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Introduction Lung cancer is a major global health problem because of its high incidence and mortality. Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung cancer (NSCLC). Nevertheless, recent studies demonstrated that cardiovascular disease (CVD) was the second leading cause of mortality in cancer survivors now, management of patients’ cardiovascular health during the course of anticancer therapy has become a great challenge faced by the oncologists. Anticancer related cardiovascular (CV) complications are not limited to traditional chemotherapy, but are also increasingly recognized in targeted therapy. Case Report We present a case of pulmonary embolism (PE) and bradycardia in a 91-year-old NSCLC patient treated with crizotinib for a rare MET Y1003S mutation. To our knowledge, this is the second report to show antitumor response of crizotinib in lung cancer patients with such a rare mutation. However, the patient complained chest tightness and shortness of breath after a month of standard dose crizotinib therapy. Non-invasive examination revealed new onset bradycardia and PE. Management & Outcome Such clinical manifestations were associated with targeted therapy-related CV toxicity, on which the emerging discipline cardio-oncology focused, and a multidisciplinary investigation and treatment was conducted. Discussion This case highlights the CV adverse events of novel therapies and the current challenges to be tackled in cardio-oncology.

Bone is a hard-connective tissue composed of matrix, cells and bioactive factors with a hierarchical structure, where the matrix is mainly composed of type I collagen and hydroxyapatite. Collagen fibers assembled by collagen are the template for mineralization and make an important contribution to bone formation and the bone remodeling process. Therefore, collagen has been widely clinically used for bone/cartilage defect regeneration. However, pure collagen implants, such as collagen scaffolds or sponges, have limitations in the bone/cartilage regeneration process due to their poor mechanical properties and osteoinductivity. Different forms of collagen-based composites prepared by incorporating natural/artificial polymers or bioactive inorganic substances are characterized by their interconnected porous structure and promoting cell adhesion, while they improve the mechanical strength, structural stability and osteogenic activities of the collagen matrix. In this review, various forms of collagen-based biocomposites, such as scaffolds, sponges, microspheres/nanoparticles, films and microfibers/nanofibers prepared by natural/synthetic polymers, bioactive ceramics and carbon-based materials compounded with collagen are reviewed. In addition, the application of collagen-based biocomposites as cytokine, cell or drug (genes, proteins, peptides and chemosynthetic) delivery platforms for proangiogenesis and bone/cartilage tissue regeneration is also discussed. Finally, the potential application, research and development direction of collagen-based biocomposites in future bone/cartilage tissue regeneration are discussed.

Acute and chronic wounds can cause severe physical trauma to patients and also result in an immense socio-economic burden. Thus, wound management has attracted increasing attention in recent years. However, burn wound management is still a major challenge in wound management. Autografts are often considered the gold-standard for burn care, but their application is limited by many factors. Hence, ideal burn dressings and skin substitute dressings are desirable. With the development of biomaterials and progress of tissue engineering technology, some innovative dressings and tissue engineering scaffolds, such as nanofibers, films, foams and hydrogels, have been widely used in the field of biomedicine, especially in wound management. Among them, hydrogels have attracted tremendous attention with their unique advantages. In this review, we discuss the challenges in burn wound management, several crucial design considerations with respect to hydrogels for burn wound healing, and available polymers for hydrogels in burn wound care. In addition, the potential application and plausible prospect of hydrogels are also highlighted.

Physical process-based groundwater flow models are the major tools for studying fluid-flow behavior and for simulating the hydrological responses of water levels and spring discharge to human- and/or nature-induced triggers such as pumping and recharge. Such models are built with deep understanding of the physical processes and are based on geological models, developed by integrating data from geology, geophysics, and geochemistry. However, data-driven models can be built with limited data, eliminating the need for a detailed understanding of the physics. In this research, a data-driven model is built for simulating hydraulic responses (both groundwater levels and spring discharges) in a complex groundwater flow system of the Edwards Aquifer in Central Texas, USA, with the recurrent neural network (RNN) technique. The model is first trained and validated with the observation data of four targets—water levels from two index wells, and spring flow rates from San Marcos and Comal springs—from 2001 through 2015. The model is then used to predict the hydrological responses for the drought of record (1947–1958). The performance of the RNN model for the training, validation and prediction period is then quantitatively compared to that of the physical process-based MODFLOW model in terms of four statistical measures. The statistical measures suggest that the RNN model performs almost as well as the MODFLOW model. With further improvements, a data-driven model may be a surrogate to (or integrate with) a physical process-based model for simulating hydrological responses in the Edwards Aquifer.

