Somatic mosaicism: on the road to cancer Fernández, Luis C; Torres, Miguel; Real, Francisco X
Nature reviews. Cancer,
01/2016, Letnik:
16, Številka:
1
Journal Article
Recenzirano
Diversity is the basis of fitness selection. Although the genome of an individual is considered to be largely stable, there is theoretical and experimental evidence--both in model organisms and in ...humans--that genetic mosaicism is the rule rather than the exception. The continuous generation of cell variants, their interactions and selective pressures lead to life-long tissue dynamics. Individuals may thus enjoy 'clonal health', defined as a clonal composition that supports healthy morphology and physiology, or suffer from clonal configurations that promote disease, such as cancer. The contribution of mosaicism to these processes starts during embryonic development. In this Opinion article, we argue that the road to cancer might begin during these early stages.
Abstract
Typical black hole binaries in outburst show spectral states and transitions, characterized by a clear connection between the inflow on to the black hole and outflows from its vicinity. The ...transient stellar mass black hole binary V404 Cyg apparently does not fit in this picture. Its outbursts are characterized by intense flares and intermittent plateau and low-luminosity states, with a dynamical intensity range of several orders of magnitude on time-scales of hours. During the 2015 June–July X-ray outburst a joint Swift and INTEGRAL observing campaign captured V404 Cyg in one of these plateau states. The simultaneous Swift/XRT + INTRGRAL/JEM-X + INTEGRAL/IBIS-ISGRI spectrum is reminiscent of that of obscured/absorbed active galactic nuclei (AGN). It can be modelled as a Comptonization spectrum, heavily absorbed by a partial covering, high column density material (N
H ≈ 1–3 × 1024 cm−2), and a dominant reprocessed component, including a narrow iron Kα line. Such spectral distribution can be produced by a geometrically thick accretion flow able to launch a clumpy outflow, likely responsible for both the high intrinsic absorption and the intense reprocessed emission observed. Similarly to what happens in certain obscured AGN, the low-flux states might not be (solely) related to a decrease in the intrinsic luminosity, but could instead be caused by an almost complete obscuration of the inner accretion flow.
Mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain. Among ...the arsenal of antioxidants and detoxifying enzymes existing in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death. mGSH importance is based not only on its abundance, but also on its versatility to counteract hydrogen peroxide, lipid hydroperoxides, or xenobiotics, mainly as a cofactor of enzymes such as glutathione peroxidase or glutathione-S-transferase (GST). Many death-inducing stimuli interact with mitochondria, causing oxidative stress; in addition, numerous pathologies are characterized by a consistent decrease in mGSH levels, which may sensitize to additional insults. From the evaluation of mGSH influence on different pathologic settings such as hypoxia, ischemia/reperfusion injury, aging, liver diseases, and neurologic disorders, it is becoming evident that it has an important role in the pathophysiology and biomedical strategies aimed to boost mGSH levels.
Summary
Background
Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline ...phosphatase ALP and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long‐term effectiveness of second‐line treatments remains uncertain.
Aims
To evaluate the long‐term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation).
Methods
We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non‐responsive PBC patients (Paris‐II criteria) from Spain and Portugal who received OCA ± fibrates.
Results
Of 255 patients, median follow‐up was 35.1 months (IQR: 20.2–53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE‐PBC and 5‐year UK‐PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension.
Conclusion
Triple therapy was superior in achieving therapeutic goals in UDCA‐nonresponsive PBC. Decompensation was linked to pre‐existing portal hypertension.
Longitudinal, real‐world study on 255 UDCA‐nonresponsive PBC patients (Per Paris II criteria); median follow‐up of 35.1 months (IQR: 20–53). All patients received obeticholic acid (OCA), with 25% receiving later add‐on fibrate treatment (triple therapy). In multivariate analysis, triple therapy outperformed dual therapy across all surrogate biochemical endpoints of outcomes.
Fatty liver disease is one of the most prevalent forms of chronic liver disease that encompasses both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Alcoholic ...steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are intermediate stages of ALD and NAFLD, which can progress to more advanced forms, including cirrhosis and hepatocellular carcinoma. Oxidative stress and particularly alterations in mitochondrial function are thought to play a significant role in both ASH and NASH and recognized to contribute to the generation of reactive oxygen species (ROS), as documented in experimental models. Despite the evidence of ROS generation, the therapeutic efficacy of treatment with antioxidants in patients with fatty liver disease has yielded poor results. Although oxidative stress is considered to be the disequilibrium between ROS and antioxidants, there is evidence that a subtle balance among antioxidants, particularly in mitochondria, is necessary to avoid the generation of ROS and hence oxidative stress. Conclusion: As mitochondria are a major source of ROS, the present review summarizes the role of mitochondrial oxidative stress in ASH and NASH and presents emerging data indicating the need to preserve mitochondrial antioxidant balance as a potential approach for the treatment of human fatty liver disease, which may pave the way for the design of future trials to test the therapeutic role of antioxidants in fatty liver disease.
We summarize evidence indicating that oxidative stress is more than an unbalance between oxidants (ROS) and antioxidants, and that a subtle balance among antioxidants, particularly in mitochondria, is required to prevent the generation of undesirable oxidants and ROS.
