•A combined precast and in-situ-cast construction method is proposed.•Precast arches serve as a permanent formwork of the in-situ-cast concrete.•The proposed method is useful for construction of ...large-span underground vaults.•It was applied to the vault of the first column-free metro station in Shanghai.•Structural analysis of the vault is based on the extended transfer relations.
Exploitation of large underground space calls for innovative structures and construction methods. In this paper, a combined precast and in-situ-cast method for construction of large-span underground vaults is proposed. It was applied to an engineering example in the form of the vault of the Wuzhong Road Metro Station in Shanghai. This vault consists of 56 elements. Construction of an element involves the following steps. Firstly, upper ribbed arch segments are precast in a factory. After hardening, they are transported to the site and then assembled to three-hinged arches. The latter serve as a permanent formwork. Then, steel cages are made, followed by in-situ casting of concrete. As the concrete hardens, an integral arch, representing an element of the vault, is obtained. It carries the dead load of the covering soil and the overload on top of it. Structural analysis of this example is based on transfer relations, representing analytical solutions of the linear theory of slender circular arches. From the viewpoint of engineering practice and computational analysis, the advantages of the combined precast and in-situ-cast method over the in-situ-cast method are as follows: (i) the construction period is shortened by 50%, (ii) a fair-faced concrete surface of the vault is produced, rendering decoration work superfluous, and (iii) the maximum bending moment of an element of the studied vault is reduced by 40%.
Hsa-MicroRNA-124a-3p (hsa-miR-124-3p) is involved in tumor progression in certain malignant tumors. However, its function and clinical implication in hepatocellular carcinoma (HCC) have not yet been ...illustrated. In this study, we explored the expression and prognostic value of hsa-miR-124-3p in patients with HCC. Hsa-miR-124-3p expression in HCC was analyzed in silico, which was subsequently confirmed by quantitative PCR in 155 HCC biopsy samples. Overall survival (OS) and disease-free survival in HCC patients was evaluated by Kaplan–Meier survival analysis, and univariate and multivariate Cox proportional hazard models were used. The in silico results demonstrated that hsa-miR-124-3p was reduced in cell lines and tissues of HCC, and hsa-miR-124-3p expression was lower in HCC tumor samples than in normal liver tissues. Moreover, a decrease in hsa-miR-124-3p expression was closely correlated with tumor diameter (≥ 5 cm) and number of lesions (multiple). Lower hsa-miR-124-3p expression was shown to be correlated with a shorter OS and poor prognosis in HCC. Our findings demonstrate that hsa-miR-124-3p might be a potential target for the diagnosis and prognosis of HCC.
Abstract
Objectives
Osteoarthritis (OA) is a common degenerative joint disease with the pathological features of the reduced cartilage cellularity. Celastrol, a compound from Tripterygium wilfordii, ...exerted therapeutic effects on arthritis, but the potential mechanism remains unclear.
Methods
Tunicamycin was used to establish a model of OA in vitro, and ACLT surgery model in rats was applied to verify the mechanism. Chondrocytes were isolated from the knee articular cartilage of rabbit. MTT and flow cytometry assay were used to detect cell viability and apoptosis rate. Haematoxylin–eosin staining was used to assess for the histopathological changes. The activity and expression of apoptosis-related factors and ERs (endoplasmic reticulum stress)-related factors were detected by ELISA, WB, PCR and IHC, respectively.
Key findings
Celastrol exhibited significant enhancement on cell viability and reduced the rate of apoptosis in Tm-exposed chondrocytes. Celastrol reduced enzyme activity and protein expression of caspase-3, caspase-6 and caspase-9, decreased Bip, Atf6, Chop and Xbp-1 expression both at protein and mRNA levels. Celastrol showed a more significant effect on cell apoptosis rate and mRNA expression in the combination with 4-PBA.
Conclusions
This study reveals that celastrol may prevent OA by inhibiting the ERs-mediated apoptosis. All these might supply beneficial hints for celastrol on OA treatment.
Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as ...gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II–IVB nasopharyngeal carcinoma.
We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18–65 years with non-keratinising stage II–IVB (T1–4N1–3 or T3–4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up.
Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8–94·0) in the cisplatin group and 88·0% (83·5–94·5) in the nedaplatin group, with a difference of 1·9% (95% CI −4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4–94·0) in the cisplatin group and 88·7% (84·2–94·5) in the nedaplatin group, with a difference of 1·0% (95% CI −5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 18% of 198 in the cisplatin group vs 12 6% of 200 in the nedaplatin group, p<0·0001), nausea (18 9% vs four 2%, p=0·0021), and anorexia (53 27% vs 26 13%, p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three 2% in the nedaplatin group vs 11 6% in the cisplatin group, p=0·030). No patients died from treatment-related causes.
Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents.
National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.
Aerodynamic shape optimization of a hypersonic transport aircraft over a wide Mach-number range is challenging. The difficulty is not only associated with the large computational cost of ...high-fidelity CFD (computational fluid dynamics) simulations but also linked to the reasonable compromise between aerodynamic performances of aircraft at different speed ranges. This article proposes to use efficient global optimization based on surrogate models to address this type of problems. A RANS (Reynolds averaged Navier-Stokes) flow solver is adopted to evaluate objective and constraint functions; Kriging surrogate model combined with a parallel infill-sampling method and a multi-round strategy are employed to find the global optimum. First, a profile optimization with baseline airfoil of NACA64A-204 is conducted to achieve high lift-to-drag ratio (L/D) at both hypersonic (Ma=6.0) and transonic (Ma=0.8) regimes with up to 18 design variables, and significant improvement has been observed. Then, multi-objective wing optimizations of maximizing both hypersonic and transonic L/Ds with up to 54 design variables are performed and multiple optimizations with various sets of weight coefficients are investigated. The optimized wings are further evaluated and compared with the baseline wing at the flow regimes from subsonic to hypersonic speeds. Results show that by using the optimized profile, hypersonic and transonic L/Ds of a typical wing configuration are increased by 13.85% and 7.32%, respectively. After 3-D optimizations, the L/Ds at hypersonic and transonic design points are further improved by 4.47% and 3.19%, respectively, and a better performance over a wide Mach-number range is obtained. It is shown that a multi-round surrogated-based optimization is feasible and effective for aerodynamic shape optimization of hypersonic transport aircrafts over a wide Mach-number range.
Although mesenchymal stem cells (MSCs) transplantation has been shown to promote the lung respiration in acute lung injury (ALI) in vivo, its overall restorative capacity appears to be restricted ...mainly because of low retention in the injured lung. Angiotensin II (Ang II) are upregulated in the injured lung. Our previous study showed that Ang II increased MSCs migration via Ang II type 2 receptor (AT2R). To determine the effect of AT2R in MSCs on their cell migration after systemic injection in ALI mice, a human AT2R expressing lentiviral vector and a lentivirus vector carrying AT2R shRNA were constructed and introduced into human bone marrow MSCs. A mouse model of lipopolysaccharide‐induced ALI was used to investigate the migration of AT2R‐regulated MSCs and the therapeutic potential in vivo. Overexpression of AT2R dramatically increased Ang II‐enhanced human bone marrow MSC migration in vitro. Moreover, MSC‐AT2R accumulated in the damaged lung tissue at significantly higher levels than control MSCs 24 and 72 hours after systematic MSC transplantation in ALI mice. Furthermore, MSC‐AT2R‐injected ALI mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti‐inflammatory effects. In contrast, there were less lung retention in MSC‐ShAT2R‐injected ALI mice compared with MSC‐Shcontrol after transplantation. Thus, MSC‐ShAT2R‐injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. Our results demonstrate that overexpression of AT2R enhance the migration of MSCs in ALI mice and may provide a new therapeutic strategy for ALI. Stem Cells Translational Medicine 2018;7:721–730
AT2R overexpression could increase MSC migration to the injured lung in ALI mice. Meanwhile, the presence of more MSCs at the site of injury reduce the permeability of pulmonary endothelial, downregulate the inflammation reaction in ALI and promote the restoration of injured lung. This finding offer a new strategy for improved stem cell therapy for ARDS patients in future.
Hypoxic cancer cells have been shown to be more resistant to radiation therapy than normoxic cells. Hence, this study investigated whether ultrasound (US)-induced rupture of oxygen-carrying ...microbubbles (MBs) would enhance the response of breast cancer metastases to radiation.
Nude mice (n = 15) received stereotactic injections of brain-seeking MDA-MB-231 breast cancer cells into the right hemisphere. Animals were randomly assigned into 1 of 5 treatment groups: no intervention, 10 Gy radiation using a small-animal radiation research platform, nitrogen-carrying MBs combined with US-mediated MB rupture immediately before 10 Gy radiation, oxygen-carrying MBs immediately before 10 Gy radiation, and oxygen-carrying MBs with US-mediated MB rupture immediately before 10 Gy radiation. Tumor progression was monitored with 3-dimensional US, and overall survival was noted.