Lung cancer is a major global health problem because of its high incidence and mortality. Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung cancer (NSCLC). Nevertheless, recent studies demonstrated that cardiovascular disease (CVD) was the second leading cause of mortality in cancer survivors now, management of patients’ cardiovascular health during the course of anticancer therapy has become a great challenge faced by the oncologists. Anticancer related CV complications are not limited to traditional chemotherapy, but are also increasingly recognized in targeted therapy. We present a case of pulmonary embolism and bradycardia in a 91-year-old NSCLC patient treated with crizotinib for a rare MET Y1003S mutation. To our knowledge, this is the second report to show antitumor response of crizotinib in lung cancer patients with such a rare mutation. However, the patient complained chest tightness and shortness of breath after a month of standard dose crizotinib therapy. Non-invasive examination revealed new onset bradycardia and pulmonary embolism (PE). Such clinical manifestations were associated with targeted therapy-related cardiovascular（CV）toxicity, on which the emerging discipline cardio-oncology focused, and a multidisciplinary investigation and treatment was conducted. The case highlights the CV adverse events of novel therapies and the current challenges to be tackled in cardio-oncology.

Cardiac pressure overload is a crucial risk factor for cardiac hypertrophy and heart failure. Our previous study showed that depletion of the β3-adrenergic receptor (ADRB3) induced left ventricular diastolic dysfunction via potential regulation of energy metabolism and cardiac contraction. However, the effects of ADRB3 on pressure overload-induced heart failure remain unclear. In the present study, systemic ADRB3-knockout mice suffering from transverse aortic constriction (TAC) surgery were used to identify the effects of ADRB3 on pressure overload-induced heart failure. Compared to wild-type mice, ADRB3 depletion significantly improved the left ventricular ejection fraction, reduced left ventricular posterior wall thickness and interventricular septum thickness, and decreased the area of cardiomyocytes after TAC. RNA sequencing and bioinformatics analysis showed that ADRB3 depletion up-regulated 275 mRNAs and down-regulated 105 mRNAs in mice suffering TAC surgery. GO analysis, GO-tree analysis, and GSEA showed that ADRB3 depletion mainly enhanced the innate immune response of hearts in cardiac pressure overload mice. In addition, pathway analysis and Pathway-Act analysis presented that innate immune response-related pathways, including RIG-I-like receptor signaling pathway, antigen processing and presentation, Toll-like receptor signaling pathway, and cell adhesion molecules, were significantly enriched in ADRB3-KO-TAC mice. Ten hub genes were identified using protein-protein interaction network, MCODE, and cytoHubba analysis. Furthermore, the depletion and activation of ADRB3 validated the effects of ADRB3 on the innate immune response of hearts after TAC. In conclusion, ADRB3 depletion relieves pressure overload-induced cardiac hypertrophy and heart failure, and these effects could be explained by the enhancement of innate immune response.

In situ 3D printing technologies is a new frontier for highly personalized medicine, which requires suitable bioink with rheology, biocompatibility, and gelation kinetics to support the right shape and mechanical properties of the printed construct. To this end, a facile design of thermo/photo dual cure composite hydrogel was proposed using MHBC and soluble collagen in this study. M/C composite hydrogel exhibited rapid thermo-induced sol-gel transition and contraction, tunable mechanical properties, proper microstructure and biodegradability for 3D cell culture, as well as improve cyto-compatibility, all of which were dependent upon the methacrylation degree of MHBC and M/C ratios. The printability of the optimal formulation (3% MHBC/1% collagen) was validated by its mild printing condition, rapid gelation of bioink at 37 °C and simple postprocessing manipulation. Both desirable printability and cyto-compatibility enable M/C composite hydrogel a potential candidate as bioink to be applied for in situ 3D bioprinting.

