Intérêt de la tomographie par émission de positons (TEP) au 18FDG dans le suivi des patients traités pour carcinome épidermoïde des voies aérodigestives supérieures (VADS) en rémission clinique

IntroductionPosttreatment follow-up of head and neck squamous cell carcinoma (HNSCC) recurrence is a diagnostic challenge. Tissue distortions from radiation and surgery can obscure early detection of recurrence by conventional follow-up approaches such as physical examination (PE), computed tomography, and magnetic resonance imaging. A number of studies have shown that ¹⁸Fluoro-fluorodeoxyglucose (¹⁸FDG) Positron emission tomography (PET) may be an effective technique for the detection of persistent, recurrent, and distant metastatic HNSCC after treatment. The aim of this prospective study was to determine the benefits (sensitivity, specificity, predictive values, and accuracy) of ¹⁸FDG PET using hybrid PET–Computed tomography system (PET/CT) in the detection of HNSCC subclinical locoregional recurrence and distant metastases, in patients 12 months after curative treatment with a negative conventional follow up.Materials and MethodsNinety-one patients cured from head and neck squamous cell carcinoma (HNSCC) without any clinical element for recurrence were included. Whole-body ¹⁸FDG PET/CT examination was performed 11.6 ± 4.4 months after the end of the treatment. The gold standard was histopathology or 6 months imaging follow-up.ResultsThe whole-body ¹⁸FDG PET/CT of the 91 patients in this study consisted of 52 negative and 39 positive results. Nine of these patients who exhibited abnormal ¹⁸FDG uptake in head and neck area did not have subsequently proven recurrent HNSCC (false positive). Thirty had proven recurrence (true positive). All 52 patients with negative readings of ¹⁸FDG PET/CT remained free of disease at 6 months (true negative). The sensitivity and specificity of ¹⁸FDG PET/CT in this study for the diagnosis of HNSCC recurrence were 100% (30/30) and 85% (52/61) respectively. The positive predictive value was 77% (30/39). The negative predictive value was 100% (52/52). The overall accuracy was 90% (82/91).ConclusionThe results of our study confirm the high effectiveness of ¹⁸FDG PET/CT in assessment of HNSCC recurrence. It suggests that this modality is more accurate than conventional follow-up PE alone in the assessment of patient recurrence after previous curative treatment for HNSCC. Therefore, a PET study could be systematically proposed at 12 months after the end of the treatment.     

Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis

Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease. Thus, we investigated the effects of acute and chronic exposure to increasing concentrations of amyloid beta (Abeta) on mitochondrial function and nitric oxide (NO) production in vitro and in vivo. Our data demonstrate that PC12 cells and human embryonic kidney cells bearing the Swedish double mutation in the amyloid precursor protein gene (APPsw), exhibiting substantial Abeta levels, have increased NO levels and reduced ATP levels. The inhibition of intracellular Abeta production by a functional gamma-secretase inhibitor normalizes NO and ATP levels, indicating a direct involvement of Abeta in these processes. Extracellular treatment of PC12 cells with comparable Abeta concentrations only leads to weak changes, demonstrating the important role of intracellular Abeta. In 3-month-old APP transgenic (tg) mice, which exhibit no plaques but already detectable Abeta levels in the brain, reduced ATP levels can also be observed showing the in vivo relevance of our findings. Moreover, we could demonstrate that APP is present in the mitochondria of APPsw PC12 cells. This presence might be directly involved in the impairment of cytochrome c oxidase activity and depletion of ATP levels in APPsw PC12 cells. In addition, APPsw human embryonic kidney cells, which produce 20-fold increased Abeta levels compared with APPsw PC12 cells, and APP tg mice already show a significantly decreased mitochondrial membrane potential under basal conditions. We suggest a hypothetical sequence of pathogenic steps linking mutant APP expression and amyloid production with enhanced NO production and mitochondrial dysfunction finally leading to cell death.     

Osmotic adjustment, gas exchanges and chlorophyll fluorescence of a hexaploid triticale and its parental species under salt stress

The effect of salt stress (NaCl 85.7 or 110 mmol/L) was investigated in the triticale T300 and its parental species, Triticum dicoccum farrum (Triticum df) and Secale cereale cv. Petkus. Triticum df and T300 were more salt-tolerant than the rye (110 mmol/L NaCl was the highest concentration allowing rye growth to the three-leaf stage). Na+, K+ and Cl- ions accounted for almost half of the osmotic adjustment in Triticum df and T300, and up to 90% in rye. Salinity decreased the net photosynthesis and transpiration rates of the three cereals as compared to control plants, but induced no significant change in chlorophyll a fluorescence parameters. Water-use efficiency (WUE) increased with salinity. In the presence of 110 mmol/L NaCl, the K+/Na+ ratio decreased markedly in rye as compared to the other two cereals. Proline concentration, which increased in Triticum df and T300, could have protected membrane selectivity in favour of K+. Proline content remained low in rye, and increasing soluble sugar content did not appear to prevent competition between Na+ and K+. The salt sensitivity of rye could be due to low K+ uptake in the presence of a high NaCl concentration.     

