•ATM-defective LCLs are hypersensitive to KBrO3 in terms of chromosomal damage.•PARP modulates KBrO3-induced chromosomal aberrations in ATM-defective LCLs.•Different mutations in AT patients are ...equally sensitive to oxidative DNA damage.
The ataxia telangiectasia mutated (ATM) protein is a pivotal multifunctional protein kinase predominantly involved in DNA damage response, as well as in maintaining overall functional integrity of the cells. Apart from playing its major role in regulating the cellular response to DNA damage, ATM, when mutated, can additionally determine oxidative stress, metabolic syndrome, mitochondrial dysfunction and neurodegeneration.
In the present paper we aim to investigate the levels of oxidative stress potentially induced by the oxidizing rodent renal carcinogen KBrO3 in ATM-defective lymphoblastoid cell lines (LCLs) established from four classical AT patients (with different ATM mutations), one AT variant with reduced hypersensitivity to X rays, obligate AT heterozygotes and wild type intrafamilial control. A possible modulatory involvement of PARP in potentially induced oxidative stress is also evaluated following its inhibition with 3-aminobenzamide (3-AB).
Treatments with KBrO3 clearly showed a marked hypersensitivity of the ATM-defective LCLs, including the AT variant. A marked and statistically significant reduction of KBrO3-induced chromosomal damage following inhibition of PARP by 3-AB, was observed in all AT LCLs, but not in those from the AT variant, AT heterozygotes and wild type intrafamilial control. This result is suggestive of a modulatory involvement of PARP in the hypersensitivity of ATM-defective cells to DNA oxidative damage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The sea urchin
Paracentrotus lividus
is common in the Mediterranean Sea in shallow subtidal rocky habitats, and it is intensely harvested for commercial and recreational purposes. This study is aimed ...at investigating whether the effects of harvest restrictions of
P. lividus
in rocky reef habitats interact with the accessibility of locations in structuring sea urchin population (total and commercial-sized individuals). These results are important for generating hypotheses about the influence of human harvesting on
P. lividus
and for addressing suitable measures of conservation.
Paracentrotus lividus
was sampled after the end of the sea urchin harvesting period (May–July 2007) within the Gulf of Alghero (North West Sardinia), where the Capo Caccia–Isola Piana Marine Protected Area (MPA) was established since 2002.
Paracentrotus lividus
was sampled at sixteen locations and attributed in groups of four to 4 combinations of harvest restrictions (Restricted Harvest, RH, vs. Unlimited Harvest, UH) and accessibility (Boat vs. Car), which correspond to a gradient of potential human activity on
P. lividus
in the ranked order of very low (RHBoatfar), low (RHBoatclose), moderate (RHCar) and high (UHCar). At each location, two depth ranges of 3–7 and 8–12 m were considered. At each of these depths, two areas of about 100-m
2
size were chosen. The density of
P. lividus
was assessed in ten quadrats of 1 × 1 m, and the size of 100 individuals (test diameter) was considered. Human activity has been found to significantly affect population structure of
P. lividus
influencing the proportion of individuals larger than 50 mm. Although harvest was restricted by MPA regulations, a significantly lower abundance of large individuals was found at sites accessible by car. This result highlights that there is an effect of harvest restrictions in relation to accessibility and emphasizes the need to carefully address the enforcement of the MPA toward easily accessible sites. Thus, surveillance and investment in enforcement of marine reserves seem crucial points that may provide the greatest return on maintaining the ecological benefits to the fishery activities.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
It is well known that interferon-α (IFN-α), used for long time as the main therapy for HCV-related disease, induces thyroid alterations, but the impact of the new direct-acting antivirals ...(DAAs) on thyroid is not established. Aim of this prospective study was to evaluate if DAAs therapy may induce thyroid alterations.
Methods
A total of 113 HCV patients, subdivided at the time of the enrollment in naïve group (
n
= 64) and in IFN-α group (
n
= 49) previously treated with pegylated interferon-α and ribavirin, were evaluated for thyroid function and autoimmunity before and after 20–32 weeks of DAAs.
Results
Before starting DAAs, a total of 8/113 (7.1%) patients showed Hashimoto's thyroiditis (HT) all belonging to IFN-α group (8/49, 16.3%), while no HT cases were found in the naïve group. Overall, 7/113 (6.2%) patients were hypothyroid: 3/64 (4.7%) belonging to naïve group and 4/49 (8.2%) to IFN-α group. Furthermore, a total of 8/113 patients (7.1%) showed subclinical hyperthyroidism: 2/64 (3.1%) were from naïve group and 6/49 (12.2%) from IFN-α group. Interestingly, after DAAs therapy, no new cases of HT, hypothyroidism and hyperthyroidism was found in all series, while 6/11 (54.5%) patients with non-autoimmune subclinical thyroid dysfunction became euthyroid. Finally, the only association between viral genotypes and thyroid alterations was genotype 1 and hypothyroidism.
Conclusions
This study supports evidence that DAAs have a limited or missing influence on thyroid in patients with HCV-related diseases. Moreover, it provides preliminary evidence that subclinical non-autoimmune thyroid dysfunction may improve after HCV infection resolution obtained by DAAs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background. It has been shown in the very recent literature that human walking generates rhythmic motor patterns with hidden time harmonic structures that are represented (at the subject’s ...comfortable speed) by the occurrence of the golden ratio as the the ratio of the durations of specific walking gait subphases. Such harmonic proportions may be affected—partially or even totally destroyed—by several neurological and/or systemic disorders, thus drastically reducing the smooth, graceful, and melodic flow of movements and altering gait self-similarities. Aim. In this paper we aim at, preliminarily, showing the reliability of a technologically assisted methodology—performed with an easy to use wearable motion capture system—for the evaluation of motion abilities in Ataxia-Telangiectasia (AT), a rare infantile onset neurodegenerative disorder, whose typical neurological manifestations include progressive gait unbalance and the disturbance of motor coordination. Methods. Such an experimental methodology relies, for the first time, on the most recent accurate and objective outcome measures of gait recursivity and harmonicity and symmetry and double support subphase consistency, applied to three AT patients with different ranges of AT severity. Results. The quantification of the level of the distortions of harmonic temporal proportions is shown to include the qualitative evaluations of the three AT patients provided by clinicians. Conclusions. Easy to use wearable motion capture systems might be used to evaluate AT motion abilities through recursivity and harmonicity and symmetry (quantitative) outcome measures.
