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Abstract Background Vasculogenic mimicry (VM), defined as a capability of aggressive tumor Cells to mimic embryonic vasculogenic networks, caused poor prognosis in hepatocellular carcinoma (HCC). Rho kinases (ROCK), p21-activated kinase (PAK), hypoxia or epithelial-mesenchymal transition (EMT) contributed to the VM potential. However, the details underlying these biological behaviors have not been completely elucidated. Methods Kaplan-Meier analysis was conducted to predict relationship with hypoxia Inducible factor (HIF-1α), EMT related markers: Vimentin and patient prognosis. CD34/periodic acid-Schiff (PAS) double staining was examined to differentiate VM-positive (VM+) and VM-negative (VM-) samples. Cells were cultured under controlled hypoxic environments (1% O2) or normoxic conditions. The effect of hypoxia on RhoA/ROCK, Rac1/PAK and EMT were evaluated by real time-qPCR and western blot. HIF-1α small interfering RNA (siRNA), overexpressed or short hairpin RNA (shRNA) of ROCK and kinase inhibitors were used to explore the effect of HIF-1α, RhoA/ROCK, Rac1/PAK and Vimentin on VM. Results HIF-1α or Vimentin was upregulated in VM+ HCC tissues, compared to non-cancerous tissues (P

Mechanical properties of 2124 aluminum alloy thick plate in short-transverse direction were investigated when ageing at 170-180℃ for different time by room temperature tensile test.The microstructure morphology of alloy after different ageing processes was studied by TEM and SEM.The results show that the suitable ageing process of 2124 aluminum alloy plates is 175℃ for 10h.Yield strength, tensile strength and elongation are 372,422MPa and 2.9%, respectively.The main precipit-ation is S' phase, and also a small quantity of GPB zone and coarse T phase exist at this moment.Ageing temperature is the main factor affecting the density and size of the alloy precipitation.The higher the ageing temperature is, the quicker the rising of strength, the shorter time to reach the maximum strength.The increasing strength difference between the matrix and grain boundary is the main cause for the decrease of the elongation.

Abstract. Background:. There have been few reports of mutations in the beta-myosin heavy chain (MYH7) gene in hypertrophic cardiomyopathy (HCM), which is associated with sudden cardiac death caused by HCM. This study aimed to screen the mutation sites in the sarcomeric gene MYH7 in Chinese patients with HCM. We also planned to analyze the pathogenicity of the mutation site as well as its significance in clinical and forensic medicine. Methods:. From January 2006 to June 2017, autopsy cases were collected from the Department of Pathology, the Affiliated Hospital of Qingdao University. The experiment was to detect MYH7 gene status in formalin-fixed paraffin-embedded tissues from 18 independent autopsy cases who suffered HCM related sudden death (fatal HCM) and 20 cases without cardiomyopathy. Common mutation exon fragments of MYH7 gene were amplified by polymerase chain reaction. The end-of-deoxygenation method and gene cloning method were further performed to analyze the mutation sites. Homologous comparison among mutant sites was conducted using BLAST online database. Results:. The 1336th nucleotide of MYH7 gene at exon 14 was converted from T to G in one HCM case, resulting in the conversion of threonine (Thr) at position 446 to proline (Pro). In another case, the 1402th nucleotide at exon 14 was converted from T to C, resulting in the conversion of phenylalanine (Phe) at position 468 to leucine (Leu). Homologous comparison results showed that the two amino acid residues of Thr446 and Phe468 are highly conserved among different species. Conclusions:. Our results showed fatal HCM harbored mutations of Thr446Pro and Phe468Leu in the MYH7 gene. It is significant for clinical and forensic medicine to further explore the functions and detailed mechanisms of these mutations.

