Interplay between base excision repair protein XRCC1 and ALDH2 predicts overall survival in lung and liver cancer patients.

Background To deliver efficacious personalised cancer treatment, it is essential to characterise the cellular metabolism as well as the genetic stability of individual tumours. In this study, we describe a new axis between DNA repair and detoxification of aldehyde derivatives with important implications for patient prognosis and treatment.Methods Western blot and qPCR analyses were performed in relevant non-transformed and cancer cell lines from lung and liver tissue origin in combination with bioinformatics data mining of The Cancer Genome Atlas database from lung and hepatocellular cancer patients.Results Using both biochemical and bioinformatics approaches, we revealed an association between the levels of expression of the aldehyde detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) and the key DNA base excision repair protein XRCC1. Across cancer types, we found that if one of the corresponding genes exhibits a low expression level, the level of the other gene is increased. Surprisingly, we found that low ALDH2 expression levels associated with high XRCC1 expression levels are indicative for a poor overall survival, particularly in lung and liver cancer patients. In addition, we found that Mithramycin A, a XRCC1 expression inhibitor, efficiently kills cancer cells expressing low levels of ALDH2.Conclusions Our data suggest that lung and liver cancers require efficient single-strand break repair for their growth in order to benefit from a low aldehyde detoxification metabolism. We also propose that the ratio of XRCC1 and ALDH2 levels may serve as a useful prognostic tool in these cancer types

A prospective clinical trial on the influence of a triamcinolone/demeclocycline and a calcium hydroxide based temporary cement on pain perception

<p>Abstract</p> <p>Introduction</p> <p>The aim of this clinical trial was to compare the degree of short term post-operative irritation after application of a triamcinolone/demeclocycyline based or a calcium hydroxide based provisional cement.</p> <p>Methods</p> <p>A total of 109 patients (55 female and 54 male; mean age: 51 ± 14 years) with primary or secondary dentinal caries were randomly assigned to the two treatment groups of this biomedical clinical trial (phase III). Selection criteria were good systemic health and treated teeth, which were vital and showed no symptoms of pulpitis. Up to three teeth were prepared for indirect metallic restorations, and the provisional restorations were cemented with a triamcinolone/demeclocycyline (Ledermix) or a calcium hydroxide (Provicol) based material. The intensity of post-operative pain experienced was documented according to the VAS (4, 12, 20, 24, and 82 h) and compared to VAS baseline.</p> <p>Results</p> <p>A total of 159 teeth were treated (Ledermix: 83 teeth, Provicol: 76 teeth). The minor irritation of the teeth, experienced prior to treatment, was similar in both groups; however, 4 h after treatment this value was significantly higher in the Provicol group than in the Ledermix group (p < 0.005, t-test). After 12 h, the difference was no longer significant. The number of patients taking analgesics for post-treatment pain was higher in the Provicol group (n = 11/53) than in the Ledermix group (n = 3/56).</p> <p>Conclusions</p> <p>The patients had no long term post-operative pain experience in both groups. However, within the first hours after cementation the sensation of pain was considerably higher in the Provicol group than in the Ledermix group.</p

Impact of physical activity level and dietary fat content on passive overconsumption of energy in non-obese adults

Background: Passive overconsumption is the increase in energy intake driven by the high-fat energy-dense food environment. This can be explained in part because dietary fat has a weaker effect on satiation (i.e. process that terminates feeding). Habitually active individuals show improved satiety (i.e. process involved in post-meal suppression of hunger) but any improvement in satiation is unknown. Here we examined whether habitual physical activity mitigates passive overconsumption through enhanced satiation in response to a high-fat meal. Methods: Twenty-one non-obese individuals with high levels of physical activity (HiPA) and 19 individuals with low levels of physical activity (LoPA) matched for body mass index (mean = 22.8 kg/m2) were recruited. Passive overconsumption was assessed by comparing ad libitum energy intake from covertly manipulated high-fat (HFAT; 50% fat) or high-carbohydrate (HCHO; 70% carbohydrate) meals in a randomized crossover design. Habitual physical activity was assessed using SenseWear accelerometers (SWA). Body composition, resting metabolic rate, eating behaviour traits, fasting appetite-related peptides and hedonic food reward were also measured. Results: In the whole sample, passive overconsumption was observed with greater energy intake at HFAT compared to HCHO (p  0.05). SWA confirmed that HiPA were more active than LoPA (p  0.05 for all). Conclusions: Non-obese individuals with high or low physical activity levels but matched for BMI showed similar susceptibility to passive overconsumption when consuming an ad libitum high-fat compared to a high-carbohydrate meal. This occurred despite increased total daily energy expenditure and improved body composition in HiPA. Greater differences in body composition and/or physical activity levels may be required to impact on satiation

