Background & Aims Colorectal cancer (CRC) is highly metastatic. Metastases spread directly into local tissue or invade distant organs via blood and lymphatic vessels, but the role of ...lymphangiogenesis in CRC progression has not been determined. Lymphangiogenesis is induced via vascular endothelial growth factor C (VEGFC) activation of its receptor, VEGFR3; high levels of VEGFC have been measured in colorectal tumors undergoing lymphangiogenesis and correlated with metastasis. We investigated VEGFC signaling and lymphatic barriers in human tumor tissues and mice with orthotopic colorectal tumors. Methods We performed immunohistochemical, immunoblot, and real-time polymerase chain reaction analyses of colorectal tumor specimens collected from patients; healthy intestinal tissues collected during operations of patients without CRC were used as controls. CT26 CRC cells were injected into the distal posterior rectum of BALB/c-nude mice. Mice were given injections of an antibody against VEGFR3 or an adenovirus encoding human VEGFC before orthotopic tumors and metastases formed. Lymph node, lung, and liver tissues were collected and evaluated by flow cytometry. We measured expression of vascular endothelial cadherin (CDH5) on lymphatic vessels in mice and in human intestinal lymphatic endothelial cells. Results Levels of podoplanin (a marker of lymphatic vessels), VEGFC, and VEGFR3 were increased in colorectal tumor tissues, compared with controls. Mice that expressed VEGFC from the adenoviral vector had increased lymphatic vessel density and more metastases in lymph nodes, lungs, and livers, compared with control mice. Anti-VEGFR3 antibody reduced numbers of lymphatic vessels in colons and prevented metastasis. Expression of VEGFC compromised the lymphatic endothelial barrier in mice and endothelial cells, reducing expression of CDH5, increasing permeability, and increasing trans-endothelial migration by CRC cells. Opposite effects were observed in mice and cells when VEGFR3 was blocked. Conclusions VEGFC signaling via VEGFR3 promotes lymphangiogenesis and metastasis by orthotopic colorectal tumors in mice and reduces lymphatic endothelial barrier integrity. Levels of VEGFC and markers of lymphatic vessels are increased in CRC tissues from patients, compared with healthy intestine. Strategies to block VEGFR3 might be developed to prevent CRC metastasis in patients.
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology that are associated with an aberrant mucosal immune response. Neoangiogenesis and ...vascular injury are observed in IBD along with increased lymphangiogenesis. While the pathogenic role of angiogenesis in IBD is well characterized, it is not clear how or if increased lymphangiogenesis promotes disease. Here, we determined that enhancing lymphangiogenesis and lymphatic function reduces experimental IBD. Specifically, we demonstrated that adenoviral induction of prolymphangiogenic factor VEGF-C provides marked protection against the development of acute and chronic colitis in 2 different animal models. VEGF-C-dependent protection was observed in combination with increased inflammatory cell mobilization and bacterial antigen clearance from the inflamed colon to the draining lymph nodes. Moreover, we found that the VEGF-C/VEGFR3 pathway regulates macrophage (MΦ) plasticity and activation both in cultured MΦs and in vivo, imparting a hybrid M1-M2 phenotype. The protective function of VEGF-C was meditated by the so-called resolving MΦs during chronic experimental colitis in a STAT6-dependent manner. Together, these findings shed light on the contribution of lymphatics to the pathogenesis of gut inflammation and suggest that correction of defective lymphatic function with VEGF-C has potential as a therapeutic strategy for IBD.
In this paper, a Firefly algorithm is proposed for identification and comparative study of five, seven and eight parameters of a single and double diode solar cell and photovoltaic module under ...different solar irradiation and temperature. Further, a metaheuristic algorithm is proposed in order to predict the electrical parameters of three different solar cell technologies. The first is a commercial RTC mono-crystalline silicon solar cell with single and double diodes at 33 °C and 1000 W/m2. The second, is a flexible hydrogenated amorphous silicon a-Si:H solar cell single diode. The third is a commercial photovoltaic module (Photowatt-PWP 201) in which 36 polycrystalline silicon cells are connected in series, single diode, at 25 °C and 1000 W/m2 from experimental current-voltage. The proposed constrained objective function is adapted to minimize the absolute errors between experimental and predicted values of voltage and current in two zones. Finally, for performance validation, the parameters obtained through the Firefly algorithm are compared with recent research papers reporting metaheuristic optimization algorithms and analytical methods. The presented results confirm the validity and reliability of the Firefly algorithm in extracting the optimal parameters of the photovoltaic solar cell.
