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Why is an energy metabolic defect the common outcome in BMFS?
No full textInherited bone marrow failure syndromes (BMFS) are rare, distressing, inherited blood disorders of children. Although the genetic origin of these pathologies involves genes with different functions, all are associated with progressive haematopoietic impairment and an excessive risk of malignancies. Defects in energy metabolism induce oxidative stress, impaired energy production and an unbalanced ratio between ATP and AMP. This assumes an important role in self-renewal and differentiation in haematopoietic stem cells (HSC) and can play an important role in bone marrow failure. Defects in energetic/respiratory metabolism, in particular in FA and SDS cells, have been described recently and seem to be a pertinent argument in the discussion of the haematopoietic defect in BMFS, as an alternative to the hypotheses already established on this subject, which may shed new light on the evolution of these diseases
Aerobic metabolism dysfunction as one of the links between Fanconi anemia-deficient pathway and the aggressive cell invasion in head and neck cancer cells
No full textNew Insights and Perspectives in Fanconi Anemia Research
No full textFanconi anemia is a rare, cancer-prone disease with mutations in 22 genes. The primary defect results in altered DNA repair mechanisms that fuel a severe proinflammatory condition in the bone marrow, leading to cellular depletion of the hematopoietic system and eventually to bone marrow failure. During the past three decades, a plethora of dysfunctions have been highlighted in the Fanconi anemia phenotype, but recent research allows us to glimpse an even more complex scenario where defective lipid metabolism could have important consequences in hematopoietic stem cell differentiation
Mutated FANCA Gene Role in the Modulation of Energy Metabolism and Mitochondrial Dynamics in Head and Neck Squamous Cell Carcinoma
No full textFanconi Anaemia (FA) is a rare recessive genetic disorder characterized by a defective DNA repair mechanism. Although aplastic anaemia is the principal clinical sign in FA, patients develop a head and neck squamous cell carcinoma (HNSCC) with a frequency 500–700 folds higher than the general population, which appears more aggressive, with survival of under two years. Since FA gene mutations are also associated with a defect in the aerobic metabolism and an increased oxidative stress accumulation, this work aims to evaluate the effect of FANCA mutation on the energy metabolism and the relative mitochondrial quality control pathways in an HNSCC cellular model. Energy metabolism and cellular antioxidant capacities were evaluated by oximetric, luminometric, and spectrophotometric assays. The dynamics of the mitochondrial network, the quality of mitophagy and autophagy, and DNA double-strand damage were analysed by Western blot analysis. Data show that the HNSCC cellular model carrying the FANCA gene mutation displays an altered electron transport between respiratory Complexes I and III that does not depend on the OxPhos protein expression. Moreover, FANCA HNSCC cells show an imbalance between fusion and fission processes and alterations in autophagy and mitophagy pathways. Together, all these alterations associated with the FANCA gene mutation cause cellular energy depletion and a metabolic switch to glycolysis, exacerbating the Warburg effect in HNSCC cells and increasing the growth rate. In addition, the altered DNA repair due to the FANCA mutation causes a higher accumulation of DNA damage in the HNSCC cellular model. In conclusion, changes in energy metabolism and mitochondrial dynamics could explain the strict correlation between HNSCC and FA genes, helping to identify new therapeutic targets
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Altered Calcium and Red-ox homeostasis underline defective haematopoiesis in Fanconi Anemia.
No full textDysregulated Ca2+ homeostasis in Fanconi anemia cells
No full textFanconi Anemia (FA) is a rare and complex inherited blood disorder associated with bone marrow failure and malignancies. Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio. These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology. Due to the importance of the intracellular calcium signaling and its key function in the control of intracellular functions we were interested to study calcium homeostasis in FA. We found that FANCA cells display a dramatically low intracellular calcium concentration ([Ca(2+)]i) in resting conditions. This condition affects cellular responses to stress. The flux of Ca(2+) mobilized by H2O2 from internal stores is significantly lower in FANCA cells in comparison to controls. The low basal [Ca(2+)]i in FANCA appears to be an actively maintained process controlled by a finely tuned interplay between different intracellular Ca(2+) stores. The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis
Normality ranges of urine oxidative stress markers (8-OHdG and isoprostane) in Italian people free from respiratory diseases-Preliminary results
Full text linkBACKGROUND: The study of oxidative stress (OxS) is becoming increasingly important in
respiratory disease research. To our knowledge, the reference ranges of urinary
8-hydroxy-deoxy-guanosine (8-OHdG) and 8-isoprostane (isoprostane), a DNA and a lipid oxidation product
respectively, have not yet been determined in subjects without respiratory diseases. AIM: To assess the
reference range of OxS markers in Italian people aged 20-64 free from respiratory diseases (controls).
METHODS: 8-OHdG and isoprostane were measured in spot-urine samples collected in the frame of
Gene-Environment Interactions in Respiratory Diseases (GEIRD) study, a nested multi-case control survey.
The biomarkers levels were corrected on creatinine concentration. Only controls (n=239) were considered
for the aim of this work. The possible effects of potential determinants on OxS-biomarkers were studied
before determining the normality range in selected subgroups of controls. Multiple linear regression was
fitted to data using the logarithm of 8OHdG or isoprostane as dependent variables and sex, age, season,
smoke, body mass index, as covariates. The appropriate percentiles were calculated. RESULTS: Both
8OHdG and isoprostane concentrations were significantly higher in smokers than in non smokers (p=0.025
and 0.047 respectively), while the other covariates did not influence OxS. The 95% 8OHdG normality range
in non smokers varied from 0.26 to 25.94 ng/mg. The 95% isoprostane reference interval was 0.03 -5.42
ng/mg in non smokers. CONCLUSION: Provisional 95% normality range for urinary 8OHdG and isoprostane
were determined in subjects free from respiratory diseases
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