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.
An anomaly in differential scanning calorimetry has been reported in a number of metallic glass materials in which a broad exothermal peak was observed between the glass and crystallization ...temperatures. The mystery surrounding this calorimetric anomaly is epitomized by four decades long studies of Pd-Ni-P metallic glasses, arguably the best glass-forming alloys. Here we show, using a suite of in situ experimental techniques, that Pd-Ni-P alloys have a hidden amorphous phase in the supercooled liquid region. The anomalous exothermal peak is the consequence of a polyamorphous phase transition between two supercooled liquids, involving a change in the packing of atomic clusters over medium-range length scales as large as 18 Å. With further temperature increase, the alloy reenters the supercooled liquid phase, which forms the room-temperature glass phase on quenching. The outcome of this study raises a possibility to manipulate the structure and hence the stability of metallic glasses through heat treatment.
The effects of microstructure on crack resistance and toughening mechanism of an ultra-low carbon steel were investigated. The microstructures were controlled via thermal-mechanical control ...processing (TMCP) and heat-treatments. Distribution of stress concentration, microcracks formation and propagation during Charpy impacting were investigated in detail. The results indicate that the lath martensitic structure provided a higher yield stress together with a better impact property, compared to the polygonal ferritic structure. The high strength can be attributed to the high density of dislocations in the lath martensitic structure introduced by quenching. The instrumented Charpy impact results indicated that the crack initiation energy in the lath martensitic structure was similar to that in the ferritic structure while the crack propagation energy was significantly greater than that in the ferritic structure, leading to the high toughness of the steel with the lath martensitic structure. Local stress concentration distributed uniformly in lath martensitic structure, leading to the homogeneous nucleation of microcrack. The high crack propagation energy in the lath martensitic structure can be attributed to the high fraction of high angle grain boundaries and fine effective grains, which deflected the cleavage crack propagation direction.
Display omitted
•60 °C decrement in DBTT was obtained through controlling microstructure.•The lath martensite provides a good combination of strength and toughness.•The high crack propagation energy of lath martensite benefits to the good toughness.•HAGB and EGS deflect the cleavage crack propagation direction.
To explore the characteristics of Helicobacter pylori resistance in China and the association between antibiotic resistance and several clinical factors.
H. pylori strains were collected from ...patients in 13 provinces or cities in China between 2010 and 2016. Demographic data including type of disease, geographic area, age, gender and isolation year were collected to analyse their association with antibiotic resistance. Antibiotic resistance was detected using the Etest test and the Kirby-Bauer disc diffusion method.
H. pylori were successfully cultured from 1117 patients. The prevalence of metronidazole, clarithromycin (CLA), azithromycin, levofloxacin (LEV), moxifloxacin, amoxicillin (AMO), tetracycline and rifampicin resistance was 78.2, 22.1, 23.3, 19.2, 17.2, 3.4, 1.9 and 1.5%, respectively. No resistance to furazolidone was observed. The resistance rates to LEV and moxifloxacin were higher in strains isolated from patients with gastritis compared to those with duodenal ulcer and among women. Compared to patients ≥40 years old, younger patients exhibited lower resistance rates to CLA, azithromycin, LEV and moxifloxacin. The resistance rates to CLA and AMO were higher in strains isolated more recently, and we also found that the prevalence of resistance to metronidazole, CLA, azithromycin and AMO were significantly different among different regions of China.
The resistance rates to metronidazole, CLA and LEV were high in China. Patient age, gender, disease and location were associated with the resistance of H. pylori to some antibiotics. Furazolidone, AMO and tetracycline are better choices for H. pylori treatment in China.
Radioresistance hampers success in the treatment of patients with advanced colorectal cancer (CRC). Improving our understanding of the underlying mechanisms of radioresistance could increase ...patients' response to irradiation (IR). MicroRNAs are a class of small RNAs involved in tumor therapy response to radiation. Here we found that miR-214 was markedly decreased in CRC cell lines and blood of CRC patients after IR exposure. Meanwhile, autophagy was enhanced in irradiated CRC cells. Mechanically, ATG12 was predicted and identified as a direct target of miR-214 by dual luciferase assay, qPCR, and Western blot. In vitro and in vivo experiments showed that miR-214 promoted radiosensitivity by inhibiting IR-induced autophagy. Restoration of ATG12 attenuated miR-214-mediated inhibition of cell growth and survival in response to IR. Importantly, miR-214 was highly expressed in radiosensitive CRC specimens and negatively correlated with plasma level of CEA. Moreover, ATG12 and LC3 expressions were increased in radioresistant CRC specimens. Our study elucidates that miR-214 promotes radiosensitivity by inhibition of ATG12-mediated autophagy in CRC. Importantly, miR-214 is a determinant of CRC irradiation response and may serve as a potential therapeutic target in CRC treatment.
