Increased vascular permeability facilitates metastasis. Emerging evidence indicates that secreted microRNAs (miRNAs) may mediate the crosstalk between cancer and stromal cells. To date, whether and ...how secreted miRNAs affect vascular permeability remains unclear. Based on deep sequencing and quantitative PCR, we found that higher level of serum miR‐103 was associated with higher metastasis potential of hepatocellular carcinoma (HCC). The in vitro endothelial permeability and transendothelial invasion assays revealed that the conditioned media or exosomes derived from high miR‐103‐expressing hepatoma cells increased the permeability of endothelial monolayers, but this effect was attenuated if exosome secretion of hepatoma cells was blocked by silencing ALIX and HRS or if miR‐103 within hepatoma or endothelial cells was antagonized. Most importantly, pretreating endothelial monolayers with exosomes that were from stable miR‐103‐expressing hepatoma cells facilitated the transendothelial invasion of tumor cells, and this role of exosomes was abrogated by inhibiting miR‐103 in endothelial cells. Further in vivo analyses disclosed that mice with xenografts of stable miR‐103‐expressing hepatoma cells exhibited higher vascular permeability in tumor, higher level of exosomal miR‐103 and greater number of tumor cells in blood circulation, and increased rates of hepatic and pulmonary metastases, compared to control mice. Mechanism investigations revealed that hepatoma cell‐secreted miR‐103 could be delivered into endothelial cells via exosomes, and then attenuated the endothelial junction integrity by directly inhibiting the expression of VE‐Cadherin (VE‐Cad), p120‐catenin (p120) and zonula occludens 1. Moreover, miR‐103 could also promote tumor cell migration by repressing p120 expression in hepatoma cells. Conclusion: Hepatoma cell‐secreted exosomal miR‐103 increases vascular permeability and promotes tumor metastasis by targeting multiple endothelial junction proteins, which highlights secreted miR‐103 as a potential therapeutic target and a predictive marker for HCC metastasis. (Hepatology 2018).
Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon–hydrogen (C–H) bond activation. Despite the substantial improvement in developing more ...efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well. Here we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C–H bonds. Arylation of a wide range of aldehydes and ketones at the β or γ positions proceeds in the presence of a palladium catalyst and a catalytic amount of amino acid. The feasibility of achieving enantioselective C–H activation reactions using a chiral amino acid as the transient directing group is also demonstrated.
Silent information regulator 1 (Sirt1) is a deacetylase, which plays an important role in the occurrence and development of diabetic nephropathy (DN). Our previous study shows that Yin yang 1 (YY1), ...a widely expressed zinc finger DNA/RNA-binding transcription factor, is a novel regulator of renal fibrosis in diabetic nephropathy. Since the activity of YY1 is regulated via acetylation and deacetylation modification, this study aimed to explore whether Sirt1-induced deacetylation of YY1 mediated high glucose (HG)-induced renal tubular epithelial-mesenchymal transition (EMT) and renal fibrosis in vivo and in vitro. We first confirmed that Sirt1 expression level was significantly decreased in the kidney of db/db mice and in HG-treated HK-2 cells. Diabetes-induced Sirt1 reduction enhanced the level of YY1 acetylation and renal tubular EMT. Then, we manipulated Sirt1 expression in vivo and in vitro by injecting resveratrol (50 mg·kg
·d
. ip) to db/db mice for 2 weeks or application of SRT1720 (2.5 μM) in HG-treated HK-2 cells, we found that activation of Sirt1 reversed the renal tubular EMT and YY1 acetylation induced by HG condition. On the contrary, Sirt1 was knocked down in db/m mice or EX527 (1 μM) was added in HK-2 cells, we found that inhibition of Sirt1 exacerbated renal fibrosis in diabetic mice and enhanced level of YY1 acetylation in HK-2 cells. Furthermore, knockdown of YY1 inhibited the ameliorating effect of resveratrol on renal tubular EMT and renal fibrosis in db/db mice. In conclusion, this study demonstrates that Sirt1 plays an important role in renal tubular EMT of DN through mediating deacetylation of YY1.
