were prepared by the electrospinning process to study the effects of these governing parameters on the morphological changes of the charged cone and jet, as well as the diameter and birefringence of the fibers collected. Both jet diameter (d j) and fiber diameter (d f) were scaled with the processing variables, i.e., solution flow-rate (Q), applied voltage (V) and working distance (H), with a power law model. Knowledge of these exponents provided insight into how to manipulate the electrified jet and spun fibers for a given solution. Results showed that Q was the dominant factor in determining the fiber diameter and the Q dependences of d j and d f were approximately scaled with: d j ∼ Q 0.5 and d f ∼ Q 0.25. The applied electric field (V/H) did affect the cone volume and the length of the electrified jet. Either increasing V or decreasing H produced a slightly thinner jet and smaller fiber, but the effects were not significant due to the limited processing range available for the stable cone-jet mode, and the nonuniformity of the electric field resulting from the point-to-plate electrode configuration used in this study. Regardless of the variations of the processing variables (Q, V, and H), a master curve between d j and d f was found for a solution with fixed properties, from which a simple equation was obtained and expressed by: d f ∼ md j 0.45 where m was a prefactor depending upon solution properties, such as the viscosity (ηο), conductivity (κ) and surface tension. Values of m were found to be lower for solutions with lower viscosity and/or higher conductivity, and were successfully scaled to be as follows: m ∼ ηo 0.38κ-0.12. As far as the solution properties were concerned, the concentration emerged as the most important parameter because of its interaction with all aspects of the electrospinning process. The rheological properties of the polymer solution showed a significant effect on the formation of smooth electrospun fibers. On the basis of the Graessley's concentration-molecular weight diagram, various PS fiber morphologies were discussed and the minimum polymer concentration at a given polymer molecular weight required for preparing smooth PS fibers could be estimated. For the present PS solutions, a scaling law was found between the fiber diameter and solution viscosity: d f ∼ ηo 0.41, if other governing parameters (Q, V, H, κ, and surface tension) were fixed.
Orchidaceae are well known for their fascinating floral morphologic features, specialized pollination, and distinctive ecological strategies. With their long-lasting flowers of various colors and pigmentation patterning, Phalaenopsis spp. have become important ornamental plants worldwide. In this study, we identified three R2R3-MYB transcription factors PeMYB2, PeMYB11, and PeMYB12. Their expression profiles were concomitant with red color formation in Phalaenopsis spp. flowers. Transient assay of overexpression of three PeMYBs verified that PeMYB2 resulted in anthocyanin accumulation, and these PeMYBs could activate the expression of three downstream structural genes Phalaenopsis spp. Flavanone 3-hydroxylase5, Phalaenopsis spp. Dihydroflavonol 4-reductase1, and Phalaenopsis spp. Anthocyanidin synthase3. In addition, these three PeMYBs participated in the distinct pigmentation patterning in a single flower, which was revealed by virus-induced gene silencing. In the sepals/petals, silencing of PeMYB2, PeMYB11, and PeMYB12 resulted in the loss of the full-red pigmentation, red spots, and venation patterns, respectively. Moreover, different pigmentation patterning was regulated by PeMYBs in the sepals/petals and lip. PeMYB11 was responsive to the red spots in the callus of the lip, and PeMYB12 participated in the full pigmentation in the central lobe of the lip. The differential pigmentation patterning was validated by RNA in situ hybridization. Additional assessment was performed in six Phalaenopsis spp. cultivars with different color patterns. The combined expression of these three PeMYBs in different ratios leads to a wealth of complicated floral pigmentation patterning in Phalaenopsis spp.
Using a jacket-type heat exchanger to control the solution temperature, the electrospinning of polyacrylonitrile/dimethylformamide (PAN/DMF) solutions with various concentrations was carried out at temperatures ranging from ambient to 88.7 °C. The purpose of this is to investigate the temperature effect on the cone/jet/fiber morphologies that developed. By varying the solution temperature, the chain entanglement status existing in the solution (which is the prerequisite condition for preparing uniform fibers) remained intact. However, the solution properties were significantly altered, thereby giving rise to a feasible route to manipulate the as-spun fiber diameter. By increasing the solution temperature, it was found that the viscosity (η o ) and surface tension (γ) of the PAN/DMF solutions were decreased, but the solution conductivity (κ) was increased; all these trends favored the development of thinner electrospun PAN fibers at high electrospinning temperatures. For instance, with the 6 wt % solutions, PAN fibers with a diameter of 65-85 nm were readily prepared by electrospinning at 88.7 °C, whereas larger fibers with a diameter of 190-240 nm were frequently obtained at room temperature. The temperature dependence of η o , γ, and κ followed the Arrhenius equation, and the corresponding activation energies were composition dependent and found to be ca. 15-28, ∼10 and ∼3.7 kJ/mol, respectively. Hightemperature electrospinning eventually produced PAN fibers with less crystallinity but higher chain orientation as revealed by the wide-angle X-ray diffraction and birefringence measurements. Moreover, the scaling law for the viscosity dependence of fiber diameter, d f , was also altered from d f ) 14.8η o 0.52 (unit: d f in nm and η o in cP) at room temperature to d f ) 3.0η o 0.74 at 88.7 °C, suggesting that high-temperature electrospinning was an effective method to produce ultrathin fibers.
Introduction: Osimertinib is the current recommended treatment for EGFR T790M-positive NSCLC after EGFR tyrosine kinase inhibitor therapy. However, resistance to osimertinib therapy is inevitably acquired after a period of effective treatment. We had a patient with EGFR L858R/ T790M-positive NSCLC who initially responded to osimertinib therapy but eventually experienced development of resistance. Plasma cell-free DNA analysis revealed the occurrence of exon 16-skipping HER2, which may have resulted in the erb-b2 receptor tyrosine kinase 2 gene (HER2) splice variant HER2D16. HER2D16 has never been reported in lung cancer, and HER2D16-driven signaling is known to be regulated by Src kinase in breast cancer. We investigated the role of HER2D16 as an osimertinibresistant mechanism.Methods: We constructed and established H1975 cells stably expressing HER2D16. The dimeric formation of HER2D16 was tested by using nonreducing polyacrylamide gel electrophoresis. The effects of the study drugs on signaling transduction were examined by using Western blot. Synergistic effect was assessed by using the Chou-Talalay method.Results: We found that HER2D16 can form a homodimer in NSCLC cells. HER2D16-expressing H1975 cells were resistant to osimertinib treatment. We also found that mutant EGFR and HER2D16 cooperated to activate downstream signaling for osimertinib resistance. In addition, cotreatment with osimertinib and an Src kinase inhibitor failed to reverse resistance, indicating that HER2D16-driven signaling in NSCLC did not occur through a canonical pathway. Finally, we revealed that the combination of osimertinib with the pan-HER small-molecule inhibitor afatinib could synergistically repress cell growth and signaling in H1975-HER2D16 cells. Conclusion:HER2D16 can contribute to osimertinib resistance through an Src-independent pathway. HER2D16 should be included in the molecular diagnosis panel for lung cancer.
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