Grain sorghum (
) is a gluten-free cereal grown around the world and is a food staple in semi-arid and subtropical regions. Sorghum is a diverse crop with a range of pericarp colour including white, ...various shades of red, and black, all of which show health-promoting properties as they are rich sources of antioxidants such as polyphenols, carotenoids, as well as micro- and macro-nutrients. This work examined the grain composition of three sorghum varieties possessing a range of pericarp colours (white, red, and black) grown in the Mediterranean region. To determine the nutritional quality independent of the contributions of phenolics, mineral and fatty acid content and composition were measured. Minor differences in both protein and carbohydrate were observed among varieties, and a higher fibre content was found in both the red and black varieties. A higher amount of total saturated fats was found in the white variety, while the black variety had a lower amount of total unsaturated and polyunsaturated fats than either the white or red varieties. Oleic, linoleic, and palmitic were the primary fatty acids in all three analysed sorghum varieties. Significant differences in mineral content were found among the samples with a greater amount of Mg, K, Al, Mn, Fe, Ni, Zn, Pb and U in both red and black than the white sorghum variety. The results show that sorghum whole grain flour made from grain with varying pericarp colours contains unique nutritional properties.
The ATM protein, encoded by the gene responsible for the human genetic disorder ataxia telangiectasia (A-T), regulates several cellular responses to DNA breaks. ATM shares a phosphoinositide ...3-kinase-related domain with several proteins, some of them protein kinases. A wortmannin-sensitive protein kinase activity was associated with endogenous or recombinant ATM and was abolished by structural ATM mutations. In vitro substrates included the translation repressor PHAS-I and the p53 protein. ATM phosphorylated p53 in vitro on a single residue, serine-15, which is phosphorylated in vivo in response to DNA damage. This activity was markedly enhanced within minutes after treatment of cells with a radiomimetic drug; the total amount of ATM remained unchanged. Various damage-induced responses may be activated by enhancement of the protein kinase activity of ATM.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Summary
Nucleos(t)ide analogues (NAs) and peginterferon have complementary effects in chronic hepatitis B, but it is unclear whether combination therapy improves responses in genotype D‐infected ...patients. We conducted an open‐label study of peginterferon alfa‐2a 180 μg/wk added to ongoing NA therapy in hepatitis B e antigen (HBeAg)‐negative, genotype D‐infected patients with hepatitis B virus DNA <20 IU/mL. The primary endpoint was proportion of patients with ≥50% decline in serum HBsAg by the end of the 48‐week add‐on phase. Seventy patients received treatment, 11 were withdrawn at week 24 for no decrease in HBsAg, and 14 withdrew for other reasons. Response rate (per‐protocol population) was 67.4% (29/43) at week 48 (95% confidence interval CI: 51, 81) and 50.9% (28/55) at week 96 (95% CI: 38, 66). Median serum HBsAg decreased throughout peginterferon alfa‐2a treatment and was significantly lower than baseline at weeks 48, 72 and 96 (P < 0.001). Decreases in HBsAg of ≥0.5‐log10 and ≥1‐log10 were documented in 19 (44.2%) and 6 (14.0%) patients at week 48 and 6 (10.9%) and 17 (30.9%) patients at week 96. The proportion of patients with HBsAg <1000, <500, <100 and <10 IU/mL at ≥1 timepoint during treatment was 78.6% (n = 44), 57.1% (n = 32), 21.4% (n = 12) and 7.1% (n = 4). Interferon gamma‐induced protein 10 increased from baseline up to week 48, with week 12 levels significantly associated with response at week 48. Addition of peginterferon alfa‐2a to ongoing NA therapy significantly decreased HBsAg levels in HBeAg‐negative patients with genotype D infection (ClinicalTrials.gov NCT01706575).
In this open‐label study in patients with genotype D, HBeAg‐negative chronic hepatitis B receiving nucleos(t)ide analogue therapy and with HBV DNA <20 IU/mL, peginterferon alfa‐2a add‐on therapy reduced HBsAg levels, with 29/43 (67.4%) patients having a >50% decline in HBsAg at week 48. An increase in Interferon gamma‐induced protein 10 from baseline up to week 48 was significantly associated with response.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing ...concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled-NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription-stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53-independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof-of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The cells of an ataxia-oculomotor apraxia type 1 (AOA1) patient, homozygous for a new aprataxin mutation (T739C), were treated with camptothecin, an inhibitor of DNA topoisomerase I which induces DNA ...single-strand breaks. DNA damage was evaluated by cytogenetic analysis of chromosomal aberrations. The results obtained showed marked and dose-related increases in induced chromosomal aberrations in the patient and her heterozygous mother compared to the intrafamilial wild-type control. The alkaline comet assay confirmed this pattern. Moreover, the AOA1 cells did not show hypersensitivity to ionizing radiation, i.e. X-rays. These findings clearly indicate the direct involvement of aprataxin in the DNA single-strand-break repair machinery.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
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