Bone marrow derived mesenchymal stem cells (BM-MSCs) have been shown to enhance wound healing; however, the mechanisms involved are barely understood. In this study, we examined paracrine factors ...released by BM-MSCs and their effects on the cells participating in wound healing compared to those released by dermal fibroblasts. Analyses of BM-MSCs with Real-Time PCR and of BM-MSC-conditioned medium by antibody-based protein array and ELISA indicated that BM-MSCs secreted distinctively different cytokines and chemokines, such as greater amounts of VEGF-alpha, IGF-1, EGF, keratinocyte growth factor, angiopoietin-1, stromal derived factor-1, macrophage inflammatory protein-1alpha and beta and erythropoietin, compared to dermal fibroblasts. These molecules are known to be important in normal wound healing. BM-MSC-conditioned medium significantly enhanced migration of macrophages, keratinocytes and endothelial cells and proliferation of keratinocytes and endothelial cells compared to fibroblast-conditioned medium. Moreover, in a mouse model of excisional wound healing, where concentrated BM-MSC-conditioned medium was applied, accelerated wound healing occurred compared to administration of pre-conditioned or fibroblast-conditioned medium. Analysis of cell suspensions derived from the wound by FACS showed that wounds treated with BM-MSC-conditioned medium had increased proportions of CD4/80-positive macrophages and Flk-1-, CD34- or c-kit-positive endothelial (progenitor) cells compared to wounds treated with pre-conditioned medium or fibroblast-conditioned medium. Consistent with the above findings, immunohistochemical analysis of wound sections showed that wounds treated with BM-MSC-conditioned medium had increased abundance of macrophages. Our results suggest that factors released by BM-MSCs recruit macrophages and endothelial lineage cells into the wound thus enhancing wound healing.
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The trade-off of strength and ductility of metals has long plagued materials scientists. To resolve this issue, great efforts have been devoted over the past decades to developing a ...variety of technological pathways for effectively tailoring the microstructure of metallic materials. Here, we review the recent advanced nanostructure design strategies for purposely fabricating heterogeneous nanostructures in crystalline and non-crystalline metallic materials. Several representative structural approaches are introduced, including (1) hierarchical nanotwinned (HNT) structures, extreme grain refinement and dislocation architectures etc. for crystalline metals; (2) nanoglass structure for non-crystalline alloys, i.e. metallic glasses (MGs); and (3) a series of supra-nano-dual-phase (SNDP) nanostructures for composite alloys. The mechanical properties are further optimized by manipulating these nanostructures, especially coupling multiple advanced nanostructures into one material. Particularly, the newly developed SNDP nanostructures greatly enrich the nanostructure design strategies by utilizing supra-nano sized crystals and MGs, which exhibit unique size and synergistic effects. The origins of these gratifying properties are discussed in this review. Furthermore, based on a comprehensive understanding of microscopic mechanisms, a broad vision of strategies towards high strength and high ductility are proposed to promote future innovations.
Accurate segmentation of the jaw (i.e., mandible and maxilla) and the teeth in cone beam computed tomography (CBCT) scans is essential for orthodontic diagnosis and treatment planning. Although ...various (semi)automated methods have been proposed to segment the jaw or the teeth, there is still a lack of fully automated segmentation methods that can simultaneously segment both anatomic structures in CBCT scans (i.e., multiclass segmentation). In this study, we aimed to train and validate a mixed-scale dense (MS-D) convolutional neural network for multiclass segmentation of the jaw, the teeth, and the background in CBCT scans. Thirty CBCT scans were obtained from patients who had undergone orthodontic treatment. Gold standard segmentation labels were manually created by 4 dentists. As a benchmark, we also evaluated MS-D networks that segmented the jaw or the teeth (i.e., binary segmentation). All segmented CBCT scans were converted to virtual 3-dimensional (3D) models. The segmentation performance of all trained MS-D networks was assessed by the Dice similarity coefficient and surface deviation. The CBCT scans segmented by the MS-D network demonstrated a large overlap with the gold standard segmentations (Dice similarity coefficient: 0.934 ± 0.019, jaw; 0.945 ± 0.021, teeth). The MS-D network–based 3D models of the jaw and the teeth showed minor surface deviations when compared with the corresponding gold standard 3D models (0.390 ± 0.093 mm, jaw; 0.204 ± 0.061 mm, teeth). The MS-D network took approximately 25 s to segment 1 CBCT scan, whereas manual segmentation took about 5 h. This study showed that multiclass segmentation of jaw and teeth was accurate and its performance was comparable to binary segmentation. The MS-D network trained for multiclass segmentation would therefore make patient-specific orthodontic treatment more feasible by strongly reducing the time required to segment multiple anatomic structures in CBCT scans.