Traumatic brain injury (TBI) is a principal cause of death and disability worldwide. Melatonin, a hormone made by the pineal gland, is known to have anti-inflammatory and antioxidant properties. In ...this study, using a weight-drop model of TBI, we investigated the protective effects of ramelteon, a melatonin MT1/MT2 receptor agonist, and its underlying mechanisms of action. Administration of ramelteon (10 mg/kg) daily at 10:00 a.m. alleviated TBI-induced early brain damage on day 3 and long-term neurobehavioral deficits on day 28 in C57BL/6 mice. Ramelteon also increased the protein levels of interleukin (IL)-10, IL-4, superoxide dismutase (SOD), glutathione, and glutathione peroxidase and reduced the protein levels of IL-1β, tumor necrosis factor, and malondialdehyde in brain tissue and serum on days 1, 3, and 7 post-TBI. Similarly, ramelteon attenuated microglial and astrocyte activation in the perilesional cortex on day 3. Furthermore, ramelteon decreased Keap 1 expression, promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation, and increased levels of downstream proteins, including SOD-1, heme oxygenase-1, and NQO1 on day 3 post-TBI. However, in Nrf2 knockout mice with TBI, ramelteon did not decrease the lesion volume, neuronal degeneration, or myelin loss on day 3; nor did it mitigate depression-like behavior or most motor behavior deficits on day 28. Thus, timed ramelteon treatment appears to prevent inflammation and oxidative stress via the Nrf2-antioxidant response element pathway and might represent a potential chronotherapeutic strategy for treating TBI.
Display omitted
•Ramelteon provided marked neuroprotection after TBI.•Ramelteon activated the Nrf2-ARE pathway in the brain after TBI.•The protection by ramelteon was partially lost in Nrf2-/- mice with TBI.
The effects of local body cooling on thermal comfort and sleep quality in a hot environment were investigated in an experiment with 16 male subjects. Sleep quality was evaluated subjectively, using ...questionnaires completed in the morning, and objectively, by analysis of electroencephalogram (EEG) signals that were continuously monitored during the sleeping period. Compared with no cooling, the largest improvement in thermal comfort and sleep quality was observed when the back and head (neck) were both cooled at a room temperature of 32°C. Back cooling alone also improved thermal comfort and sleep quality, although the effects were less than when cooling both back and head (neck). Mean sleep efficiency was improved from 84.6% in the no cooling condition to 95.3% and 92.8%, respectively, in these conditions, indicating good sleep quality. Head (neck) cooling alone slightly improved thermal comfort and subjective sleep quality and increased Stage N3 sleep, but did not otherwise improve sleep quality. The results show that local cooling applied to large body sections (back and head) could effectively maintain good sleep and improve thermal comfort in a hot environment.
The dynamic features of the low-intermediate-high-(L-I-H) confinement transitions on HL-2A tokamak are presented. Here we report the discovery of two types of limit cycles (dubbed type-Y and type-J), ...which show opposite temporal ordering between the radial electric field and turbulence intensity. In type-Y, which appears first after an L-I transition, the turbulence grows first, followed by the localized electric field. In contrast, the electric field leads type-J. The turbulence-induced zonal flow and pressure-gradient-induced drift play essential roles in the two types of limit cycles, respectively. The condition of transition between types-Y and -J is studied in terms of the normalized radial electric field. An I-H transition is demonstrated to occur only from type-J.
A low carbon bainitic steel with varying strength was obtained through change in the thermo-mechanical processing parameters. In this regard, we elucidate the relationship between processing ...parameters, microstructure, and mechanical properties. The study underscores that the volume fraction of martensite–austenite (M–A) constituent is strongly governed by the rolling reduction ratio. The tensile strength was increased with increase in the volume fraction of lath bainite (LB) and M–A constituent, while the yield strength increased monotonically with increase in the volume fraction of LB, and was not sensitive to the volume fraction of M–A constituent. Acicular ferrite (AF) was responsible for high impact energy. Large blocky M–A constituent facilitated initiation of cracks at the M–A constituent/matrix interface, while small M–A constituent of size less than 1μm was helpful in improving toughness. The volume fraction of retained increased austenite with increase in rolling reduction ratio, which neutralized the negative effect of the increase in the volume fraction of M–A constituent on impact toughness, contributing to improvement in toughness.
PDF
