Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1:a novel anticancer small-molecule

Restoration of the p53 pathway, namely by reactivation of mutant (mut) p53, represents a valuable anticancer strategy. Herein, we report the identification of the enantiopure tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a novel reactivator of wild-type (wt) and mut p53, using a yeast-based screening strategy. SLMP53-1 has a p53-dependent anti-proliferative activity in human wt and mut p53R280K-expressing tumor cells. Additionally, SLMP53-1 enhances p53 transcriptional activity and restores wt-like DNA binding ability to mut p53R280K. In wt/mut p53-expressing tumor cells, SLMP53-1 triggers p53 transcription-dependent and mitochondrial apoptotic pathways involving BAX, and wt/mut p53 mitochondrial translocation. SLMP53-1 inhibits the migration of wt/mut p53-expressing tumor cells, and it shows promising p53-dependent synergistic effects with conventional chemotherapeutics. In xenograft mice models, SLMP53-1 inhibits the growth of wt/mut p53-expressing tumors, but not of p53-null tumors, without apparent toxicity. Collectively, besides the potential use of SLMP53-1 as anticancer drug, the tryptophanol-derived oxazoloisoindolinone scaffold represents a promissing starting point for the development of effective p53-reactivating drugs

Measuring Black Hole Spin using X-ray Reflection Spectroscopy

I review the current status of X-ray reflection (a.k.a. broad iron line) based black hole spin measurements. This is a powerful technique that allows us to measure robust black hole spins across the mass range, from the stellar-mass black holes in X-ray binaries to the supermassive black holes in active galactic nuclei. After describing the basic assumptions of this approach, I lay out the detailed methodology focusing on "best practices" that have been found necessary to obtain robust results. Reflecting my own biases, this review is slanted towards a discussion of supermassive black hole (SMBH) spin in active galactic nuclei (AGN). Pulling together all of the available XMM-Newton and Suzaku results from the literature that satisfy objective quality control criteria, it is clear that a large fraction of SMBHs are rapidly-spinning, although there are tentative hints of a more slowly spinning population at high (M>5*10^7Msun) and low (M<2*10^6Msun) mass. I also engage in a brief review of the spins of stellar-mass black holes in X-ray binaries. In general, reflection-based and continuum-fitting based spin measures are in agreement, although there remain two objects (GROJ1655-40 and 4U1543-475) for which that is not true. I end this review by discussing the exciting frontier of relativistic reverberation, particularly the discovery of broad iron line reverberation in XMM-Newton data for the Seyfert galaxies NGC4151, NGC7314 and MCG-5-23-16. As well as confirming the basic paradigm of relativistic disk reflection, this detection of reverberation demonstrates that future large-area X-ray observatories such as LOFT will make tremendous progress in studies of strong gravity using relativistic reverberation in AGN.Comment: 19 pages. To appear in proceedings of the ISSI-Bern workshop on "The Physics of Accretion onto Black Holes" (8-12 Oct 2012). Revised version adds a missing source to Table 1 and Fig.6 (IRAS13224-3809) and corrects the referencing of the discovery of soft lags in 1H0707-495 (which were in fact first reported in Fabian et al. 2009

Nucleation and growth of biomimetic apatite layers on 3D plotted biodegradable polymeric scaffolds : effect of static and dynamic coating conditions

Apatite layers were grown on the surface of newly developed starch/polycaprolactone (SPCL)-based scaffolds by a 3D plotting technology. To produce the biomimetic coatings, a sodium silicate gel was used as nucleating agent, followed by immersion in a simulated body fluid (SBF) solution. After growing a stable apatite layer for 7 days, the scaffolds were placed in SBF under static, agitated (80 strokes min!1) and circulating flow perfusion (Q = 4 ml min!1; tR = 15 s) for up to 14 days. The materials were characterized by scanning electron microscopy/energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy and thin-film X-ray diffraction. Cross-sections were obtained and the coating thickness was measured. The elemental composition of solution and coatings was monitored by inductively coupled plasma spectroscopy. After only 6 h of immersion in SBF it was possible to observe the formation of small nuclei of an amorphous calcium phosphate (ACP) layer. After subsequent SBF immersion from 7 to 14 days under static, agitated and circulating flow perfusion conditions, these layers grew into bone-like nanocrystalline carbonated apatites covering each scaffold fiber without compromising its initial morphology. No differences in the apatite composition/chemical structure were detectable between the coating conditions. In case of flow perfusion, the coating thickness was significantly higher. This condition, besides mimicking better the biological milieu, allowed for the coating of complex architectures at higher rates, which can greatly reduce the coating step.The authors acknowledge the Portuguese Foundation for Science and Technology (PhD grant to A.L.O., SFRH/BD/10956/2002 and post-doctoral Grant to R.A.S., SFRH/BPD/17151/2004, under the POCTI Program). This work was partially supported by FCT through POCTI and/or FEDER programmes and also partially supported by the EU Project HIPPOCRATES (NMP3-CT-2003-505758) and EXPERTISSUES (NMP-CT-2004-500283)