Recently, N6-methyl-adenosine (m6A) ribonucleic acid (RNA) modification, a critical and common internal RNA modification in higher eukaryotes, has generated considerable research interests. Extensive studies have revealed that non-coding RNA m6A modifications (e.g. microRNAs, long non-coding RNAs, and circular RNAs) are associated with tumorigenesis, metastasis, and other tumour characteristics; in addition, they are crucial molecular regulators of cancer progression. In this review, we discuss the relationship between non-coding RNA m6A modification and cancer progression from the perspective of various cancers. In particular, we focus on important mechanisms in tumour progression such as proliferation, apoptosis, invasion and metastasis, tumour angiogenesis. In addition, we introduce clinical applications to illustrate more vividly that non-coding RNA m6A modification has broad research prospects. With this review, we aim to summarize the latest insights and ideas into non-coding RNA m6A modification in cancer progression and targeted therapy, facilitating further research.

The PI3K/Akt pathway—and in particular PI3Kδ—is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression usingin vitro and in vivo models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535.

Quantum key distribution (QKD).sup.1-3 is a theoretically secure way of sharing secret keys between remote users. It has been demonstrated in a laboratory over a coiled optical fibre up to 404 kilometres long.sup.4-7. In the field, point-to-point QKD has been achieved from a satellite to a ground station up to 1,200 kilometres away.sup.8-10. However, real-world QKD-based cryptography targets physically separated users on the Earth, for which the maximum distance has been about 100 kilometres.sup.11,12. The use of trusted relays can extend these distances from across a typical metropolitan area.sup.13-16 to intercity.sup.17 and even intercontinental distances.sup.18. However, relays pose security risks, which can be avoided by using entanglement-based QKD, which has inherent source-independent security.sup.19,20. Long-distance entanglement distribution can be realized using quantum repeaters.sup.21, but the related technology is still immature for practical implementations.sup.22. The obvious alternative for extending the range of quantum communication without compromising its security is satellite-based QKD, but so far satellite-based entanglement distribution has not been efficient.sup.23 enough to support QKD. Here we demonstrate entanglement-based QKD between two ground stations separated by 1,120 kilometres at a finite secret-key rate of 0.12 bits per second, without the need for trusted relays. Entangled photon pairs were distributed via two bidirectional downlinks from the Micius satellite to two ground observatories in Delingha and Nanshan in China. The development of a high-efficiency telescope and follow-up optics crucially improved the link efficiency. The generated keys are secure for realistic devices, because our ground receivers were carefully designed to guarantee fair sampling and immunity to all known side channels.sup.24,25. Our method not only increases the secure distance on the ground tenfold but also increases the practical security of QKD to an unprecedented level. An efficient entanglement-based quantum key distribution is sent from the Micius satellite to two ground observatories 1,120 kilometres apart to establish secure quantum cryptography for the exchange of quantum keys., Author(s): Juan Yin [sup.1] [sup.2] [sup.3] , Yu-Huai Li [sup.1] [sup.2] [sup.3] , Sheng-Kai Liao [sup.1] [sup.2] [sup.3] , Meng Yang [sup.1] [sup.2] [sup.3] , Yuan Cao [sup.1] [sup.2] [sup.3] [...]

Abstract Mesenchymal stromal cell‐derived extracellular vesicles (MSC‐EVs) turn out to be a promising source of cell‐free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose‐derived MSC‐EVs (haMSC‐EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC‐EVs in healthy volunteers. DiR‐labelled haMSC‐EVs were used to explore the distribution of nebulized haMSC‐EVs in the murine model. Pseudomonas aeruginosa‐induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL‐6, TNF‐α and IL‐10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC‐EVs through the nebulized route. Twenty‐four healthy volunteers were involved and received the haMSC‐EVs once, ranging from 2 × 108 particles to 16 × 108 particles (MEXVT study, NCT04313647). Nebulizing haMSC‐EVs improved survival rate to 80% at 96 h in P. aeruginosa‐induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC‐EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC‐EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC‐EVs in lung injury diseases.

