55 research outputs found
Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas
Abstract: Background: Cytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology. Nevertheless, the molecular consequences of numerous genetic alterations still remain unclear.
Methods: To identify novel genes implicated in HNSCC pathogenesis, we analyzed the genomic alterations present in five HNSCC-derived cell lines by array CGH, and compared high level focal gene amplifications with gene expression levels to identify genes whose expression is directly impacted by these genetic events. Next, we knocked down TRPC6, one of the most highly amplified and over-expressed genes, to characterize the biological roles of TRPC6 in carcinogenesis. Finally, real time PCR was performed to determine TRPC6 gene dosage and mRNA levels in normal mucosa and human HNSCC tissues.
Results: The data showed that the HNSCC-derived cell lines carry most of the recurrent genomic abnormalities previously described in primary tumors. High-level genomic amplifications were found at four chromosomal sites (11q21-q22.2, 18p11.31-p11.21, 19p13.2-p13.13, and 21q11) with associated gene expression changes in selective candidate genes suggesting that they may play an important role in the malignant behavior of HNSCC. One of the most dramatic alterations of gene transcription involved the TRPC6 gene (located at 11q21-q22.2) which has been recently implicated in tumour invasiveness. siRNA-induced knockdown of TRPC6 expression in HNSCC-derived cells dramatically inhibited HNSCC-cell invasion but did not significantly alter cell proliferation. Importantly, amplification and concomitant overexpression of TRPC6 was also found in HNSCC tumour samples.
Conclusions: Altogether, these data show that TRPC6 is likely to be a target for 11q21-22.2 amplification that confers enhanced invasive behavior to HNSCC cells. Therefore, TRPC6 may be a promising therapeutic target in the treatment of HNSCC.This work was supported by Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria [FIS PI11/929 to M.-D.C and C. S.]; Red Tematica de Investigacion Cooperativa en Cancer [RD12/0036/0015] Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF); and Obra Social CajAstur-Instituto Universitario de Oncologia del Principado de Asturias.Bernaldo De Quirós, S.; Merlo, A.; Secades, P.; Zambrano, I.; Saenz De Santa María, I.; Ugidos, N.; Jantus Lewintre, E.... (2013). Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas. 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ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition
ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in three infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALKrearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (seven and twelve from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, ten with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis, and provides guidance for the clinical management of this emerging histiocytic entity.Molecular tumour pathology - and tumour genetic
Airworthiness Tests of the UAV Structure − Fatigue Issues
The paper presents investigations undertaken in order to support developing the UAV airworthiness requirements, in particular those concerning fatigue aspects. Knowledge about UAVs load spectra is of vital importance for fatigue issues. The results of preliminary research are presented in this paper. A description of the load spectrum processing is given, starting from filtering the input-data, and then either counting the load signal transfers or implementing the Rainflow Counting algorithm and presenting the results in the form of a transfer array or halfcycles array. This description is illustrated by three examples of flight tests of 4-meter class UAVs, designed at Warsaw University of Technology. They concern flights controlled in a manual and
automatic way in order to show differences between the LSs for such control modes. Besides the LS processing, a method for statistical analysis of load spectra from several flights is also
presented to address the important problem of LS dispersion. Finally, there are shown selected tests of the UAV structure elements for which load spectra may have a crucial importance
Estimation of Fatigue Properties of Composite Structures
The paper presents the proposal of a simplified method of fatigue properties estimation for polymer composite structures
Investigation into Fatigue Behaviour of Metal-Composite Glue Connection
