Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) ...metastasis and chemoresistance have not been fully characterized.
CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1.
CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients.
CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.
Background
Sarcopenia is an age-related disease, which is characterized by a decline in muscle mass and function. It is one of the most important health issues in the elderly and often leads to a ...high rate and variety of adverse outcomes.
Objectives
To evaluate the screening accuracy of SARC-F for sarcopenia in the elderly.
Design
We conducted a meta-analysis using articles available in 6 databases including PubMed (Medline), Web of Science, Embase, Cochrane Controlled Register of Trials (CENTRAL), China Knowledge Resource Integrated Database (CNKI), and Wanfang databases from inception to May 2020. Participants: Adults aged 60 years and older.
Measurements
Sarcopenia was defined by EWGSOP2, EWGSOP, AWGS, FNIH and IWGS. Two authors independently extracted data based on predefined criteria. Where data were available we calculated pooled summary estimates of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and their 95% confidence interval (CI) based on different criteria using the hierarchical logistic regression modeling including bivariate modeling and hierarchical summary receiver operating characteristic (HSROC) modeling.
Results
We included 20 studies, with the prevalence of sarcopenia ranging from 6.42% to 21.56%. The number of the literatures using EWGSOP, EWGSOP2, AWGS, IWGS and FNIH as diagnostic criteria was 13, 4, 13, 8, 7, respectively. Bivariate analysis yielded a pooled sensitivity of 32% (95%CI: 19%–47%), 77% (95%CI: 49%–92%), 27% (95%CI: 16%–42%), 39% (95%CI: 27%–52%), 35% (95%CI: 23%–49%) and a pooled specificity of 86% (95%CI:77%–92%), 63% (95%CI: 43%–79%), 91% (95%CI: 85%–95%), 86% (95%CI: 76%–92%), 89% (95%CI: 81%–93%), respectively. The area under the HSROC curve were 0.68 (95%CI: 0.64–0.72), 0.75 (95%CI: 0.71–0.78), 0.73 (95%CI: 0.69–0.77), 0.67 (95%CI: 0.62–0.71), 0.70 (95%CI: 0.65–0.73), respectively.
Conclusions
The screening accuracy of SARC-F was various based on different diagnostic criteria. There were some limitations for SARC-F, however, considering the higher practicability and specificity for screening sarcopenia in practice, SARC-F was still an effective screening tool for sarcopenia in the elderly. And the screening accuracy of SARC-F needs further exploration when EWGSOP2 is applied as diagnostic criteria and geriatric inpatients are the target participants.
Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, ...randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation.
Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety.
Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group.
First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.
We analyzed the measurements of ozone (O3) and its precursors made at rural/suburban sites downwind of four large Chinese cities – Beijing, Shanghai, Guangzhou and Lanzhou, to elucidate their ...pollution characteristics, regional transport, in situ production, and impacts of heterogeneous processes. The same measurement techniques and observation-based model were used to minimize uncertainties in comparison of the results due to difference in methodologies. All four cities suffered from serious O3 pollution but showed different precursor distributions. The model-calculated in situ O3 production rates were compared with the observed change rates to infer the relative contributions of on-site photochemistry and transport. At the rural site downwind of Beijing, export of the well-processed urban plumes contributed to the extremely high O3 levels (up to an hourly value of 286 ppbv), while the O3 pollution observed at suburban sites of Shanghai, Guangzhou and Lanzhou was dominated by intense in situ production. The O3 production was in a volatile organic compound (VOC)-limited regime in both Shanghai and Guangzhou, and a NOx-limited regime in Lanzhou. The key VOC precursors are aromatics and alkenes in Shanghai, and aromatics in Guangzhou. The potential impacts on O3 production of several heterogeneous processes, namely, hydrolysis of dinitrogen pentoxide (N2O5), uptake of hydro peroxy radical (HO2) on particles and surface reactions of NO2 forming nitrous acid (HONO), were assessed. The analyses indicate the varying and considerable impacts of these processes in different areas of China depending on the atmospheric abundances of aerosol and NOx, and suggest the urgent need to better understand these processes and represent them in photochemical models.
Anisotropy and Corotation of Galactic Cosmic Rays Amenomori, M; Ayabe, S; Bi, X.J ...
