PTHrP Induces Autocrine/Paracrine Proliferation of Bone Tumor Cells through Inhibition of Apoptosis

Giant Cell Tumor of Bone (GCT) is an aggressive skeletal tumor characterized by local bone destruction, high recurrence rates and metastatic potential. Previous work in our lab has shown that the neoplastic cell of GCT is a proliferating pre-osteoblastic stromal cell in which the transcription factor Runx2 plays a role in regulating protein expression. One of the proteins expressed by these cells is parathryroid hormone-related protein (PTHrP). The objectives of this study were to determine the role played by PTHrP in GCT of bone with a focus on cell proliferation and apoptosis. Primary stromal cell cultures from 5 patients with GCT of bone and one lung metastsis were used for cell-based experiments. Control cell lines included a renal cell carcinoma (RCC) cell line and a human fetal osteoblast cell line. Cells were exposed to optimized concentrations of a PTHrP neutralizing antibody and were analyzed with the use of cell proliferation and apoptosis assays including mitochondrial dehydrogenase assays, crystal violet assays, APO-1 ELISAs, caspase activity assays, flow cytometry and immunofluorescent immunohistochemistry. Neutralization of PTHrP in the cell environment inhibited cell proliferation in a consistent manner and induced apoptosis in the GCT stromal cells, with the exception of those obtained from a lung metastasis. Cell cycle progression was not significantly affected by PTHrP neutralization. These findings indicate that PTHrP plays an autocrine/paracrine neoplastic role in GCT by allowing the proliferating stromal cells to evade apoptosis, possibly through non-traditional caspase-independent pathways. Thus PTHrP neutralizing immunotherapy is an intriguing potential therapeutic strategy for this tumor

Analytical model for the calculation of lateral velocity distributions in potential cross-sections

[EN] The hydraulic modeling of water depth and flow velocities in open channel flows that were fitted by power-law cross-section stand out for their versatility, allowing their use in numerous practical applications, both in natural and artificial channels. The determination of the hydraulic variables of depth and average velocity has been widely studied in potential cross-sections; however, the variation seen in these variables along the cross-section was not found in the literature. Knowledge of this variation allows the development of studies (e.g. to know the approximate damage in different areas of the cross-section, to analyse sediment transport, or other applications in river hydraulics). This paper presents a methodology which allows calculation of the hydraulic variables in any area of a power-law cross-section. The methodology is applied to symmetrical cross-sections, comparing its generated results with the obtained values by different computational hydraulic codes, which are thoroughly accepted by scientific community, such as CES, HEC-RAS and IBER. The obtained predictions of hydraulic parameters (using the explicit formulation described in this research) present very low errors when compared with results of other models, with great computational cost. These errors reach a root mean square error (RMSE) of 0.13 and 0.05 in the determination of velocities' lateral distribution and the ratio between velocity and average velocity. These values indicate a very successful validation for the analysed symmetrical sections.[ES] La modelización hidráulica de calados y velocidades de flujo, en cauces con secciones que admiten una representación de tipo potencial, se destaca por su versatilidad, permitiendo su utilización en numerosas aplicaciones prácticas tanto en canales naturales como artificiales. El cálculo de las variables hidráulicas (calado y velocidad media) ha sido ampliamente estudiado para este tipo de secciones. Sin embargo, en la literatura técnica no se han encontrado estudios que muestren la variación de estas magnitudes a lo largo de la sección transversal. El conocimiento de esta variación permite desarrollar estudios (ejemplo: conocer de manera aproximada los daños en diferentes zonas de la sección, analizar el transporte de sedimentos, estudiar los procesos de erosión u otras aplicaciones en hidráulica fluvial). Presentamos una metodología que permite el cálculo de las variables hidráulicas en cualquier zona de una sección tipo potencial. La metodología es aplicada a secciones simétricas, comparando los resultados generados con los obtenidos por diferentes códigos hidráulicos computacionales ampliamente aceptados por la comunidad científica (p-e- CES, HECRAS e IBER). Las predicciones de los parámetros hidráulicos obtenidas (usando la formulación explícita descrita en este artículo) presentan errores muy bajos, en comparación con otros modelos con mayor costo computacional. Estos errores alcanzan un valor promedio para la raíz del error cuadrático medio (RMSE) en el cálculo de la distribución lateral de velocidades de 0.13 y de 0.05, en el cálculo de la relación de velocidades respecto a la velocidad media. Estos valores indican una validación muy satisfactoria para las secciones simétricas analizadas.Sánchez-Romero, F.; Pérez-Sánchez, M.; López Jiménez, PA. (2018). Modelo analítico para el cálculo de distribuciones de velocidad laterales en secciones tipo potencial-ley. RIBAGUA - Revista Iberoamericana del Agua. 5(1):29-47. doi:10.1080/23863781.2018.1442189S29475

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m2 and grade 2 in two, one who received a cumulative dose of 960 mg m2 and the other a cumulative dose of 600 mg m2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated

Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at s√=8 TeV with ATLAS

Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of s√=8 TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) − 2.9 + 3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations

Evidence for the Higgs-boson Yukawa coupling to tau leptons with the ATLAS detector