Abstract
The black hole (BH) binary V404 Cyg entered the outburst phase in 2015 June after 26 yr of X-ray quiescence, and with its behaviour broke the outburst evolution pattern typical of most BH ...binaries. We observed the entire outburst with the Swift satellite and performed time-resolved spectroscopy of its most active phase, obtaining over a thousand spectra with exposures from tens to hundreds of seconds. All the spectra can be fitted with an absorbed power-law model, which most of the time required the presence of a partial covering. A blueshifted iron-Kα line appears in 10 per cent of the spectra together with the signature of high column densities, and about 20 per cent of the spectra seem to show signatures of reflection. None of the spectra showed the unambiguous presence of soft disc–blackbody emission, while the observed bolometric flux exceeded the Eddington value in 3 per cent of the spectra. Our results can be explained assuming that the inner part of the accretion flow is inflated into a slim disc that both hides the innermost (and brightest) regions of the flow, and produces a cold, clumpy, high-density outflow that introduces the high absorption and fast spectral variability observed. We argue that the BH in V404 Cyg might have been accreting erratically or even continuously at Eddington/super-Eddington rates – thus sustaining a surrounding slim disc – while being partly or completely obscured by the inflated disc and its outflow. Hence, the largest flares produced by the source might not be accretion-driven events, but instead the effects of the unveiling of the extremely bright source hidden within the system.
The effect of Ultra-High Pressure Homogenization (UHPH, 100–300MPa) on the physicochemical properties of oil-in-water emulsions prepared with 4.0% (w/v) of soy protein isolate (SPI) and soybean oil ...(10 and 20%, v/v) was studied and compared to emulsions treated by conventional homogenization (CH, 15MPa). CH emulsions were prepared with non-heated and heated (95°C for 15min) SPI dispersions. Emulsions were characterized by particle size determination with laser diffraction, rheological properties using a rotational rheometer by applying measurements of flow curve and by transmission electron microscopy. The variation on particle size and creaming was assessed by Turbiscan® analysis, and visual observation of the emulsions was also carried out. UHPH emulsions showed much smaller d3.2 values and greater physical stability than CH emulsions. The thermal treatment of SPI prior CH process did not improve physical stability properties. In addition, emulsions containing 20% of oil exhibited greater physical stability compared to emulsions containing 10% of oil. Particularly, UHPH emulsions treated at 100 and 200MPa with 20% of oil were the most stable due to low particle size values (d3.2 and Span), greater viscosity and partial protein denaturation. These results address the physical stability improvement of protein isolate-stabilized emulsions by using the emerging UHPH technology.
•Emulsions were treated by conventional and Ultra-High Pressure Homogenization.•Physicochemical properties of emulsions were studied.•Emulsions treated at 100 and 200MPa with 20% of oil were the most stable.•Physical stability depended on the particle size, rheology, and protein denaturation.
Autophagy is a process that maintains homeostasis during stress, although it also contributes to cell death under specific contexts. Ceramides have emerged as important effectors in the regulation of ...autophagy, mediating the crosstalk with apoptosis. Melatonin induces apoptosis of cancer cells; however, its role in autophagy and ceramide metabolism has yet to be clearly elucidated. This study was aimed to evaluate the effect of melatonin administration on autophagy and ceramide metabolism and its possible link with melatonin‐induced apoptotic cell death in hepatocarcinoma (HCC) cells. Melatonin (2 mm) transiently induced autophagy in HepG2 cells through JNK phosphorylation, characterized by increased Beclin‐1 expression, p62 degradation, and LC3II and LAMP‐2 colocalization, which translated in decreased cell viability. Moreover, ATG5 silencing sensitized HepG2 cells to melatonin‐induced apoptosis, suggesting a dual role of autophagy in cell death. Melatonin enhanced ceramide levels through both de novo synthesis and acid sphingomyelinase (ASMase) stimulation. Serine palmitoyltransferase (SPT) inhibition with myriocin prevented melatonin‐induced autophagy and ASMase inhibition with imipramine‐impaired autophagy flux. However, ASMase inhibition partially protected HepG2 cells against melatonin, while SPT inhibition significantly enhanced cell death. Findings suggest a crosstalk between SPT‐mediated ceramide generation and autophagy in protecting against melatonin, while specific ASMase‐induced ceramide production participates in melatonin‐mediated cell death. Thus, dual blocking of SPT and autophagy emerges as a potential strategy to potentiate the apoptotic effects of melatonin in liver cancer cells.
Remineralization of caries lesions is naturally achieved by salivary ions, and it can be enhanced by external factors or elements such as fluoride. Numerous studies have demonstrated the ...remineralizing efficacy of fluoride therapies as well as the limitations with some groups of the population. Consequently, developing new remineralization therapies to close this gap in efficacy has been a priority for the last 2 decades. In this review, we summarize and briefly discuss some of the latest advances in remineralization therapies. Most new therapies try to enhance the effect of fluoride by adding other potentially active ingredients to the formulation, such as calcium, phosphate, stannous, xylitol, and arginine. Other remineralization strategies have focused on creating remineralizing scaffolds within the lesions (e.g., self-assembling peptides). While several of the new remineralization strategies have progressed significantly in recent years, for most of them, the evidence is still insufficient to assess their true clinical potential.
Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as ...endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)‐containing plasmalogens, expression of glyceronephosphate O‐acyltransferase (Gnpat; the rate‐limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin‐induced depletion of FC transactivated Δ‐6 desaturase by increasing sterol regulatory element‐binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ‐6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator‐activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA‐containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα‐dependent increase in fatty acid oxidation. Gnpat+/– mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. Conclusion: Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416–431).
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