The low-permeability conglomerate reservoir in the Mahu Sag has great resource potential, but its strong heterogeneity and complex microscopic pore structure lead to a high oil-gas decline ratio and low recovery ratio. Clarifying the migration rule of crude oil in microscopic pore throat of different scales is the premise of efficient reservoir development. The low-permeability conglomerate reservoir of the Baikouquan Formation in the Mahu Sag is selected as the research object, and two NMR experimental methods of centrifugal displacement and imbibition replacement are designed to reveal the differences in the migration rule of crude oil in different pore throats. According to the lithology and physical properties, the reservoirs in the study area can be divided into four categories: sandy grain-supported conglomerates, gravelly coarse sandstones, sandy-gravelly matrix-supported conglomerates and argillaceous-supported conglomerates. From type I to type IV, the shale content of the reservoir increases, and the physical property parameters worsen. Centrifugal displacement mainly produces crude oil in large pore throats, while imbibition replacement mainly produces crude oil in small pores. In the process of centrifugal displacement, for type I reservoirs, the crude oil in the pore throats with radii greater than 0.5 μm is mainly displaced, and for the other three types, it is greater than 0.1 μm. The crude oil in the pore throats with radii of 0.02–0.1 μm, which is the main storage space for the remaining oil, is difficult to effectively displace. The crude oil in the pore throats with radii less than 0.02 μm cannot be displaced. The two experimental methods of centrifugation and imbibition correspond to the two development methods of displacement and soaking in field development, respectively. The combination of displacement and soaking can effectively use crude oil in the full-scale pore throat space to greatly improve the recovery of low-permeability conglomerate reservoirs.

With the rapid development of urbanization, the scales of urban population and land use are tremendously expanding [...]

Ordinary cement is not environmentally friendly, has high cost and lacks superior performance. Many scholars use various admixtures to adjust the properties of cement slurry, but admixtures are usually not environmentally friendly, and it is difficult to ensure that the properties after deployment meet engineering requirements. In this study, a variety of admixtures were obtained using the environmental protection method, and the optimal mixing ratio was analyzed by combining the entropy weight method and the Taguchi grey relational analysis method. The developed cement slurry was compared with conventional slurry from both macroscopic and microscopic aspects. Aiming at the problem that previous scholars lacked the engineering feasibility verification of the developed slurry, this study combined the constitutive equation regression analysis method, discrete element numerical simulation and other methods to study various actual engineering conditions. The results show that the optimal mix ratio of silica fume cement slurry has good permeability characteristics under the conditions of different roughness, grouting pressure and confining pressure. At the same time, under different geological temperatures and different erosive liquid states, the cement slurry stone body shows good properties of reinforcement materials.

Abstract Addressing the high false‐positive rate of conventional low‐dose computed tomography (LDCT) for lung cancer diagnosis, the efficacy of incorporating blood‐based noninvasive testing for assisting practicing clinician's decision making in diagnosis of pulmonary nodules (PNs) is investigated. In this prospective observative study, next generation sequencing‐ (NGS‐) based cell‐free DNA (cfDNA) mutation profiling, NGS‐based cfDNA methylation profiling, and blood‐based protein cancer biomarker testing are performed for patients with PNs, who are diagnosed as high‐risk patients through LDCT and subsequently undergo surgical resections, with tissue sections pathologically examined and classified. Using pathological classification as the gold standard, statistical and machine learning methods are used to select molecular markers associated with tissue's malignant classification based on a 98‐patient discovery cohort (28 benign and 70 malignant), and to construct an integrative multianalytical model for tissue malignancy prediction. Predictive models based on individual testing platforms have shown varying levels of performance, while their final integrative model produces an area under the receiver operating characteristic curve (AUC) of 0.85. The model's performance is further confirmed on a 29‐patient independent validation cohort (14 benign and 15 malignant, with power > 0.90), reproducing AUC of 0.86, which translates to an overall sensitivity of 80% and specificity of 85.7%.