Background Cardiac fibrosis is an important cause of heart failure (HF) after myocardial infarction (MI). Cyclin-dependent kinase inhibitor 2b (CDKN2b) regulates the cell cycle by encoding the p15 protein and participates in the development of various tumours. However, the role of CDKN2b/p15 in cardiac fibrosis and HF after MI remains unclear. Methods Lentivirus was used to induce the silence and overexpression of CDKN2b. Cardiac function was detected with the use of echocardiography. Immunohistochemistry, immunofluorescence, Western blotting, Cell Counting Kit 8, and wound healing assay were used to illustrate the potential mechanism associated with CDKN2b. Results The p15 protein expression was significantly down-regulated in both human and mouse failing hearts. Cardiac down-regulation of CDKN2b promoted myocardial fibrosis and worsened cardiac function in MI mice, while systemic CDKN2b silencing induced diastolic dysfunction in vivo. In addition, cardiac overexpression of CDKN2b ameliorated cardiac fibrosis and improved cardiac function in MI mice. Mechanistically, silencing CDKN2b gene enhanced the phosphorylation of retinoblastoma (Rb) protein and reinforced the migration and proliferation capabilities of cardiac fibroblasts. B Lymphoma Mo-MLV insertion region 1 homolog (BMI1) was up-regulated in failing heart and inversely regulated the expression of CDKN2b/p15 and the phosphorylation of Rb protein. The BMI1-p15-Rb signalling pathway is a potential mechanism of ischemia-induced cardiac fibrosis and HF. Conclusions Cardiac fibrosis and heart function could be worsened by the down-regulation and relieved by the up-regulation of CDKN2b/p15 in ischemia-induced HF via regulating the proliferation and migration capabilities of cardiac fibroblasts. These effects could be partially explained by the regulation of the BMI1-p15-Rb signalling pathway.

Oxidative stress plays an important role in the pathogenesis of chronic heart failure (CHF) in many tissues. Increasing evidence suggests that systemic activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling can protect against postinfarct cardiac remodeling by reducing oxidative stress. However, it remains to be elucidated if Nrf2 activation exerts therapeutic effects in the CHF state. Here, we investigated the beneficial hemodynamic effects of bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me), a pharmacological activator of Nrf2, in a rodent model of CHF. Based on echocardiographic analysis, rats at 12 weeks post-myocardial infarction (MI) were randomly split into four groups. CDDO-Me (5 mg/kg, i.p.) was administered daily for another 2 weeks in sham and CHF rats and compared with vehicle treatment. Echocardiographic and hemodynamic analysis suggest that short-term CDDO-Me administration increased stroke volume and cardiac output in CHF rats and decreased left ventricle end-diastolic pressure. Molecular studies revealed that CDDO-Me-induced cardiac functional improvement was attributed to an increase of both Nrf2 transcription and translation, and a decrease of oxidative stress in the noninfarcted areas of the heart. Furthermore, CDDO-Me reduced NF-κB binding and increased Nrf2 binding to the CREB-binding protein, which may contribute to the selective increase of Nrf2 downstream targets, including NADPH Oxidase Quinone 1, Heme Oxygenase 1, Catalase, and Glutamate-Cysteine Ligase Catalytic Subunit, and the attenuation of myocardial inflammation in CHF rats. Our findings suggest that Nrf2 activation may provide beneficial cardiac effects in MI-mediated CHF. SIGNIFICANCE STATEMENT: Chronic heart failure (CHF) is the leading cause of death among the aged worldwide. The imbalance between pro- and antioxidant pathways is a determinant in the pathogenesis of CHF. Systemic activation of Nrf2 and antioxidant protein signaling by bardoxolone methyl may have beneficial effects on cardiac function and result in improvements by enhancing antioxidant enzyme expression and attenuating myocardial inflammation.

As a framework for tissue engineering regeneration, the characteristics of cell scaffold materials directly affect cell adhesion, migration and metabolism. In this study, we have fabricated decellularized and decalcified fish scale-derived scaffolds and determined its basic physicochemical properties to serve as cell scaffolds in tissue engineering. Scanning electron microscopy (SEM) results showed that there were radial grooves and ring ridges on the surface of the scale-derived scaffolds, which could simulate three-dimensional microenvironment for cells culture. Similarity to the bone extracellular matrix, the main components of the fish scales were hydroxyapatite (HA) and type I collagen fibers, which were conducive to cells spreading and proliferation. Moreover, for culturing L929 cells and rat bone marrow mesenchymal stem cells (BMSCs), the fish scales as cell scaffolds exhibited high cytocompatibility to enhance cells adhesion and proliferation, and also displayed the ability to guide cells migration along the ridge channels. Accordingly, the results suggested that the fish scale-derived scaffolds had a great potential as a natural extracellular matrix for tissue engineering.

we demonstrate a hybrid structure fabricated by depositing SiN, cylinders arrays in organic polymer film Poly [2- (2', 5" -bis (2" -ethylhexyloxy)-phenyl)-l, 4-phenylene vinylene] (BEHP-PPV). The gain emission peak is at about 518 nm, and threshold is around 3.3 mJ/cm2.