The paper presents the results of experimental investigations into fatigue properties of metal and CFRP-composite glued joints. The object of investigation was adhesive joints between metal sheets made from iron alloy 30HGS (popular steel in the Polish aviation industry) and CFRP orthogonal reinforced sheets made from 10 layers of SIGRATEX CE3208 pre-preg. The main adhesive was the WK-3 glue (applied in the form of 0.2 mm thin foil) while the DP-490 - liquid epoxy glue was used as technological aid for specimen manufacturing. Two kinds of specimens were prepared and tested: single-lap joints and double-lap joints. The paper presents S-N curves for both kinds of those specimens. Besides fatigue life of the glued joints, the interest was focused on the NDT tests regarding damage propagation inside the glue-connection. The paper presents several C-scans made at different stages of fatigue testing. It has been found that the damage occurs almost equally in the whole volume of the glue layer (contrary to the expectation following from the physical model of the glue-connection internal loading). The results of experiments regarding thermal effect of cyclic loading of the glued joints are also described. It has been found that this effect could be used as an important parameter for diagnostics purposes of the glued joints
Airworthiness Tests of the UAV Structure − Fatigue Issues
The paper presents investigations undertaken in order to support developing the UAV airworthiness requirements, in particular those concerning fatigue aspects. Knowledge about UAVs load spectra is of vital importance for fatigue issues. The results of preliminary research are presented in this paper. A description of the load spectrum processing is given, starting from filtering the input-data, and then either counting the load signal transfers or implementing the Rainflow Counting algorithm and presenting the results in the form of a transfer array or halfcycles array. This description is illustrated by three examples of flight tests of 4-meter class UAVs, designed at Warsaw University of Technology. They concern flights controlled in a manual and
automatic way in order to show differences between the LSs for such control modes. Besides the LS processing, a method for statistical analysis of load spectra from several flights is also
presented to address the important problem of LS dispersion. Finally, there are shown selected tests of the UAV structure elements for which load spectra may have a crucial importance
Methods of measurement and registration of loads on the fly of the composite construction aircraft
W pracy omówiono metodykę pomiarów i rejestracji obciążeń w locie statku powietrznego o konstrukcji kompozytowej, przedstawiono podstawowy cel rejestracji obciążeń w locie. Dalej odniesiono się do dotychczasowej praktyki przeprowadzania takich pomiarów oraz ograniczeń występujących na etapie akwizycji danych i sposobów ich kompensacji. Następnie omówiono czujniki i aparaturę pomiarową do badania obciążeń, w tym różnego typu cyfrowe rejestratory sygnałów oraz krosownice sygnałów. Przy omawianiu czujników skupiono się na akcelerometrach, tensometrach i wzmacniaczach sygnałów, czujnikach indukcyjnych przemieszczeń, czujnikach wychyleń sterów i modemach transmisji telemetrycznej. Szeroko przedstawione zostało zagadnienie dotyczące spektrum obciążeń, metod jego wyznaczania oraz sposobu aplikacji. Zaprezentowany materiał bazuje na doświadczeniach z badań zmęczeniowych szybowców kompozytowych, ale wskazuje na wiele analogii natury konstrukcyjnej i obliczeniowej pomiędzy grupami szybowców oraz lekkich samolotów kompozytowych. Zwrócono uwagę na problem zapisu spektrum obciążeń i w tym kontekście omówiono specjalną metodę zapisu spektrum obciążeń, otwierającą drogę do odtworzenia stochastycznego charakteru obciążeń na stanowisku badawczym. Innym problemem jest ekstrapolacja zmierzonego spektrum obciążeń, ponieważ na podstawie pomiaru obejmującego kilkanaście lub kilkadziesiąt godzin lotu trzeba wygenerować spektrum obciążeń obejmujące np. 1000 godzin lotu. Na zakończenie przedstawione zostały metody akwizycji danych pomiarowych dla spektrum obciążeń.The study developed a methodology of measurement and registration of loads in-flight of the composite structures aircraft, shows a basic purpose of the registration of loads on the fly. The reference was made to the previous practice of carrying out such measurements and constraints on the stage of data acquisition and methods for their compensation. It then discusses sensors and measuring equipment for testing loads, including various types of digital recorders and matrix of signals. When discussing the sensors, it focuses on accelerometers, strain gauges of signal amplifiers, inductive displacement sensors, sensors of rudder deflections and telemetric transmission modems. Issue has been widely shown on the spectrum of loads, methods of its determination and application method. Presented material is based on the issues of fatigue tests of composite gliders, but emphasizes the many analogies of structural and calculation nature between the groups of gliders and light composite aircrafts. Attention was drawn to the problem of recording the loads spectrum, and in this context there is discussed a special method to record the loads spectrum opening the way to reproduce the stochastic nature of the loads on the test bench. Another problem is the extrapolation of the measured the loads spectrum, because on the basis of measurements including several or dozens of hours of flight, the loads spectrum including eg 1000 hours of flight must be generated. In conclusion, data acquisition method for the loads spectrum was presented
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