Science (American Association for the Advancement of Science),
10/2006, Volume:
314, Issue:
5798
Journal Article
Peer reviewed
Open access
The intensity of Galactic cosmic rays is nearly isotropic because of the influence of magnetic fields in the Milky Way. Here, we present two-dimensional high-precision anisotropy measurement for ...energies from a few to several hundred teraelectronvolts (TeV), using the large data sample of the Tibet Air Shower Arrays. Besides revealing finer details of the known anisotropies, a new component of Galactic cosmic ray anisotropy in sidereal time is uncovered around the Cygnus region direction. For cosmic-ray energies up to a few hundred TeV, all components of anisotropies fade away, showing a corotation of Galactic cosmic rays with the local Galactic magnetic environment. These results have broad implications for a comprehensive understanding of cosmic rays, supernovae, magnetic fields, and heliospheric and Galactic dynamic environments.
We present the large-scale sidereal anisotropy of Galactic cosmic-ray intensity in the multi-TeV region observed with the Tibet-III air shower array during the period from 1999 through 2003. The ...sidereal daily variation of cosmic rays observed in this experiment shows an excess of relative intensity around 4-7 hr local sidereal time as well as a deficit around 12 hr local sidereal time. While the amplitude of the excess is not significant when averaged over all declinations, the excess in individual declination bands becomes larger and clearer as the viewing direction moves toward the south. The maximum phase of the excess intensity changes from similar to 7 hr at the Northern Hemisphere to similar to 4 hr at the equatorial region. We also show that both the amplitude and the phase of the first harmonic vector of the daily variation are remarkably independent of primary energy in the multi-TeV region. This is the first result determining the energy and declination dependences of the full 24 hr profiles of the sidereal daily variation in the multi-TeV region with a single air shower experiment.
We present an updated all-particle energy spectrum of primary cosmic rays in a wide range from image to image eV using image events collected from 2000 November through 2004 October by the Tibet-III ...air-shower array located 4300 m above sea level (an atmospheric depth of 606 g cm(-2)). The size spectrum exhibits a sharp knee at a corresponding primary energy around 4 PeV. This work uses increased statistics and new simulation calculations for the analysis. We discuss our extensive Monte Carlo calculations and the model dependencies involved in the final result, assuming interaction models QGSJET01c and SIBYLL2.1, and heavy dominant (HD) and proton dominant (PD) primary composition models. Pure proton and pure iron primary models are also examined as extreme cases. A detector simulation was also performed to improve our accuracy in determining the size of the air showers and the energy of the primary particle. We confirmed that the all-particle energy spectra obtained under various plausible model parameters are not significantly different from each other, which was the expected result given the characteristics of the experiment at high altitude, where the air showers of the primary energy around the knee reach near-maximum development, with their features dominated by electromagnetic components, leading to a weak dependence on the interaction model or the primary mass. This is the highest statistical and the best systematics-controlled measurement covering the widest energy range around the knee energy region.
Abstract Objective Cryopreserved-thawed rat islets were cocultured with Sertoli cells to examine whether they could decrease the loss and improve islet function. Methods Islets and Sertoli cells were ...harvested from the pancreas and the testis of Sprague-Dawley rats, respectively. Cryopreserved, stored islets were thawed and divided into groups of coculture with Sertoli cells versus single cells. We measured islets recovery rate and function. Apoptotic-related proteins and gene expressions were detected by Western blot and reverse-transcriptase polymerase chain reaction. Soluble factors secreted by Sertoli cells in to the supernate were detected by enzyme-linked immunosorbent assay. We compared islet graft survival times in diabetic mice. Results In contrast to the single culture controls, thawed islets cocultured with Sertoli cells exhibited improved morphology. Recovery rates and insulin secretion were significantly higher among coculture cells. Four soluble factors were detected in supernates from Sertoli cell cultures including transforming growth factor-β, insulin-like growth factor-1, epidermal growth factor, and basic fibroblast growth factor. Expression of proapoptotic Bax and caspase 3, 7 were down-regulated while that of antiapoptotic Bcl-2 was up-regulated. Cotransplantation with Sertoli cells significantly prolonged islet graft survival. Conclusion These results suggested that coculture with Sertoli cells significantly improved islet yields and function after thawing and depressed islet apoptosis.
Free-electron lasers have been successfully operated with ultrahigh brightness and excellent transverse coherence at X-ray wavelengths. One of the next goals for further improvements is full ...coherence. An obvious approach is to seed the free-electron laser interaction using a conventional source that has good temporal coherence. Here, we show the first lasing of a free-electron laser with an echo-enabled harmonic generation scheme, which shows great promise for producing coherent lasing at short wavelengths, even in the X-ray regime. The experiment was conducted at a test facility that combines a 135.4 MeV electron accelerator with an amplifier consisting of a series of undulator magnets. Lasing was achieved at the third harmonic of the seed with a gain of ∼100,000 over spontaneous radiation. The measurements show typical exponential growth and excellent spectral characteristics, as well as good intensity stability.
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