Phylogeography of a successful aerial disperser: the golden orb spider Nephila on Indian Ocean islands

Abstract Background The origin and diversification patterns of lineages across the Indian Ocean islands are varied due to the interplay of the complex geographic and geologic island histories, the varying dispersal abilities of biotas, and the proximity to major continental landmasses. Our aim was to reconstruct phylogeographic history of the giant orbweaving spider (Nephila) on western Indian Ocean islands (Madagascar, Mayotte, Réunion, Mauritius, Rodrigues), to test its origin and route of dispersal, and to examine the consequences of good dispersal abilities for colonization and diversification, in comparison with related spiders (Nephilengys) inhabiting the same islands, and with other organisms known for over water dispersal. We used mitochondrial (COI) and nuclear (ITS2) markers to examine phylogenetic and population genetic patterns in Nephila populations and species. We employed Bayesian and parsimony methods to reconstruct phylogenies and haplotype networks, respectively, and calculated genetic distances, fixation indices, and estimated clade ages under a relaxed clock model. Results Our results suggest an African origin of Madagascar Nephila inaurata populations via Cenozoic dispersal, and the colonization of the Mascarene islands from Madagascar. We find evidence of gene flow across Madagascar and Comoros. The Mascarene islands share a common 'ancestral' COI haplotype closely related to those found on Madagascar, but itself absent, or as yet unsampled, from Madagascar. Each island has one or more unique haplotypes related to the ancestral Mascarene haplotype. The Indian Ocean N. inaurata are genetically distinct from the African populations. Conclusions Nephila spiders colonized Madagascar from Africa about 2.5 (0.6-5.3) Ma. Our results are consistent with subsequent, recent and rapid, colonization of all three Mascarene islands. On each island, however, we detected unique haplotypes, consistent with a limited gene flow among the islands subsequent to colonization, a scenario that might be referred to as speciation in progress. However, due to relatively small sample sizes, we cannot rule out that we simply failed to collect Mascarene haplotypes on Madagascar, a scenario that might imply human mediated dispersal. Nonetheless, the former interpretation better fits the available data and results in a pattern similar to the related Nephilengys. Nephilengys, however, shows higher genetic divergences with diversification on more remote islands. That the better disperser of the two lineages, Nephila, has colonized more islands but failed to diversify, demonstrates how dispersal ability can shape both the patterns of colonization and formation of species across archipelagos.</p

Diabetes mellitus in dogs attending UK primary-care practices: frequency, risk factors and survival

