Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

Enhanced lithium depletion in Sun-like stars with orbiting planets

The surface abundance of lithium on the Sun is 140 times less than protosolar, yet the temperature at the base of the surface convective zone is not hot enough to burn Li. A large range of Li abundances in solar type stars of the same age, mass and metallicity is observed, but theoretically difficult to understand. An earlier suggestion that Li is more depleted in stars with planets was weakened by the lack of a proper comparison sample of stars without detected planets. Here we report Li abundances for an unbiased sample of solar-analogue stars with and without detected planets. We find that the planet-bearing stars have less than 1 per cent of the primordial Li abundance, while about 50 per cent of the solar analogues without detected planets have on average 10 times more Li. The presence of planets may increase the amount of mixing and deepen the convective zone to such an extent that the Li can be burned.Comment: 13 pages, 2 figure

Geographic distribution at subspecies resolution level: closely related Rhodopirellula species in European coastal sediments.

Members of the marine genus Rhodopirellula are attached living bacteria and studies based on cultured Rhodopirellula strains suggested that three closely related species R. baltica, 'R. europaea' and 'R. islandica' have a limited geographic distribution in Europe. To address this hypothesis, we developed a nested PCR for a single gene copy detection of a partial acetyl CoA synthetase (acsA) from intertidal sediments collected all around Europe. Furthermore, we performed growth experiments in a range of temperature, salinity and light conditions. A combination of Basic Local Alignment Search Tool (BLAST) and Minimum Entropy Decomposition (MED) was used to analyze the sequences with the aim to explore the geographical distribution of the species and subspecies. MED has been mainly used for the analysis of the 16S rRNA gene and here we propose a protocol for the analysis of protein-coding genes taking into account the degeneracy of the codons and a possible overestimation of functional diversity. The high-resolution analysis revealed differences in the intraspecies community structure in different geographic regions. However, we found all three species present in all regions sampled and in agreement with growth experiments we demonstrated that Rhodopirellula species do not have a limited geographic distribution in Europe

Salvage radiotherapy for patients with PSA relapse after radical prostatectomy: a single institution experience

<p>Abstract</p> <p>Background</p> <p>To assess the efficacy of salvage radiotherapy (RT) for persistent or rising PSA after radical prostatectomy and to determine prognostic factors identifying patients who may benefit from salvage RT.</p> <p>Methods</p> <p>Between 1990 and 2003, 59 patients underwent RT for PSA recurrence after radical prostatectomy. Patients received a median of 66 Gy to the prostate bed with 3D or 2D RT. The main end point was biochemical failure after salvage RT, defined as an increase of the serum PSA value >0.2 ng/ml confirmed by a second elevation.</p> <p>Results</p> <p>Median follow-up was 38 months. The 3-year and 5-year bDFS rates were 56.1% and 41.2% respectively. According to multivariate analysis, only preRT PSA ≥1 ng/ml was associated with biochemical relapse.</p> <p>Conclusion</p> <p>When delivered early, RT is an effective treatment after radical prostatectomy. Only preRT PSA ≥1 ng/ml predicted relapse.</p

Notch Signaling Regulates Late-Stage Epidermal Differentiation and Maintains Postnatal Hair Cycle Homeostasis

Notch signaling involves ligand-receptor interactions through direct cell-cell contact. Multiple Notch receptors and ligands are expressed in the epidermis and hair follicles during embryonic development and the adult stage. Although Notch signaling plays an important role in regulating differentiation of the epidermis and hair follicles, it remains unclear how Notch signaling participates in late-stage epidermal differentiation and postnatal hair cycle homeostasis.We applied Cre/loxP system to generate conditional gene targeted mice that allow inactivation of critical components of Notch signaling pathway in the skin. Rbpj, the core component of all four Notch receptors, and Pofut1, an essential factor for ligand-receptor interactions, were inactivated in hair follicle lineages and suprabasal layer of the epidermis using the Tgfb3-Cre mouse line. Rbpj conditional inactivation resulted in granular parakeratosis and reactive epidermal hyperplasia. Pofut1 conditional inactivation led to ultrastructural abnormalities in the granular layer and altered filaggrin processing in the epidermis, suggesting a perturbation of the granular layer differentiation. Disruption of Pofut1 in hair follicle lineages resulted in aberrant telogen morphology, a decrease of bulge stem cell markers, and a concomitant increase of K14-positive keratinocytes in the isthmus of mutant hair follicles. Pofut1-deficent hair follicles displayed a delay in anagen re-entry and dysregulation of proliferation and apoptosis during the hair cycle transition. Moreover, increased DNA double stand breaks were detected in Pofut1-deficent hair follicles, and real time PCR analyses on bulge keratinocytes isolated by FACS revealed an induction of DNA damage response and a paucity of DNA repair machinery in mutant bulge keratinocytes.our data reveal a role for Notch signaling in regulating late-stage epidermal differentiation. Notch signaling is required for postnatal hair cycle homeostasis by maintaining proper proliferation and differentiation of hair follicle stem cells

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies

p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus

Background: Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings: We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett’s esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions: The results of this study suggest the environment of the esophagus in BE patients can both generate an

A formally verified abstract account of Gödel's incompleteness theorems

We present an abstract development of Gödel’s incompleteness theorems, performed with the help of the Isabelle/HOL theorem prover. We analyze sufficient conditions for the theorems’ applicability to a partially specified logic. In addition to the usual benefits of generality, our abstract perspective enables a comparison between alternative approaches from the literature. These include Rosser’s variation of the first theorem, Jeroslow’s variation of the second theorem, and the S ́wierczkowski–Paulson semantics-based approach. As part of our framework’s validation, we upgrade Paulson’s Isabelle proof to produce a mech- anization of the second theorem that does not assume soundness in the standard model, and in fact does not rely on any notion of model or semantic interpretation