The fast increase in Electric Vehicles usage in the last 10 years has raised the need to forecast their energy consumption during charge properly. Lithium-ion batteries have become the major storage ...component for electric vehicles, avoiding their overcharge can preserve their health and prolong their lifetime. This paper proposes a Machine Learning model based on the K-nearest neighbors classification algorithm for electric vehicle charging session duration forecast. The model forecasts the duration of the charge by assigning the event to its correct class. Each class contains the charging events whose duration is comprised of a certain interval. The only information used by the algorithm is the one available at the beginning of the charging event (arrival time, starting SOC, calendar data). The model is validated on a real-world dataset containing records of charging sessions from more than 100 users, a sensitivity analysis is performed to assess the impact of different information given as input. The effectiveness of the model with respect to the benchmark models is demonstrated with an increase in performance.
Reflectarray antennas are low-profile high-gain systems widely applied in the aerospace industry. The increase in their application is leading to the problem of getting more advanced performance ...while keeping the system as simple as possible. In these cases, their design cannot be conducted via analytical methods, thus evolutionary optimization algorithms are often implemented. Indeed, the design is characterized by the presence of many local minima, by high number of design variables, and by the high computational burden required to evaluate the antenna performance. The purpose of this paper is to develop, implement, and test a complete Optimization Environment that can be applied to achieve high scanning capabilities with a reflectarray. The design of the optimization environment has been selected to be flexible enough to be applied also with other different algorithms.
Understanding how, why and when energy consumption changes provides a tool for decision makers throughout the power networks. Thus, energy forecasting provides a great service. This research proposes ...a probabilistic approach to capture the five inherent dimensions of a forecast: three dimensions in space, time and probability. The forecasts are generated through different models based on artificial neural networks as a post-treatment of point forecasts based on shallow artificial neural networks, creating a dynamic ensemble. The singular value decomposition (SVD) technique is then used herein to generate temperature scenarios and project different futures for the probabilistic forecast. In additional to meteorological conditions, time and recency effects were considered as predictor variables. Buildings that are part of a university campus are used as a case study. Though this methodology was applied to energy demand forecasts in buildings alone, it can easily be extended to energy communities as well.
The correct design of a Wireless Sensor Network (WSN) is a very important task because it can highly influence its installation and operational costs. An important aspect that should be addressed ...with WSN is the routing definition in multi-hop networks. This problem is faced with different methods in the literature, and here it is managed with a recently developed swarm intelligence algorithm called Social Network Optimization (SNO). In this paper, the routing definition in WSN is approached with two different problem codifications and solved with SNO and Particle Swarm Optimization. The first codification allows the optimization algorithm more degrees of freedom, resulting in a slower and in many cases sub-optimal solution. The second codification reduces the degrees of freedom, speeding significantly the optimization process and blocking in some cases the convergence toward the real best network configuration.
Inflammation plays crucial roles in the pathogenesis of several chronic inflammatory disorders, including Crohn's disease (CD) and UC, the two major forms of IBD. The urokinase plasminogen activator ...receptor (uPAR) exerts pleiotropic functions over the course of both physiological and pathological processes. uPAR not only has a key role in fibrinolysis but also modulates the development of protective immunity. Additionally, uPAR supports extracellular matrix degradation and regulates cell migration, adhesion and proliferation, thus influencing the development of inflammatory and immune responses. This study aimed to evaluate the role of uPAR in the pathogenesis of IBD.
The functional role of uPAR was assessed in established experimental models of colitis. uPAR deficiency effects on cytokine release, polarisation and bacterial phagocytosis were analysed in colonic macrophages. uPAR expression was analysed in surgical specimens collected from normal subjects and patients with IBD.
In mice, uPAR expression is positively regulated as colitis progresses. uPAR-KO mice displayed severe inflammation compared with wild-type littermates, as indicated by clinical assessment, endoscopy and colon histology. The absence of uPAR led to an increased production of inflammatory cytokines by macrophages that showed an M1 polarisation and impaired phagocytosis. In human IBD, CD68(+) macrophages derived from the inflamed mucosa expressed low levels of uPAR.
These findings point to uPAR as an essential component of intestinal macrophage functions and unravel a new potential target to control mucosal inflammation in IBD.
The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that ...uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development.
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