Neural machine translation (NMT) has achieved notable success in recent times, however it is also widely recognized that this approach has limitations with handling infrequent words and word pairs. This paper presents a novel memory-augmented NMT (M-NMT) architecture, which stores knowledge about how words (usually infrequently encountered ones) should be translated in a memory and then utilizes them to assist the neural model. We use this memory mechanism to combine the knowledge learned from a conventional statistical machine translation system and the rules learned by an NMT system, and also propose a solution for out-of-vocabulary (OOV) words based on this framework. Our experiments on two Chinese-English translation tasks demonstrated that the M-NMT architecture outperformed the NMT baseline by $9.0$ and $2.7$ BLEU points on the two tasks, respectively. Additionally, we found this architecture resulted in a much more effective OOV treatment compared to competitive methods.

It has been shown that Chinese poems can be successfully generated by sequence-to-sequence neural models, particularly with the attention mechanism. A potential problem of this approach, however, is that neural models can only learn abstract rules, while poem generation is a highly creative process that involves not only rules but also innovations for which pure statistical models are not appropriate in principle. This work proposes a memory augmented neural model for Chinese poem generation, where the neural model and the augmented memory work together to balance the requirements of linguistic accordance and aesthetic innovation, leading to innovative generations that are still rule-compliant. In addition, it is found that the memory mechanism provides interesting flexibility that can be used to generate poems with different styles.

Conjugated light-emitting polymer materials have demonstrated many useful photonic applications, attracting a lot of research interest in recent years. In this work, we present a novel hybrid photonic platform based on conjugated polymer Poly[2-(2’,5′-bis(2”-ethylhexyloxy)- phenyl) −1,4phenylene vinylene] (BEHP-PPV) integrated with a silicon nitride (SiNx) grating. By directly growing a low temperature SiNx layer on the thin organic polymer film, the degradation of organic polymer is significantly minimized. More importantly, the grating structure can effectively improve the amplified spontaneous emission (ASE) properties, reducing the threshold of ASE by up to 60%. These results demonstrated that the hybrid integration of light-emitting polymer with the SiNx grating is an effective solution to combine cost-effective and easy-to-process organic photonic materials with high-performance inorganic dielectric nanostructures, which could find many applications in the future.

Purpose: To establish a method for mouse coronary angiography in vivo using synchrotron radiation, which is es- sential for physiological and pathological research on coronary diseases. Methods: 1) The imaging parameters (e.g., photon energy, spatial resolution of the detector, and injection rate of contrast agent) optimal for the quality of acquired images in a simulation were determined. 2) Through animal experiments, the effectiveness of these optimal parameters and the repeata- bility of in vivo coronary angiography were verified. 3) An algorithm for background subtraction and contrast enhancement was designed and employed to compensate for the effects of interference and the effective information extracted used for diagnosing coronary disease. Results and conclusions: An optimal set of the imaging parameters was finally determined: photon energy of 33-34 keV, detector's spatial resolution of 30 �m or higher, image capture rate of 20 f/s or more, concen- tration of lopamidol solution of 75% as contrast agent and a pulse injection of contrast agent at a high rate.

A savanna system is a natural ecosystem in which the competition between grass and woody vegetation in a semi-arid rangeland should be maintained for its sustainable development. Finding an optimal management plan for obtaining maximum economic profit from raising cattle without loss of sustainability of the savanna system during a planning period is a great challenge for rangeland managers. In this study, we formulate the sustainable development planning of the savanna system as an optimal control model, in which maximization of the stocking rate of cattle during the planning period is chosen as the objective while sustainable development requirements are achieved through the constraints represented by the desired final state of the system. Using Pontryagin's maximum principle, the model is transformed into a two-point boundary-value problem with nonlinear differential equations that is then solved using an iterative approach. An example with a specified desired final state in a savanna system without fire is used to demonstrate the performance of the model and the algorithm. Numerical experiments show that the planning strategy obtained from the optimal control model achieves maximum economic profit from raising cattle during the planning period and simultaneously improves the resilience of the system and maintains sustainable development of the rangeland. The outcomes demonstrate that resilience, sustainable development and economic profit are consistent concepts in optimal management strategy for rangeland management.