The phase III, randomized, open-label ENSURE study (NCT01342965) evaluated first-line erlotinib versus gemcitabine/cisplatin (GP) in patients from China, Malaysia and the Philippines with epidermal ...growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC).
Patients ≥18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0-2 were randomized 1:1 to receive erlotinib (oral; 150 mg once daily until progression/unacceptable toxicity) or GP G 1250 mg/m(2) i.v. days 1 and 8 (3-weekly cycle); P 75 mg/m(2) i.v. day 1, (3-weekly cycle) for up to four cycles. Primary end point: investigator-assessed progression-free survival (PFS). Other end points include objective response rate (ORR), overall survival (OS), and safety.
A total of 217 patients were randomized: 110 to erlotinib and 107 to GP. Investigator-assessed median PFS was 11.0 months versus 5.5 months, erlotinib versus GP, respectively hazard ratio (HR), 0.34, 95% confidence interval (CI) 0.22-0.51; log-rank P < 0.0001. Independent Review Committee-assessed median PFS was consistent (HR, 0.42). Median OS was 26.3 versus 25.5 months, erlotinib versus GP, respectively (HR, 0.91, 95% CI 0.63-1.31; log-rank P = .607). ORR was 62.7% for erlotinib and 33.6% for GP. Treatment-related serious adverse events (AEs) occurred in 2.7% versus 10.6% of erlotinib and GP patients, respectively. The most common grade ≥3 AEs were rash (6.4%) with erlotinib, and neutropenia (25.0%), leukopenia (14.4%), and anemia (12.5%) with GP.
These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965).
Epithelial ovarian cancer (EOC) is a highly lethal gynaecological malignancy. Cisplatin is the basal chemotherapeutic agent used to treat EOC, but resistance to cisplatin leads to chemotherapy ...failure. MicroRNAs are a novel class of regulators that function by controlling gene expression at the post-transcriptional level. Several recent reports have identified some microRNAs that are related to chemotherapy sensitivity. In this study, we found two microRNAs miR-152 and miR-185 that were significantly downregulated in the cisplatin-resistant ovarian cell lines SKOV3/DDP and A2780/DDP, compared with their sensitive parent line SKOV3 and A2780, respectively. Subsequently, the roles of miR-152 and miR-185 were evaluated in vitro and in vivo. The overexpression of miR-152 or miR-185 increased cisplatin sensitivity of SKOV3/DDP and A2780/DDP cells by inhibiting proliferation and promoting apoptosis, then we further confirmed that these miRNAs functioned through suppressing DNA methyltransferase 1 (DNMT1) directly. Concordantly, CD-1/CD-1 nude mice that were injected intraperitoneally with SKOV3/DDP cells transfected with miR-152 mimics exhibited upregulated cisplatin sensitivity in vivo. Interestingly, we found that there were no significant changes in the expression of these two microRNAs after treatment with decitabine (DAC), a traditional epigenetic therapeutic agent, suggesting these miRNAs represented two new regulators independent of DAC. Finally, the survival assay in A549 and HepG2 cells revealed that the two microRNAs involved in cisplatin sensitivity were related to cell types. Our results indicated that miR-152 and miR-185 were involved in ovarian cancer cisplatin resistance in vitro and in vivo by targeting DNMT1 directly. These molecules may serve as potential epigenetic therapeutic targets in other cancers.
Bedaquiline treatment significantly improves multidrug-resistant tuberculosis (MDR-TB) patient treatment outcomes. However, safety and efficacy data are lacking for bedaquiline used with background ...regimens to treat Chinese TB patients. Here, we describe our initial clinical experience for bedaquiline treatment of a large multicentre cohort of MDR-TB and extensively drug-resistant tuberculosis (XDR-TB) patients in China.
