Sestrins as a therapeutic bridge between ROS and autophagy in cancer

The regulation of Reactive Oxygen Species (ROS) levels and the contribution therein from networks regulating cell metabolism, such as autophagy and the mTOR-dependent nutrient-sensing pathway, constitute major targets for selective therapeutic intervention against several types of tumors, due to their extensive rewiring in cancer cells as compared to healthy cells. Here, we discuss the sestrin family of proteins-homeostatic transducers of oxidative stress, and drivers of antioxidant and metabolic adaptation-as emerging targets for pharmacological intervention. These adaptive regulators lie at the intersection of those two priority nodes of interest in antitumor intervention-ROS control and the regulation of cell metabolism and autophagy-therefore, they hold the potential not only for the development of completely novel compounds, but also for leveraging on synergistic strategies with current options for tumor therapy and classification/stadiation to achieve personalized medicine

Interplay between ROS and Autophagy in Cancer and Aging: From Molecular Mechanisms to Novel Therapeutic Approaches

[no abstract available

Canonical DNA minor groove insertion of bisbenzamidine-Ru(ii) complexes with chiral selectivity

We report the first Ru(ii) coordination compounds that interact with DNA through a canonical minor groove insertion mode and with selectivity for A/T rich sites. This was made possible by integrating a bis-benzamidine minor groove DNA-binding agent with a ruthenium(ii) complex. Importantly, one of the enantiomers (Δ-[Ru(bpy)2b4bpy]2+, Δ-4Ru) shows a considerably higher DNA affinity than the parent organic ligand and the other enantiomer, particularly for the AATT sequence, while the other enantiomer preferentially targets long AAATTT sites with overall lower affinity. Finally, we demonstrate that the photophysical properties of these new binders can be exploited for DNA cleavage using visible light

A fast and efficient protocol for small RNA extraction in Japanese plum and other Prunus species

Background: Small ribonucleic acids represent an important repertoire of mobile molecules that exert key roles in several cell processes including antiviral defense. Small RNA based repertoire includes both small interfering RNA (siRNA) and microRNA (miRNA) molecules. In the Prunus genus, sharka disease, caused by the Plum pox virus (PPV), first occurred on European plum ( Prunus domestica ) and then spread over among all species in this genus and thus classified as quarantine pathogen. Next-generation sequencing (NGS) was used for the study of siRNA/miRNA molecules; however, NGS relies on adequate extraction protocols. Currently, knowledge of PPV-Prunus interactions in terms of siRNA populations and miRNA species is still scarce, and siRNA/miRNA extraction protocols are limited to species such as peach, almond, and sweet cherry. Results: We describe a reliable procedure for siRNA/miRNA purification from Prunus salicina trees, in which previously used protocols did not allow adequate purification. The procedure was based on a combination of commercially available RNA purification kits and specific steps that yielded high quality purifications. The resulting molecules were adequate for library construction and NGS, leading to the development of a pipeline for analysis of both siRNAs and miRNAs in the PPV\u2013P. salicina interactions. Results showed that PPV infection led to altered siRNA profiles in Japanese plum as characterized by decreased 24-nt and increased 21- and 22-nt siRNAs. Infections showed miR164 and miR160 generation and increased miR166, miR171, miR168, miR319, miR157, and miR159. Conclusion:We propose this protocol as a reliable and reproducible small RNA isolation procedure for P. salicina and other Prunus species

Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

<p><b>Background</b> Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.</p> <p><b>Methods</b> We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.</p> <p><b>Results</b> Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02).</p> <p><b>Conclusion</b> Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.</p&gt

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

J/ψ\rm{J}/\psi production at low transverse momentum in p+p and d+Au collisions at sNN\sqrt{s_{NN}} = 200 GeV

We report on the measurement of $\rm{J}/\psi$ production in the dielectron channel at mid-rapidity (|y|<1) in p+p and d+Au collisions at $\sqrt{s_{NN}}$ = 200 GeV from the STAR experiment at the Relativistic Heavy Ion Collider. The transverse momentum $p_{T}$ spectra in p+p for $p_{T}$ < 4 GeV/c and d+Au collisions for $p_{T}$ < 3 GeV/c are presented. These measurements extend the STAR coverage for $\rm{J}/\psi$ production in p+p collisions to low $p_{T}$. The $$ from the measured $\rm{J}/\psi$ invariant cross section in p+p and d+Au collisions are evaluated and compared to similar measurements at other collision energies. The nuclear modification factor for $\rm{J}/\psi$ is extracted as a function of $p_{T}$ and collision centrality in d+Au and compared to model calculations using the modified nuclear Parton Distribution Function and a final-state $\rm{J}/\psi$ nuclear absorption cross section

Observation of Z production in proton-lead collisions at LHCb

The first observation of Z boson production in proton-lead collisions at a centre-of-mass energy per proton-nucleon pair of root(s) N N = 5TeV is presented. The data sample corresponds to an integrated luminosity of 1.6 nb(-1) collected with the LHCb detector. The Z candidates are reconstructed from pairs of oppositely charged muons with pseudorapidities between 2.0 and 4.5 and transverse momenta above 20 GeV/c. The invariant dimuon mass is restricted to the range 60-120 GeV/c. The Z production cross-section is measured to be sigma(Z ->mu+mu-) (fwd) = 13.5(-4.0)(+5.4)(stat.) +/- 1.2(syst.) nb in the direction of the proton beam and sigma(Z ->mu+mu-) (bwd) = 10.7(-5.1)(+8.4)(stat.) +/- 1.0(syst.) nb in the direction of the lead beam, where the first uncertainty is statistical and the second systematic

Measurement of the Bs0→J/ψK∗0B^0_s\rightarrow J/\psi K^{*0} branching fraction and angular amplitudes

A search for the decay $B^0_s\rightarrow J/\psi K^{*0}$ with $K^{*0} \rightarrow K^-\pi^+$ is performed with 0.37 fb$^{-1}$ of $pp$ collisions at $\sqrt{s}$ = 7 TeV collected by the LHCb experiment, finding a \Bs \to J\psi K^-\pi^+ peak of $114 \pm 11$ signal events. The $K^-\pi^+$ mass spectrum of the candidates in the $B^0_s$ peak is dominated by the $K^{*0}$ contribution. Subtracting the non-resonant $K^-\pi^+$ component, the branching fraction of \BsJpsiKst is $(4.4_{-0.4}^{+0.5} \pm 0.8) \times 10^{-5}$, where the first uncertainty is statistical and the second systematic. A fit to the angular distribution of the decay products yields the \Kst polarization fractions $f_L = 0.50 \pm 0.08 \pm 0.02$ and $f_{||} = 0.19^{+0.10}_{-0.08} \pm 0.02$