Quality control (QC) and preprocessing are essential steps for sequencing data analysis to ensure the accuracy of results. However, existing tools cannot provide a satisfying solution with integrated ...comprehensive functions, proper architectures, and highly scalable acceleration. In this article, we demonstrate SOAPnuke as a tool with abundant functions for a "QC-Preprocess-QC" workflow and MapReduce acceleration framework. Four modules with different preprocessing functions are designed for processing datasets from genomic, small RNA, Digital Gene Expression, and metagenomic experiments, respectively. As a workflow-like tool, SOAPnuke centralizes processing functions into 1 executable and predefines their order to avoid the necessity of reformatting different files when switching tools. Furthermore, the MapReduce framework enables large scalability to distribute all the processing works to an entire compute cluster.We conducted a benchmarking where SOAPnuke and other tools are used to preprocess a ∼30× NA12878 dataset published by GIAB. The standalone operation of SOAPnuke struck a balance between resource occupancy and performance. When accelerated on 16 working nodes with MapReduce, SOAPnuke achieved ∼5.7 times the fastest speed of other tools.
Huge challenges remain regarding the facile fabrication of neat metallic nanowires mesh for high‐quality transparent conductors (TCs). Here, a scalable metallic nanowires bundle micromesh is achieved ...readily by a spray‐assisted self‐assembly process, resulting in a conducting mesh with controllable ring size (4–45 µm) that can be easily realized on optional polymer substrates, rendering it transferable to various deformable and transparent substrates. The resultant conductors with the embedded nanowires bundle micromesh deliver superior and customizable optoelectronic performances, and can sustain various mechanical deformations, environmental exposure, and severe washing, exhibiting feasibility for large‐scale manufacturing. The silver nanowires bundle micromesh with explicit conductive paths is embedded into an ethyl cellulose (EC) transparent substrate to achieve superior optoelectronic properties endowed by a low amount of incorporated nanowires, which leads to reduced extinction cross‐section as verified by optical simulation. A representative EC conductor with a low sheet resistance of 25 Ω □−1, ultrahigh transmittance of 97%, and low haze of 2.6% is attained, with extreme deformability (internal bending radius of 5 µm) and waterproofing properties, opening up new possibilities for low‐cost and scalable TCs to replace indium‐tin oxide (ITO) for future flexible electronics, as demonstrated in a capacitive touch panel in this work.
A scalable silver nanowires bundle micromesh is readily achieved by spray‐assisted self‐assembly, rendering a conducting mesh with superior and customizable optoelectronic performance, which is transferable to various deformable and transparent substrates. A washable ethyl cellulose conductor embedded with the AgNWs micromesh is attained, demonstrating additional extreme deformability and chemical reliability, which is promising to replace indium‐tin oxide (ITO) for future flexible electronics.
Valuation of the EQ-5D-5L in Taiwan Lin, Hsiang-Wen; Li, Chia-Ing; Lin, Fang-Ju ...
PloS one,
12/2018, Letnik:
13, Številka:
12
Journal Article
Recenzirano
Odprti dostop
To date, a value set for the EQ-5D-5L based on the health state preferences of the general Taiwanese population has not been available. This study aimed to develop a Taiwanese value set for EQ-5D-5L ...to facilitate health technology assessment for medical products and services.
An international standardized protocol for EQ-5D-5L valuation studies developed by the EuroQol group was adopted. Adult members of the general public were recruited from six geographic regions in Taiwan. In computer-based face-to-face interviews, each participant completed 10 composite time trade-off (C-TTO) tasks and 7 discrete choice experiment (DCE) tasks. The C-TTO and DCE data were modeled alone or in combination (using hybrid models) with additive models containing 20 dummy variables as main effects. The model performance was assessed both quantitatively and qualitatively (mainly logical consistency and prediction patterns).
Of 1,073 recruited participants, 1,000 completed the study. Approximately 13% of observed utility values were -1 in the C-TTO tasks. The hybrid model, using all available data that assumed C-TTO response values left-censored at -1 and with main effects coefficients with logical consistency (monotonicity), was considered as the most appropriate model. The predicted utility ranged from -1.0259 to 1.