Patients (177) received 24-week bedaquiline treatment combined with personalized anti-TB drug background regimens. As primary efficacy endpoints, times to initial sputum culture conversion were measured.
Of 177 MDR-TB patients completing the 24-week treatment course, sputum culture conversion occurred for 151/177 (85.3%), while 26 had unfavourable outcomes, including 3/177 (1.7%) deaths and 23/177 (13.0%) non-responders at treatment completion. The median time to sputum culture conversion was 4 (interquartile range 2–8) weeks. Conversion rates were 33/39 (84.6%, 95% confidence interval (CI) 73.3–95.9) for MDR-TB patients, 47/56 (83.9%, 95% CI 74.3–93.6) for pre-XDR-TB patients and 71/82 (86.6%, 95% CI 79.2–94.0) for XDR-TB patients. Multivariate analysis demonstrated that patients with low body mass index (odds ratio 7.356; 95% CI 2.652–20.401) were at significantly high risk of unfavourable outcomes, with serious adverse events noted in 15 (8.5%) patients, including six with corrected QT interval (QTc) prolongation times (>500 ms).
Bedaquiline, when included in background regimens for treatment of MDR-TB and XDR-TB patients in China, was safe and associated with a high rate of culture conversion.
The increasing severity of droughts/floods and worsening air quality from increasing aerosols in Asia monsoon regions are the two gravest threats facing over 60% of the world population living in ...Asian monsoon regions. These dual threats have fueled a large body of research in the last decade on the roles of aerosols in impacting Asian monsoon weather and climate. This paper provides a comprehensive review of studies on Asian aerosols, monsoons, and their interactions. The Asian monsoon region is a primary source of emissions of diverse species of aerosols from both anthropogenic and natural origins. The distributions of aerosol loading are strongly influenced by distinct weather and climatic regimes, which are, in turn, modulated by aerosol effects. On a continental scale, aerosols reduce surface insolation and weaken the land‐ocean thermal contrast, thus inhibiting the development of monsoons. Locally, aerosol radiative effects alter the thermodynamic stability and convective potential of the lower atmosphere leading to reduced temperatures, increased atmospheric stability, and weakened wind and atmospheric circulations. The atmospheric thermodynamic state, which determines the formation of clouds, convection, and precipitation, may also be altered by aerosols serving as cloud condensation nuclei or ice nuclei. Absorbing aerosols such as black carbon and desert dust in Asian monsoon regions may also induce dynamical feedback processes, leading to a strengthening of the early monsoon and affecting the subsequent evolution of the monsoon. Many mechanisms have been put forth regarding how aerosols modulate the amplitude, frequency, intensity, and phase of different monsoon climate variables. A wide range of theoretical, observational, and modeling findings on the Asian monsoon, aerosols, and their interactions are synthesized. A new paradigm is proposed on investigating aerosol‐monsoon interactions, in which natural aerosols such as desert dust, black carbon from biomass burning, and biogenic aerosols from vegetation are considered integral components of an intrinsic aerosol‐monsoon climate system, subject to external forcing of global warming, anthropogenic aerosols, and land use and change. Future research on aerosol‐monsoon interactions calls for an integrated approach and international collaborations based on long‐term sustained observations, process measurements, and improved models, as well as using observations to constrain model simulations and projections.
Key Points
The fast‐developing Asia has suffered severe air pollution problem
Aerosol affects the Asian monsoon
Aerosol‐monsoon interactions dictate the climate change in the region
Variations in stress conditions of rocks have been observed during blasting for excavation or large-scale seismic events such as an earthquake. A triaxial Hopkinson bar is developed to apply initial ...pre-stresses achieving various in situ stress conditions, including uniaxial (principal stresses
σ
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>
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=
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= 0), biaxial (
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= 0) and triaxial (
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≠ 0) confinements, and then to determine properties of materials under multiaxial pre-stress states at high strain rate. A series of tests was conducted on sandstone specimens to investigate dynamic responses under multiaxial pre-stress states. A high-speed camera at the frame rate of 200,000 fps with a resolution of 256 × 256 pixels was used to capture the fracture characteristics rocks under biaxial compression tests. Experiments show that under the same impact velocity, dynamic properties (e.g. dynamic strength, elastic modulus, fracture modes) of sandstone exhibit confinement dependence. Dynamic strength decreases with increasing axial pre-stress
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along the impact direction, while it increases with the increase of lateral pre-stresses
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and
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. The elastic modulus increases with the confinement varying from uniaxial, biaxial to triaxial compression. Rocks are pulverised into powder under uniaxial pre-stress impact, and fragments are ejected from the free face under biaxial compression, while they show slightly damaged or a macroscopic shear fracture under triaxial compression. The 3D imaging of fracture networks in the damaged/fractured specimens was acquired via the X-ray computed tomography system.