The GC-Rich Transposon <Emphasis Type="Italic">Bytmar1</Emphasis> from the Deep-Sea Hydrothermal Crab, <Emphasis Type="Italic">Bythograea thermydron</Emphasis>, May Encode Three Transposase Isoforms from a Single ORF

Mariner-like elements (MLEs) are classII transposons with highly conserved sequence properties and are widespread in the genome of animal species living in continental environments. We describe here the first full-length MLE found in the genome of a marine crustacean species, the deep-sea hydrothermal crab Bythograea thermydron (Crustacea), named Bytmar1. A comparison of its sequence features with those of the MLEs contained in the genomes of continental species reveals several distinctive characteristics. First, Bytmar1 elements contains an ORF that may encode three transposase isoforms 349, 379, and 398 amino acids (aa) in long. The two biggest proteins are due to the presence of a 30- and 49-aa flag, respectively, at the N-terminal end of the 349-aa cardinal MLE transposase. Their GC contents are also significantly higher than those found in continental MLEs. This feature is mainly due to codon usage in the transposase ORF and directly interferes with the curvature propensities of the Bytmar1 nucleic acid sequence. Such an elevated GC content may interfere with the ability of Bytmar 1 to form an excision complex and, in consequence, with its efficiency to transpose. Finally, the origin of these characteristics and their possible consequences on transposition efficiency are discussed.Reviewing Editor: Dr. Nicolas Galtier     

Amyloid precursor protein family-induced neuronal death is mediated by impairment of the neuroprotective calcium/calmodulin protein kinase IV-dependent signaling pathway

The aberrant metabolism of beta-amyloid precursor protein (APP) and the progressive deposition of its derived fragment beta-amyloid peptide are early and constant pathological hallmarks of Alzheimer's disease. Because APP is able to function as a cell surface receptor, we investigated here whether a disruption of the normal function of APP may contribute to the pathogenic mechanisms in Alzheimer's disease. To this aim, we generated a specific chicken polyclonal antibody directed against the extracellular domain of APP, which is common with the beta-amyloid precursor-like protein type 2. Exposure of cultured cortical neurons to this antibody (APP-Ab) induced cell death preceded by neurite degeneration, oxidative stress, and nuclear condensation. Interestingly, caspase-3-like protease was not activated in this neurotoxic action suggesting a different mode of cell death than classical apoptosis. Further analysis of the molecular mechanisms revealed a calpain- and calcineurin-dependent proteolysis of the neuroprotective calcium/calmodulin-dependent protein kinase IV and its nuclear target protein cAMP responsive element binding protein. These effects were abolished by the G protein inhibitor pertussis toxin, strongly suggesting that APP binding operates via a GTPase-dependent pathway to cause neuronal death.     

Effect of nitrogen-rich cell culture surfaces on type X collagen expression by bovine growth plate chondrocytes

Background  

Recent evidence indicates that osteoarthritis (OA) may be a systemic disease since mesenchymal stem cells (MSCs) from OA patients express type X collagen, a marker of late stage chondrocyte hypertrophy (associated with endochondral ossification). We recently showed that the expression of type X collagen was suppressed when MSCs from OA patients were cultured on nitrogen (N)-rich plasma polymer layers, which we call "PPE:N" (N-doped plasma-polymerized ethylene, containing up to 36 atomic percentage (at.%) of N.     

A DNA biosensor based on peptide nucleic acids on gold surfaces

We present a DNA biosensor based on self-assembled monolayers (SAMs) of thiol-derivatized peptide nucleic acid (PNA) molecules adsorbed on gold surfaces. Previous works have shown that PNA molecules at an optimal concentration can be self-assembled with their molecular axes normal to the surface. In such structural configuration BioSAMs of PNAs maintain their capability for recognizing complementary DNA. We describe the combined use of PM-RAIRS and synchrotron radiation XPS for the detection and spectroscopic characterization of PNA-DNA hybridization process on gold surfaces. RAIRS and XPS are powerful techniques for surface characterization and molecular detection, which do not require a fluorescence labeling of the target. We present a characterization of the spectroscopic IR and XPS features, some of them associated to the phosphate groups of the DNA backbone, as an unambiguous signature of the PNA-DNA heteroduplex formation. The N(1s) XPS core level peak after DNA hybridization is decomposed in curves components, and every component assigned to different chemical species. Therefore, the results obtained by means of two complementary structural characterization techniques encourage the use of PNA-based biosensors for the detection of DNA molecules on natural samples.     

Endogenous ARF6 interacts with Rac1 upon angiotensin II stimulation to regulate membrane ruffling and cell migration

ARF6 and Rac1 are small GTPases known to regulate remodelling of the actin cytoskeleton. Here, we demonstrate that these monomeric G proteins are sequentially activated when HEK 293 cells expressing the angiotensin type 1 receptor (AT(1)R) are stimulated with angiotensin II (Ang II). After receptor activation, ARF6 and Rac1 transiently form a complex. Their association is, at least in part, direct and dependent on the nature of the nucleotide bound to both small G proteins. ARF6-GTP preferentially interacts with Rac1-GDP. AT(1)R expressing HEK293 cells ruffle, form membrane protrusions, and migrate in response to agonist treatment. ARF6, but not ARF1, depletion using small interfering RNAs recapitulates the ruffling and migratory phenotype observed after Ang II treatment. These results suggest that ARF6 depletion or Ang II treatment are functionally equivalent and point to a role for endogenous ARF6 as an inhibitor of Rac1 activity. Taken together, our findings reveal a novel function of endogenously expressed ARF6 and demonstrate that by interacting with Rac1, this small GTPase is a central regulator of the signaling pathways leading to actin remodeling.