An EQ-5D-5L value set was developed for Taiwan using an established study protocol and a representative sample of the general population. This may facilitate health economic evaluations and decision making on resource allocation under Taiwan's national health insurance program in the future.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ATP-dependent chromatin-remodeling complexes can reorganize and remodel chromatin and thereby act as important regulator in various cellular processes. Based on considerable studies over the past two ...decades, it has been confirmed that the abnormal function of chromatin remodeling plays a pivotal role in genome reprogramming for oncogenesis in cancer development and/or resistance to cancer therapy. Recently, exciting progress has been made in the identification of genetic alteration in the genes encoding the chromatin-remodeling complexes associated with tumorigenesis, as well as in our understanding of chromatin-remodeling mechanisms in cancer biology. Here, we present preclinical evidence explaining the signaling mechanisms involving the chromatin-remodeling misregulation-induced cancer cellular processes, including DNA damage signaling, metastasis, angiogenesis, immune signaling, etc. However, even though the cumulative evidence in this field provides promising emerging molecules for therapeutic explorations in cancer, more research is needed to assess the clinical roles of these genetic cancer targets.
NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms remain unclear.
The protein ...expression of NRF2 in HNSCC specimens was examined by IHC. The regulatory effect of c-MYC on NRF2 was validated by ChIP-qPCR, RT-qPCR and western blot. The impacts of NRF2 on malignant progression of HNSCC were determined through genetic manipulation and pharmacological inhibition
and
. The gene-set enrichment analysis (GSEA) on expression data of cDNA microarray combined with ChIP-qPCR, RT-qPCR, western blot, transwell migration/ invasion, cell proliferation and soft agar colony formation assays were used to investigate the regulatory mechanisms of NRF2.
NRF2 expression is positively correlated with malignant features of HNSCC. In addition, carcinogens, such as nicotine and arecoline, trigger c-MYC-directed NRF2 activation in HNSCC cells. NRF2 reprograms a wide range of cancer metabolic pathways and the most notable is the pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) are critical downstream effectors of NRF2 that drive malignant progression of HNSCC; the coherently expressed signature NRF2/G6PD/TKT gene set is a potential prognostic biomarker for prediction of patient overall survival. Notably, G6PD- and TKT-regulated nucleotide biosynthesis is more important than redox regulation in determining malignant progression of HNSCC.
Carcinogens trigger c-MYC-directed NRF2 activation. Over-activation of NRF2 promotes malignant progression of HNSCC through reprogramming G6PD- and TKT-mediated nucleotide biosynthesis. Targeting NRF2-directed cellular metabolism is an effective strategy for development of novel treatments for head and neck cancer.
The design of efficient catalysts capable of delivering high currents at low overpotentials for hydrogen evolution reactions (HERs) is urgently needed to use catalysts in practical applications. ...Herein, we report platinum (Pt) alloyed with titanium (Ti) from the surface of Ti3C2T x MXenes to form Pt3Ti intermetallic compound (IMC) nanoparticles (NPs) via in situ coreduction. In situ X-ray absorption spectroscopy (XAS) indicates that Pt undergoes a temperature-dependent transformation from single atoms to intermetallic compounds, and the catalyst reduced at 550 °C exhibits a superior HER performance in acidic media. The Pt/Ti3C2T x -550 catalyst outperforms commercial Pt/Vulcan and has a small overpotential of 32.7 mV at 10 mA cm–2 and a low Tafel slope of 32.3 mV dec–1. The HER current was normalized by the mass and dispersion of Pt, and the mass activity and specific activity of Pt/Ti3C2T x -550 are 4.4 and 13 times higher, respectively, than those of Pt/Vulcan at an overpotential of 70 mV. The density functional theory (DFT) calculations suggest that the (111)- and (100)-terminated Pt3Ti nanoparticles exhibit *H binding comparable to Pt(111), while the (110) termination has an *H adsorption that is too exergonic, thus poisoned in the low overpotential region. This work demonstrates the potential of MXenes as platforms for the design of electrocatalysts and may spur future research for other MXene-supported metal catalysts that can be used for a wide range of electrocatalytic reactions.
Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon-hydrogen (C-H) bond activation. Despite the substantial improvement in developing more ...efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well. Here we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C-H bonds. Arylation of a wide range of aldehydes and ketones at the β or γ positions proceeds in the presence of a palladium catalyst and a catalytic amount of amino acid. The feasibility of achieving enantioselective C-H activation reactions using a chiral amino acid as the transient directing group is also demonstrated.
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