To evaluate the role of diffusion kurtosis imaging (DKI) histogram analysis in the characterization of non–small cell lung cancer (NSCLC) and to correlate DKI parameters with tumor cellularity.
...Sixty-four patients with pathologically diagnosed NSCLCs were evaluated by DKI on a 3-T scanner. Regions of interest (ROIs) were drawn on the map of b1000 manually. All NSCLCs were histologically graded according to the degree of tumor differentiation. Tumor cellularity was measured by the nuclear-to-cytoplasm (N/C) ratio and the number of tumor cell nuclei (NTCN), the expression of Ki-67 was detected using the streptavidin-peroxidase method. Histogram analysis was performed using voxel-based on raw data from each ROI.
NSCLCs were classified as grades 1, 2, and 3 according to differentiation degree. Histogram parameters of apparent diffusion coefficient (ADC) and DKI could discriminate between different grades of tumors (p<0.001). Receiver operating characteristic (ROC) curve analysis showed that Kapp 75th exhibited the best performance with an AUC of 0.936 and sensitivity/specificity of 95.74%/80% (p<0.001) in distinguishing grade 1 from grade 2, ADC mean exhibited the best performance with an AUC of 0.923 and sensitivity/specificity of 92.33%/86.67% (p<0.001) in distinguishing grade 2 from 3. N/C ratio and Ki-67 changed significantly with grade (p<0.01). Negative correlations were found between the ADC mean and the N/C ratio, Ki-67, Dapp mean and N/C ratio, whereas Kapp mean and N/C ratio, Ki-67 were positively correlated.
DKI histogram analysis could quantitatively characterize NSCLC with different grades by probing non-Gaussian diffusion properties related to changes in the tumor microenvironment or tissue complexities in the tumor.
•DKI histogram analysis can differentiate different grades of NSCLC.•DKI parameters are correlated with tumor N/C ratio and Ki-67 index.•Tumor water molecules non-Gaussian diffusion can evaluate tumor cell structure.
The mechanism of the Tibetan Plateau (TP) thermal forcing in influencing the summer climate patterns over subtropical Asia is investigated by means of NCEP/NCAR reanalysis diagnosis. Results show ...that since the TP is a huge elevated heating source with the strongest heating in the surface layers in summer, the thermal adaptation results in a shallow cyclonic circulation near the surface and a deep anticyclonic circulation above it. According to the steady barotropic vorticity equation for large scales, airflow must converge in the lower layers and diverge in the higher layers over the eastern side of the TP. However, the western side of the TP is characterized by a reversed structure, i.e., divergence in lower layers but convergence in higher layers. Hence, pumping and sucking processes bring in upward and downward movement over the east and west sides of the TP, respectively. Such a circulation is embedded in the large-scale circulation that is forced by the Eurasian continental heating. Because the TP together with Iran Plateau are located at the central and eastern parts of the continent, and, because the orography-induced circulation is in phase with the continental scale circulation, the role of the TP thermal forcing is to intensify the East Asian monsoon to its east and the dry and hot desert climate in mid-Asia to its west. The summertime thermal forcing of the Rockies and Andes can generate similar circulations along the two subtopics as the TP does since they are located near the western coasts. But, the lower troposphere poleward flow that is induced by orographic thermal forcing does not coincide with the poleward flows over the eastern coastal region that is induced by continental heating and the monsoon rainfall in North and South America is not as strong as in East Asia. However, the equatorward flow and the associated subsidence induced by the two mountain ranges along the western coasts of both North and South America are in phase with those induced by continental heating. These contribute to the formation of the stable low stratus clouds and strong long-wave radiative cooling over the eastern subtropical Pacific regions just off the western coast of the continent.
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