Proteins and their peptide motifs in acellular apatite mineralization of scaffolds for tissue engineering

Many proteins in the inorganic=organic matrix of bone induce or modulate or inhibit mineralization of apatite in vivo. Many attempts have been made to mimic and understand this mechanism as part of bone formation, and ectopic mineralization and control thereof. Many attempts have also been made to use such proteins or protein fragments to harness their potential for improved mineralization. Such proteins and peptide motifs have also been the inspiration for attempts of making mimics of their structures and motifs using chemical or biological synthesis. The aim of this review is to highlight how proteins and (poly)peptides themselves impact mineralization in the human body, and how those could be used and have been used for improving apatite mineralization, for example, on or in materials that by themselves do not induce apatite mineralization but otherwise have interesting properties for use as bone tissue engineering scaffolds.J. Benesch wishes to acknowledge the financial support from FCT, postdoctoral fellowship scholarship SFRH/BPD/17584/2004. This work was carried out under the scope of the European Union NoE EXPERTISSUES (NMP3-CT-2004500283) and partially funded by the European Union FP6 STREP Project HIPPOCRATES (NMP3-CT-2003-505758) and FCT project ProteoLight (PTDC/FIS/68517/2006)

Crossover and self-averaging in the two-dimensional site-diluted Ising model

Using the newly proposed probability-changing cluster (PCC) Monte Carlo algorithm, we simulate the two-dimensional (2D) site-diluted Ising model. Since we can tune the critical point of each random sample automatically with the PCC algorithm, we succeed in studying the sample-dependent $T_c(L)$ and the sample average of physical quantities at each $T_c(L)$ systematically. Using the finite-size scaling (FSS) analysis for $T_c(L)$, we discuss the importance of corrections to FSS both in the strong-dilution and weak-dilution regions. The critical phenomena of the 2D site-diluted Ising model are shown to be controlled by the pure fixed point. The crossover from the percolation fixed point to the pure Ising fixed point with the system size is explicitly demonstrated by the study of the Binder parameter. We also study the distribution of critical temperature $T_c(L)$. Its variance shows the power-law $L$ dependence, $L^{-n}$, and the estimate of the exponent $n$ is consistent with the prediction of Aharony and Harris [Phys. Rev. Lett. {\bf 77}, 3700 (1996)]. Calculating the relative variance of critical magnetization at the sample-dependent $T_c(L)$, we show that the 2D site-diluted Ising model exhibits weak self-averaging.Comment: 6 pages including 6 eps figures, RevTeX, to appear in Phys. Rev.

Scaling and finte-size-scaling in the two dimensional random-coupling Ising ferromagnet

It is shown by Monte Carlo method that the finite size scaling (FSS) holds in the two dimensional random-coupled Ising ferromagnet. It is also demonstrated that the form of universal FSS function constructed via novel FSS scheme depends on the strength of the random coupling for strongly disordered cases. Monte Carlo measurements of thermodynamic (infinite volume limit) data of the correlation length ($\xi$) up to $\xi \simeq 200$ along with measurements of the fourth order cumulant ratio (Binder's ratio) at criticality are reported and analyzed in view of two competing scenarios. It is demonstrated that the data are almost exclusively consistent with the scenario of weak universality.Comment: 9 pages, 4figuer

Ising model on 3D random lattices: A Monte Carlo study

We report single-cluster Monte Carlo simulations of the Ising model on three-dimensional Poissonian random lattices with up to 128,000 approx. 503 sites which are linked together according to the Voronoi/Delaunay prescription. For each lattice size quenched averages are performed over 96 realizations. By using reweighting techniques and finite-size scaling analyses we investigate the critical properties of the model in the close vicinity of the phase transition point. Our random lattice data provide strong evidence that, for the available system sizes, the resulting effective critical exponents are indistinguishable from recent high-precision estimates obtained in Monte Carlo studies of the Ising model and \phi^4 field theory on three-dimensional regular cubic lattices.Comment: 35 pages, LaTex, 8 tables, 8 postscript figure

An overview of jets and outflows in stellar mass black holes

In this book chapter, we will briefly review the current empirical understanding of the relation between accretion state and and outflows in accreting stellar mass black holes. The focus will be on the empirical connections between X-ray states and relativistic (`radio') jets, although we are now also able to draw accretion disc winds into the picture in a systematic way. We will furthermore consider the latest attempts to measure/order jet power, and to compare it to other (potentially) measurable quantities, most importantly black hole spin.Comment: Accepted for publication in Space Science Reviews. Also to appear in the Space Sciences Series of ISSI - The Physics of Accretion on to Black Holes (Springer Publisher

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types