Background: Diabetes mellitus (DM) is an important endocrine disorder of dogs. The objectives of this study were to estimate prevalence and incidence of DM in dogs, and to explore risk factors for DM and the survival of DM cases in primary-care clinics in the UK. Results: A case-control study nested in the cohort of dogs (n = 480,469) aged ≥3 years presenting at 430 VetCompass clinics was used to identify risk factors for DM, using multivariable logistic regression. Overall 409 new and 863 pre-existing DM cases (total 1272) were identified in 2016, giving an apparent annual prevalence of 0.26% (95% confidence interval (CI): 0.25–0.28%), and an annual incidence risk of 0.09% (95%CI: 0.08–0.09%) in dogs aged ≥3 years. Factors associated with increased odds for DM diagnosis were all age categories > 8 years, female entire dogs (odds ratio (OR): 3.03, 95% CI 1.69–5.44, p < 0.001) and male neutered dogs (OR: 1.99, 95% CI 1.18–3.34, p = 0.010) compared to male entire dogs, Border Terriers (OR: 3.37, 95% CI 1.04–10.98, p = 0.043) and West Highland White Terriers (WHWT) (OR: 2.88, 95% CI 1.49–5.56, p = 0.002) compared to crossbreeds. Dogs that had received previous glucocorticoid treatment (OR: 2.19, 95% CI 1.02–4.70, p = 0.044) and those with concurrent conditions (documented obese, pancreatitis, hyperadrenocorticism) also had increased odds for DM diagnosis. Cox regression modelling was used to evaluate factors associated with survival in the 409 incident DM cases in 2016. Increased hazard of death following diagnosis of DM was shown in dogs that were ≥ 10 years age, Cocker Spaniels (HR: 2.06, 95% CI 1.06–4.01, p = 0.034) compared to crossbreeds, had a blood glucose (BG) level at diagnosis > 40 mmol/L (HR: 2.73, 95% CI 1.35–5.55, p = 0.005) compared to < 20 mmol/L at diagnosis, or had received previous glucocorticoid treatment (HR: 1.86, 95% CI 1.21–2.86, p = 0.005). Dogs at reduced hazard of death included neutered dogs (HR: 0.58, 95% CI 0.42–0.79, p = 0.001), Border Collies (HR: 0.39, 95% CI 0.17–0.87, p = 0.022) and those starting insulin treatment (HR: 0.08 95% CI 0.05–0.12, p < 0.001). Conclusions: Certain breeds and concurrent health conditions are associated with an increased risk of DM. In addition to certain signalment factors, a high BG level at diagnosis and prior glucocorticoid treatment were adversely associated with survival of dogs with DM. Keywords: Diabetes mellitus, Risk factors, Survival, Case-control study, Benchmarking, VetCompas

Maintaining and breaking symmetry in homomeric coiled-coil assemblies

Higher order coiled coils with five or more helices can form α-helical barrels. Here the authors show that placing β-branched aliphatic residues along the lumen yields stable and open α-helical barrels, which is of interest for the rational design of functional proteins; whereas, the absence of β-branched side chains leads to unusual low-symmetry α-helical bundles

DNase Sda1 Allows Invasive M1T1 Group A Streptococcus to Prevent TLR9-Dependent Recognition

Group A Streptococcus (GAS) has developed a broad arsenal of virulence factors that serve to circumvent host defense mechanisms. The virulence factor DNase Sda1 of the hyperinvasive M1T1 GAS clone degrades DNA-based neutrophil extracellular traps allowing GAS to escape extracellular killing. TLR9 is activated by unmethylated CpG-rich bacterial DNA and enhances innate immune resistance. We hypothesized that Sda1 degradation of bacterial DNA could alter TLR9-mediated recognition of GAS by host innate immune cells. We tested this hypothesis using a dual approach: loss and gain of function of DNase in isogenic GAS strains and presence and absence of TLR9 in the host. Either DNA degradation by Sda1 or host deficiency of TLR9 prevented GAS induced IFN-α and TNF-α secretion from murine macrophages and contributed to bacterial survival. Similarly, in a murine necrotizing fasciitis model, IFN-α and TNF-α levels were significantly decreased in wild type mice infected with GAS expressing Sda1, whereas no such Sda1-dependent effect was seen in a TLR9-deficient background. Thus GAS Sda1 suppressed both the TLR9-mediated innate immune response and macrophage bactericidal activity. Our results demonstrate a novel mechanism of bacterial innate immune evasion based on autodegradation of CpG-rich DNA by a bacterial DNase

Mice lacking endoglin in macrophages show an impaired immune response

24 p.-9 fig.-1 tab. Ojeda Fernández, Luisa et al.Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-OslerWeber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of endoglin in macrophages in vivo, an endoglin myeloid lineage specific knock-out mouse line (Engfl/flLysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Engfl/flLysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in endoglin deficient peritoneal macrophages. Overall, the altered immune activity of endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients.This work was funded by: Ministerio de Economía y Competitividad of Spain (SAF2011-23475 to LMB; SAF2013-43421-R and SAF2010- 19222 to CB.Peer reviewe