Using the data of all listed Chinese companies from 2009 to 2014, this paper examines the impact of two typical long-term returns preferred funds, Social Security Fund and Insurance Fund, on corporate innovation. Both research and development (R&D) expenses and patents acquired by a company are adopted in this study to measure innovation input and output respectively. Our findings indicate that the shareholdings of both Social Security Fund and Insurance Fund can prompt a firm's innovation in general. Furthermore, the impact of the two funds vary from state-owned enterprises (SOE) and non-state-owned enterprises (non-SOE). In particular, Social Security Fund and Insurance Fund play a significantly positive role in enhancing corporate innovation performance in non-SOE while they don't improve innovation performance of SOE significantly. These empirical findings highlight the positive effects of Social Security Fund and Insurance Fund on corporate innovation, and will be of value to policy-makers in emerging markets in gauging the important drivers of corporate innovation ability.

In this study the generalized Darcy-Forchheimer model is used to characterize two-phase fluid flow where spatial flow characteristics may transition between Darcy and Forchheimer flow behavior. The local transition between the two flow regimes is characterized using the Forchheimer number as the criterion. A three-dimensional numerical model is developed that utilizes a control-volume method to simulate two-phase inertial, immiscible, and incompressible flow in a nondeformable homogeneous porous medium. The numerical model is validated by comparing its results with those obtained using a semianalytical solution of the Buckley-Leverett problem. The critical Forchheimer number is characterized using experimental data and is used to transition the local flow domain between Darcy and Forchheimer flow regions for both single-phase and multiphase analysis. The saturation-dependent distribution of the critical Forchheimer number is then used to analyze the Darcy and Forchheimer flow regions to provide a ...

A high-definition digital color image watermark algorithm based on QR code and DWT is studied in this paper. The basic concept, theoretical framework and the application domain of the digital watermark algorithm is introduced. From the simulation results, this algorithm can achieve better universality, and can be applied to most of the color images. Watermarked digital works can achieved better quality, and the embedded watermark is difficult to be detected. In addition, the extracted two-dimensional code image can achieve a high quality, and can be scanned through the electronic equipment and the information in it can be acquired.

This study proposes a convenient definition of the Forchheimer number for multiphase to derive a generalized Darcy-Forchheimer model. Based on this, a numerical tool using control volume finite difference method has been developed to simulate two-phase inertial immiscible and incompressible flow in non-deformable homogeneous porous media. The numerical tool has been validated by comparing the results to those obtained using a semi-analytical solution to the Buckley-Leverett problem with inertial effects and showing good agreement with the analytical solution. This study also proposes a new method to determine the critical Forchheimer number for the transition between Darcy flow and Forchheimer flow for both single phase and multiple phases and obtains the critical values for both water and CO2 by using the new method and experimental data in the literature. These critical Forchheimer numbers are then incorporated into the multiphase model. A comparison between the classical Darcy flow model and the Darcy-Forchheimer flow is conducted to reveal the importance of non-Darcy effect for high velocity case. This study provides a useful tool for future analysis and comprehension of multiphase Darcy-Forchheimer flow.

Climate change, a result of the accumulation of greenhouse gases in the atmosphere primarily from the combustion of fossil fuels, may influence public health in innumerable ways including a risk of increased frequency and intensity of heat waves, reduction in cold-related deaths, increase in extreme weather events, changes in the distribution of water-, food-, and vector-borne diseases, and a risk of malnutrition, especially in the poor. These combined effects negatively impact public health (Haines, Kovats, Campbell-Lendrum, & Corvalan, 2006). In contrast, an improvement in public health requires much input of natural and human-built resources, which should raise the emissions of CO2 even more and thus result in an increase in global temperature. Based on this interaction between climate change and public health, a semi-empirical model was built. After that, the model was calibrated with data collected between 1901 and 1960. During the calibration, climate change was represented by global average temperature while public health was represented by life expectancy at birth. Finally, the calibrated model was validated with data from 1961 to 2005. Agreement between the results and the observation data is remarkable, with almost all relative errors less than 6%. The model of climate change and public health can be used to predict trends in climate change and public health and also provide insights into strategies for controlling the rise in temperature and improving public health.