Results of a search for H → τ τ decays are presented, based on the full set of proton-proton collision data recorded by the ATLAS experiment at the LHC during 2011 and 2012. The data correspond to integrated luminosities of 4.5 fb−1 and 20.3 fb−1 at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV respectively. All combinations of leptonic (τ → `νν¯ with ` = e, µ) and hadronic (τ → hadrons ν) tau decays are considered. An excess of events over the expected background from other Standard Model processes is found with an observed (expected) significance of 4.5 (3.4) standard deviations. This excess provides evidence for the direct coupling of the recently discovered Higgs boson to fermions. The measured signal strength, normalised to the Standard Model expectation, of µ = 1.43 +0.43 −0.37 is consistent with the predicted Yukawa coupling strength in the Standard Model

The genetic architecture of low-temperature adaptation in the wine yeast Saccharomyces cerevisiae

[Background] Low-temperature growth and fermentation of wine yeast can enhance wine aroma and make them highly desirable traits for the industry. Elucidating response to cold in Saccharomyces cerevisiae is, therefore, of paramount importance to select or genetically improve new wine strains. As most enological traits of industrial importance in yeasts, adaptation to low temperature is a polygenic trait regulated by many interacting loci.[Results] In order to unravel the genetic determinants of low-temperature fermentation, we mapped quantitative trait loci (QTLs) by bulk segregant analyses in the F13 offspring of two Saccharomyces cerevisiae industrial strains with divergent performance at low temperature. We detected four genomic regions involved in the adaptation at low temperature, three of them located in the subtelomeric regions (chromosomes XIII, XV and XVI) and one in the chromosome XIV. The QTL analysis revealed that subtelomeric regions play a key role in defining individual variation, which emphasizes the importance of these regions’ adaptive nature.[Conclusions] The reciprocal hemizygosity analysis (RHA), run to validate the genes involved in low-temperature fermentation, showed that genetic variation in mitochondrial proteins, maintenance of correct asymmetry and distribution of phospholipid in the plasma membrane are key determinants of low-temperature adaptation.This work has been financially supported from the Spanish Government through MINECO and FEDER funds (AGL2013-47300-C3-3-R and PCIN-2015-143 grants) and from Generalitat Valenciana through PROMETEOII/2014/042 grant, awarded to JMG. This study has been carried out in the context of the European Project ERA-IB “YeastTempTation” EGR thanks the Spanish government for an FPI grant BES-2011-044498 and MM also thanks the Generalitat Valenciana for a VALi+d ACIF/2015/194 grant. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Searches for the Zγ decay mode of the Higgs boson and for new high-mass resonances in pp collisions at √s=13 TeV with the ATLAS detector

This article presents searches for the Zγ decay of the Higgs boson and for narrow high-mass resonances decaying to Zγ, exploiting Z boson decays to pairs of electrons or muons. The data analysis uses 36.1 fb−1 of pp collisions at √s=13 recorded by the ATLAS detector at the CERN Large Hadron Collider. The data are found to be consistent with the expected Standard Model background. The observed (expected — assuming Standard Model pp → H → Zγ production and decay) upper limit on the production cross section times the branching ratio for pp → H → Zγ is 6.6. (5.2) times the Standard Model prediction at the 95% confidence level for a Higgs boson mass of 125.09 GeV. In addition, upper limits are set on the production cross section times the branching ratio as a function of the mass of a narrow resonance between 250 GeV and 2.4 TeV, assuming spin-0 resonances produced via gluon-gluon fusion, and spin-2 resonances produced via gluon-gluon or quark-antiquark initial states. For high-mass spin-0 resonances, the observed (expected) limits vary between 88 fb (61 fb) and 2.8 fb (2.7 fb) for the mass range from 250 GeV to 2.4 TeV at the 95% confidence level

Search for a high-mass Higgs boson decaying to a W boson pair in pp collisions at √s = 8 TeV with the ATLAS detector

A search for a high-mass Higgs boson H is performed in the H → WW → ℓνℓν and H → WW → ℓνqq decay channels using pp collision data corresponding to an integrated luminosity of 20.3 fb−¹ collected at √s = 8 TeV by the ATLAS detector at the Large Hadron Collider. No evidence of a high-mass Higgs boson is found. Limits on σH × BR(H → WW) as a function of the Higgs boson mass mH are determined in three different scenarios: one in which the heavy Higgs boson has a narrow width compared to the experimental resolution, one for a width increasing with the boson mass and modeled by the complex-pole scheme following the same behavior as in the Standard Model, and one for intermediate widths. The upper range of the search is mH = 1500 GeV for the narrow-width scenario and mH = 1000 GeV for the other two scenarios. The lower edge of the search range is 200–300 GeV and depends on the analysis channel and search scenario. For each signal interpretation, individual and combined limits from the two WW decay channels are presented. At mH = 1500 GeV, the highest-mass point tested, σH × BR(H → WW) for a narrow-width Higgs boson is constrained to be less than 22 fb and 6.6 fb at 95% CL for the gluon fusion and vector-boson fusion production modes, respectively