Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. ...Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E
, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE
biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens.
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The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and is associated with tumor malignancy. Pyruvate dehydrogenase kinase-1 (PDK1) and PDK3 ...participate in the metabolic switch of cancer cells; however, the medical significance of PDK1 and PDK3 in cancer progression is not known. Here, we assessed the expression profiles of PDK1 and PDK3 in colorectal cancer. Western blot analysis ( n = 74) demonstrated that PDK3 was markedly increased in colon cancer compared to that in adjacent normal tissues, whereas PDK1 was decreased in cancer cells. In addition, PDK3 expression was positively correlated with that of hypoxia inducible factor-1α (HIF-1α) in cancer cells. Further analysis using immunohistochemical staining revealed that PDK3 levels were positively associated with severity of cancer and negatively associated with disease-free survival. In vitro studies using several colon cancer cell lines showed that PDK3 expression was controlled by HIF-1α and contributed to hypoxia-induced increased drug resistance, perhaps explaining why patients with PDK3 overexpression have a greater incidence of treatment failure. Taken together, our findings suggest that PDK3 plays an important role in the metabolic switch and drug resistance of colon cancer and is potentially a novel target for cancer therapy.
Atomic diffusion is a fundamental process that dictates material science and engineering. Direct visualization of atomic diffusion process in ultrahigh vacuum in situ TEM could comprehend the ...fundamental information about metal–semiconductor interface dynamics, phase transitions, and different nanostructure growth phenomenon. Here, we demonstrate the in situ TEM observations of the complete replacement of ZnO nanowire by indium with different growth directions. In situ TEM analyses reveal that the diffusion processes strongly depend and are dominated by the interface dynamics between indium and ZnO. The diffusion exhibited a distinct ledge migration by surface diffusion at 001-ZnO while continuous migration with slight/no ledges by inner diffusion at 100-ZnO. The process is explained based on thermodynamic evaluation and growth kinetics. The results present the potential possibilities to completely replace metal-oxide semiconductors with metal nanowires without oxidation and form crystalline metal nanowires with precise epitaxial metal–semiconductor atomic interface. Formation of such single crystalline metal nanowire without oxidation by diffusion to the metal oxide is unique and is crucial in nanodevice performances, which is rather challenging from a manufacturing perspective of 1D nanodevices.
This paper integrated multi-domain knowledge of electronics, optics, control as well as precision measurement, and proposing a high resolution subdividing electronics module to the sinusoidal encoder ...output of a positioning motor, such that the module can not only be used as a counter for linear and/or angular measurements, but also subdivide the periods of the sinusoidal encoder signals up to 1600 times. From the results of experiment test it can be seen that the whole module is suitable for those applications requiring high-resolution encoder, nanometer measurement as well as fast data acquisition with phase tolerance of plusmn 45 degrees.
Tissue stroma is known to be important in regulating Hp-mediated inflammation, but its interaction with Hp and dendritic cells (DCs) remains to be determined. To this end, the potential crosstalk ...between H. pylori (Hp) infected gastric stromal cells (Hp-GSCs) and DCs was investigated. Primary GSCs from cancerous and adjacent normal tissues were generated from gastric cancer patients, and monocyte-derived DCs were obtained from healthy individuals. Levels of cytokines and prostaglandin E
(PGE
) were measured by ELISA, and C-type lectin expression in GSCs was assessed by flow cytometry and immunohistochemistry. In a trans-well co-culture system, significantly upregulated DC-derived IL-23 expression was found when DCs were co-cultured with Hp-infected GSCs (Hp-GSCs). Further, PGE
from Hp-GSCs was discovered to possess the priming effect, which could be inhibited by anti-COLEC12 (Collectin subfamily member 12) Abs, COLEC12 knockdown or when alpha3-fucosyltransferase-null (futB; HP0651) strain of Hp was used. Also, the expression of COLEC12 was co-localized with CD90
stromal cells in cancerous tissues. Hp-GSCs-conditioned DCs were able to induce the expression of IL-17 from CD4
T cells, which could be inhibited by IL-23-neutralizing Abs. These results suggested the importance of COLEC12 as a receptor involved in Hp-stromal cell interaction and its subsequent conditioning effect on DCs.
infection is the etiology of several gastric-related diseases including gastric cancer. Cytotoxin associated gene A (CagA), vacuolating cytotoxin A (VacA) and α-subunit of urease (UreA) are three ...major virulence factors of
, and each of them has a distinct entry pathway and pathogenic mechanism during bacterial infection.
can shed outer membrane vesicles (OMVs). Therefore, it would be interesting to explore the production kinetics of
OMVs and its connection with the entry of key virulence factors into host cells. Here, we isolated OMVs from
26,695 strain and characterized their properties and interaction kinetics with human gastric adenocarcinoma (AGS) cells. We found that the generation of OMVs and the presence of CagA, VacA and UreA in OMVs were a lasting event throughout different phases of bacterial growth.