All groups except those treated with oxygen-carrying MB rupture and radiation had continued rapid tumor growth after treatment. Tumors treated with radiation alone showed a mean increase in volume ± SD of 337% ± 214% during the week after treatment. Tumors treated with oxygen-carrying MBs and radiation without MB rupture showed an increase in volume of 383% ± 226%. Tumors treated with radiation immediately after rupture of oxygen-carrying MBs showed an increase in volume of only 41% ± 1% (P = 0.045), and this group also showed a 1 week increase in survival time.
Adding US-ruptured oxygen-carrying MBs to radiation therapy appears to delay tumor progression and improve survival in a murine model of metastatic breast cancer.
Increasing evidence has shown that microRNAs (miRNAs) play a significant functional role by directly regulating respective targets in cancer stem cell (CSC)-induced non-small cell lung cancer (NSCLC) ...progression and resistance to therapy. In this study, we found that hsa-miR-124a was downregulated during spheroid formation of the NSCLC cell lines SPC-A1 and NCI-H1650 and NSCLC tissues compared with normal lung cells and tissues. Patients with lower hsa-miR-124a expression had shorter overall survival (OS) and progression free survival (PFS). Moreover, ubiquitin-specific protease 14 (USP14) was confirmed to be a direct target of hsa-miR-124a. Furthermore, concomitant low hsa-miR-124a expression and high USP14 expression were correlated with a shorter median OS and PFS in NSCLC patients. Cellular functional analysis verified that the tumor suppressor hsa-miR-124a negatively regulated cell growth and self-renewal, and promoted apoptosis and gefitinib sensitivity of lung cancer stem cells by suppressing its target gene USP14. Our results provide the first evidence that USP14 is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14. Thus, hsa-miR-124a and USP14 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC.
•Hsa-miR-124a regulates growth, self-renewal and gefitinib sensitivity of LCSCs by suppressing USP14.•USP14 is a direct target of hsa-miR-124a.•NSCLC patients with high USP14 expression and low hsa-miR-124a expression had significantly decreased OS and PFS.•Hsa-miR-124a and USP14 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC.
Span-based joint extraction simultaneously conducts named entity recognition (NER) and relation extraction (RE) in a text span form. However, since previous span-based models rely on span-level ...classifications, they cannot benefit from token-level label information, which has been proven advantageous for the task. In this paper, we propose a sequence tagging augmented span-based network (STSN), a span-based joint model that can make use of token-level label information. In STSN, we construct a core neural architecture by deep stacking multiple attention layers, each of which consists of three basic attention units. On the one hand, the core architecture enables our model to learn token-level label information via the sequence tagging mechanism and then uses the information in the span-based joint extraction; on the other hand, it establishes a bi-directional information interaction between NER and RE. Experimental results on three benchmark datasets show that STSN consistently outperforms the strongest baselines in terms of F1, creating new state-of-the-art results.
Mapping of the lymphatic chain for identification of the sentinel lymph node (SLN) is an important aspect of predicting outcomes for patients with breast cancer, and it is usually performed as an ...intraoperative procedure using blue dye and/or radiopharmaceutical agents. Recently, the use of contrast-enhanced ultrasound (CEUS) has been proposed as an alternative imaging technique for this mapping. The objective of this study was to evaluate the use of subdermal administration of the ultrasound (US) contrast agent Sonazoid (GE Healthcare, Oslo, Norway) in terms of patient safety and to select the dose to be used for lymphatic applications in humans.
This study was performed in 12 female volunteers who received bilateral subdermal injections of Sonazoid (1 or 2 mL dose) in the mid-upper outer quadrant of their breasts at 2 different time points. Contrast-enhanced US examinations were performed 0, 0.25, 0.5, 1, 2, 4, 6, and 24 hours after injection to identify SLNs.
Sentinel lymph nodes were identified within the first hour after injection as enhanced structures, and there was no significant difference by dose in the number of SLNs identified (P = .74). The volunteers only had minor adverse experiences (AEs) that resolved completely without intervention by study completion.
The subdermal use of Sonazoid in this study showed only minor local and nonsignificant AEs that were completely resolved without any intervention. Two different doses were compared with no significant differences observed between them. Hence, the lower dose studied (1 mL) was selected for use in future clinical studies.
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