Genome-wide mRNA expression profiling in vastus lateralis of COPD patients with low and normal fat free mass index and healthy controls

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) has significant systemic effects beyond the lungs amongst which muscle wasting is a prominent contributor to exercise limitation and an independent predictor of morbidity and mortality. The molecular mechanisms leading to skeletal muscle dysfunction/wasting are not fully understood and are likely to be multi-factorial. The need to develop therapeutic strategies aimed at improving skeletal muscle dysfunction/wasting requires a better understanding of the molecular mechanisms responsible for these abnormalities. Microarrays are powerful tools that allow the investigation of the expression of thousands of genes, virtually the whole genome, simultaneously. We aim at identifying genes and molecular pathways involved in skeletal muscle wasting in COPD. METHODS: We assessed and compared the vastus lateralis transcriptome of COPD patients with low fat free mass index (FFMI) as a surrogate of muscle mass (COPD(L)) (FEV(1) 30 ± 3.6%pred, FFMI 15 ± 0.2 Kg.m(−2)) with patients with COPD and normal FFMI (COPD(N)) (FEV(1) 44 ± 5.8%pred, FFMI 19 ± 0.5 Kg.m(−2)) and a group of age and sex matched healthy controls (C) (FEV(1) 95 ± 3.9%pred, FFMI 20 ± 0.8 Kg.m(−2)) using Agilent Human Whole Genome 4x44K microarrays. The altered expression of several of these genes was confirmed by real time TaqMan PCR. Protein levels of P21 were assessed by immunoblotting. RESULTS: A subset of 42 genes was differentially expressed in COPD(L) in comparison to both COPD(N) and C (PFP < 0.05; −1.5 ≥ FC ≥ 1.5). The altered expression of several of these genes was confirmed by real time TaqMan PCR and correlated with different functional and structural muscle parameters. Five of these genes (CDKN1A, GADD45A, PMP22, BEX2, CGREF1, CYR61), were associated with cell cycle arrest and growth regulation and had been previously identified in studies relating muscle wasting and ageing. Protein levels of CDKN1A, a recognized marker of premature ageing/cell cycle arrest, were also found to be increased in COPD(L). CONCLUSIONS: This study provides evidence of differentially expressed genes in peripheral muscle in COPD patients corresponding to relevant biological processes associated with skeletal muscle wasting and provides potential targets for future therapeutic interventions to prevent loss of muscle function and mass in COPD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-014-0139-5) contains supplementary material, which is available to authorized users

CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis.

Anti-angiogenic and anti-lymphangiogenic drugs slow tumor progression and dissemination. However, an important difficulty is that a tumor reacts and compensates to obtain the blood supply needed for tumor growth and lymphatic vessels to escape to distant loci. Therefore, there is a growing consensus on the requirement of multiple anti-(lymph)angiogenic molecules to stop cell invasion efficiently. Here we studied the cooperation between endogenous anti-angiogenic molecules, endostatin and fibstatin, and a chemokine, the Platelet Factor-4 variant 1, CXCL4L1. Anti-angiogenic factors were co-expressed by IRES-based bicistronic vectors and their cooperation was analyzed either by local delivery following transduction of pancreatic adenocarcinoma cells with lentivectors, or by distant delivery resulting from intramuscular administration in vivo of adeno-associated virus derived vectors followed by tumor subcutaneous injection. In this study, fibstatin and CXCL4L1 cooperate to inhibit endothelial cell proliferation, migration and tubulogenesis in vitro. No synergistic effect was found for fibstatin-endostatin combination. Importantly, we demonstrated for the first time that fibstatin and CXCL4L1 not only inhibit in vivo angiogenesis, but also lymphangiogenesis and tumor spread to the lymph nodes, whereas no beneficial effect was found on tumor growth inhibition using molecule combinations compared to molecules alone. These data reveal the synergy of CXCL4L1 and fibstatin in inhibition of tumor angiogenesis, lymphangiogenesis and metastasis and highlight the potential of IRES-based vectors to develop anti-metastasis combined gene therapies

Low frequency noise characterization and modeling of microwave bipolar devices: Application to the design of low phase noise oscillator

This paper addresses advanced low frequency noise measurements and modeling of SiGe HBTs. Results have been implemented into a non linear Gummel Poon model which has been validated through the design of a DRO made of an integrated SiGe negative resistance in the 10 GHz range. We have obtained phase noise of -105 dBc/Hz at 10 kHz offset, which is close to the state of the art, and we have demonstrated a design technique that provides an accurate phase noise prediction

Low frequency noise characterization and modeling of microwave bipolar devices : application to the design of low phase noise oscillator

This paper addresses advanced low frequency noise measurements and modeling of SiGe HBTs. Results have been implemented into a nonlinear Gummel Poon model which has been validated through the design of a DRO made of an integrated SiGe negative resistance in the 10 GHz range. We have obtained phase noise of -105 dBc/Hz at 10 kHz offset, which is close to the state of the art, and we have demonstrated a design technique that provides an accurate phase noise prediction

High Ge content Si / SiGe heterostructures for microelectronics and optoelectronics purposes

International audienceSiGe virtual substrates grown by RP-CVD onto Si(001) substrates are characterized by a macroscopic degree of strain relaxation R = 97.2 ± 1.2%, threading dislocations densities as low as 4×105 cm -2 and rather smooth surfaces (rms roughness: 2 - 5 nm). Such virtual substrates have been used as templates for the formation of SiGe-On-Insulator structures (on which we have studied the specifics of Si and SiGe re-epitaxy). We have also grown Ge thick layers directly onto Si(001). Tensile-strained (R = 107%), smooth (rms ∼ 1 nm) Ge layers with a low threading dislocation density (6×106 cm-2) are obtained that are characterized by high absorption coefficients: A = 10000 cm-1 @ 1.3μm and 4500 cm-1 @ 1.55μm. Finally, we have obtained dense, narrowly size-distributed Ge islands that, when integrated into {Ge quantum dots / Si spacer} stacks, emit light at 1520 nm (PL @ 10K) and are characterized by A ∼ 70 cm-1 in-between 1.2 and 1.7 μm

Engineering strained silicon on insulator wafers with the Smart CutTM technology

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