OMVs entered AGS cells mainly through macropinocytosis/phagocytosis. Furthermore, CagA, VacA and UreA could enter AGS cells via OMVs and the treatment with
OMVs would cause cell death. Comparison of
26,695 and clinical strains suggested that the production and characteristics of OMVs are not only limited to laboratory strains commonly in use, but a general phenomenon to most
strains.
The prevalence of diabetic retinopathy (DR) is high in individuals with diabetes mellitus. Published estimates for sight-threatening DR (STDR) prevalence range widely. There is a need for precise ...contemporary estimates of the prevalence and incidence of STDR for providing optimal strategies of clinical management in Taiwan.
To determine the precise contemporary estimates of the prevalence and incidence of STDR in patients with type 2 diabetes mellitus in Taiwan.
Data were collected from a representative database, the Longitudinal Health Insurance Database 2005, from 2005 to 2011, on a total of 2926 incident cases of patients with STDR among 63,582 patients with type 2 diabetes. Sight-threatening DR was defined as clinically significant macular edema, severe nonproliferative DR, or proliferative DR according to the classification of the Early Treatment Diabetic Retinopathy Study research group. Sex-specific and age-adjusted incidence and prevalence rates of STDR were analyzed for patients with type 2 diabetes and STDR identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes and procedure codes.
Procedure codes were used to determine the diagnosis of STDR.
The number of incident cases of STDR increased in line with the increasing diabetic population during 2005-2011. Sex differences in the age-adjusted incidence rates were observed, showing a declining trend from 10.84 (95% CI, 10.69%-10.99%) to 6.00 (95% CI, 5.86%-6.14%) per 1000 person-years for women (P < .001) contrasting with an increasing trend in men, from 14.86 (95% CI, 14.71%-15.01%) to 21.89 (95% CI, 21.76%-22.02%) per 1000 person-years (P < .001). The age-adjusted prevalence rates of STDR were in decreasing trends for both sexes, with a mean of 2.75% for women and 2.87% for men. Apart from apparent sex differences in prevalence rates of STDR, increasing trends were observed among younger patients (aged <60 years).
We found considerable variation in the incidence trends between sexes. Our findings provide evidence that the incident cases of STDR have increased among patients with type 2 diabetes, but the overall prevalence of STDR is in a declining trend in Taiwan, suggesting that decreased mortality rate, better diabetes management, and early detection of treatable DR might contribute to the prevalence patterns.
Peripheral compressive neuropathy causes significant neuropathic pain, muscle weakness and prolong neuroinflammation. Surgical decompression remains the gold standard of treatment but the outcome is ...suboptimal with a high recurrence rate. From mechanical compression to chemical propagation of the local inflammatory signals, little is known about the distinct neuropathologic patterns and the genetic signatures after nerve decompression. In this study, controllable mechanical constriction forces over rat sciatic nerve induces irreversible sensorimotor dysfunction with sustained local neuroinflammation, even 4 weeks after nerve release. Significant gene upregulations are found in the dorsal root ganglia, regarding inflammatory, proapoptotic and neuropathic pain signals. Genetic profiling of neuroinflammation at the local injured nerve reveals persistent upregulation of multiple genes involving oxysterol metabolism, neuronal apoptosis, and proliferation after nerve release. Further validation of the independent roles of each signal pathway will contribute to molecular therapies for compressive neuropathy in the future.
Helicobacter pylori infection is associated with the development of several gastric diseases including gastric cancer. To reach a long-term colonization in the host stomach, H. pylori employs ...multiple outer membrane adhesins for binding to the gastric mucosa. However, due to the redundancy of adhesins that complement the adhesive function of bacteria, targeting each individual adhesin alone usually achieves nonideal outcomes for preventing bacterial adhesion. Here, we report that key adhesins AlpA/B and BabA/B in H. pylori are modified by glycans and display a two-step molecular weight upshift pattern from the cytoplasm to the inner membrane and from the inner membrane to the outer membrane. Nevertheless, this upshift pattern is missing when the expression of some enzymes related to lipopolysaccharide (LPS) biosynthesis, including the LPS O-antigen assembly and ligation enzymes WecA, Wzk, and WaaL, is disrupted, indicating that the underlying mechanisms and the involved enzymes for the adhesin glycosylation are partially shared with the LPS biosynthesis. Loss of the adhesin glycosylation not only reduces the protease resistance and the stability of the tested adhesins but also changes the adhesin-binding ability. In addition, mutations in the LPS biosynthesis cause a significant reduction in bacterial adhesion in the in vitro cell-line model. The current findings reveal that H. pylori employs a general protein glycosylation system related to LPS biosynthesis for adhesin modification and its biological significance. The enzymes required for adhesin glycosylation rather than the adhesins themselves are potentially better drug targets for preventing or treating H. pylori infection.
Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown ...potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-β-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-β-induced pulmonary fibrosis.
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