Papel de las C-JUN cinasas N-terminales (JNK) en el desarrollo de cáncer de vías biliares

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Inmunología, Oftalmología y ORL, leída el 04/02/2021Cholangiocarcinoma (CCA) is an aggressive malignant bile duct cancer, and the second most common primary liver tumor In Europe, around 13,000 new CCA cases were diagnosed per year. However, the pathogenesis of CCA remains elusive and lack of diagnostic as well as treatment tools impede a better outcome for patients. In the present study, we use a new animal model of CCA, to understand the molecular mechanism. In the present work, we hypothesize that the synergistic dysfunction of Jnk1 and Jnk2 in hepatocytes drives the development of cholangiocarcinogenesis. Mice with specific deletion of Jnk1/2 in hepatocytes (JnkΔhepa) and floxed (Jnkf/f) control mice were sacrificed at different time points during liver disease progression. Likewise, different toxicity treatments (i.e., TAA, DEN/TAA and DEN/CCl4) and experimental models were used...El colangiocarcinoma (CCA) es un cáncer de las vías biliares maligno agresivo, y que constituye el segundo tumor primario de hígado más común. En Europa, se diagnostican alrededor de 13.000 nuevos casos de CCA por año. Sin embargo, la patogenia de CCA sigue siendo difícil de entender y la falta de herramientas de diagnóstico y tratamiento impiden un mejor resultado para los pacientes. En el presente estudio, utilizamos un nuevo modelo animales de CCA, para entender el mecanismo molecular. En el presente trabajo, planteamos la hipótesis de que la disfunción sinérgica de Jnk1 y Jnk2 en los hepatocitos impulsa el desarrollo de la colangiocarcinogénesis. Ratones con deleción específica de Jnk1/2 en hepatocitos JnkΔhepa y ratones floxeados control (Jnkf/f) fueron sacrificaron en diferentes puntos de tiempo durante la progresión de la enfermedad hepática. Así mismo, diferentes modelos experimentales tóxicos (TAA，DE/TAA, DEN/CCl4) fueron utilizados...Fac. de MedicinaTRUEunpu

DYNAMIC CONSTRUCTION CONTROL METHOD FOR A DEEP FOUNDATION PIT WITH SAND-PEBBLE GEOLOGY

Taking the water-rich sand and pebble geology deep foundation pit of Jinfu Station of Chengdu Metro Line 6 as the research object, combined with the ladder excavation method of slotting, utilizing finite difference software FLAC 3D as well as on-site monitoring result, the deformation law of the diaphragm wall during the dynamic excavation of the foundation pit is analysed, and the influence of the relative stiffness between the vertical and horizontal walls of the foundation pit on the lateral deformation of the retaining structure is discussed. The results show that while using the ladder excavation method of slotting, the maximum lateral displacement of the underground diaphragm walls decreases gradually with the excavation depth of the foundation pit, which occurs at the intersection of the middle point of the oblique excavation line and the step distance section of the transverse excavation. Additionally, the lateral displacement increases closer to the excavation section. The lateral displacement of the envelope enclosure mainly depends on the relative constraint stiffness of the vertical and horizontal underground diaphragm wall of the foundation pit. The use of the ladder layered excavation method of slotting can effectively reduce the lateral displacement of the underground diaphragm wall. The simulated result and on-site monitoring result are nearly the same. These results can provide a corresponding theory and engineering basis for the selection of excavation methods for the same type of sand and pebble stratum foundation pit

Deformation rule of bored pile & steel support for deep foundation pit in sandy pebble geology

Regarding the whole excavation process of the support system of the Southwest Jiaotong University Station of Chengdu Metro Line 6 (the deep foundation pit bored pile + steel support and support system) as the engineering background, this paper studies the deformation rule of the deep foundation pit bored pile + steel support of the sandy pebble foundation. The deformation rule of this support system, the settlement rule of the ground surface outside the pit, and the rule of the uplift of the loose at the bottom of the pit are studied. A key analysis of the positive corner of the foundation pit is conducted, and the rationality of the optimization of the support scheme is evaluated. This paper provides effective guidance for the subsequent deep foundation pit construction and provides a reference for deep foundation pit construction

Enhanced Fireworks Algorithm-Auto Disturbance Rejection Control Algorithm for Robot Fish Path Tracking

The robot fish is affected by many unknown internal and external interference factors when it performs path tracking in unknown waters. It was proposed that a path tracking method based on the EFWA-ADRC (enhanced fireworks algorithmauto disturbance rejection control) to obtain high-quality tracking effect. ADRC has strong adaptability and robustness. It is an effective method to solve the control problems of nonlinearity, uncertainty, strong interference, strong coupling and large time lag. For the optimization of parameters in ADRC, the enhanced fireworks algorithm (EFWA) is used for online adjustment. It is to improve the anti-interference of the robot fish in the path tracking process. The multi-joint bionic robot fish was taken as the research object in the paper. It was established a path tracking error model in the Serret-Frenet coordinate system combining the mathematical model of robotic fish. It was focused on the forward speed and steering speed control rate. It was constructed that the EFWA-ADRC based path tracking system. Finally, the simulation and experimental results show that the control method based on EFWAADRC and conventional ADRC makes the robotic fish track the given path at 2:8s and 3:3s respectively, and the tracking error is kept within plus or minus 0:09m and 0:1m respectively. The new control method tracking steady-state error was reduces by 10% compared with the conventional ADRC. It was proved that the proposed EFWA-ADRC controller has better control effect on the controlled system, which is subject to strong interference

Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma:The Missing Link

In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low—a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

Homeostasis; PathogenesisHomeostasis; PatogénesisHomeòstasi; PatogènesiProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.This work was supported by the MICINN Retos RTI2018-095673-B-I00, PID2020-11782RB-I00, PID2020-117941RB-I00, all of which were co-funded with FEDER funds, AMMF 2018/117, COST Action CA17112 and Comunidad de Madrid S2022/BMD-7409. This project has received funding from the European Horizon’s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement No. 101095679. The research group belongs to the validated Research Groups Ref. 970935 Liver Pathophysiology, 920631 Lymphocyte Immunobiology and IBL-6 (imas12-associated). KZ was supported by the China Scholarship Council. SM-G was supported by a predoctoral scholarship from Complutense University