Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and A

Scalar GW detection with a hollow spherical antenna

We study the response and cross sections for the absorption of GW energy in a Jordan-Brans-Dicke theory by a resonant mass detector shaped as a hollow sphere.Comment: latex file, 9 page

Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer.

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function. Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner. Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC

Chadilauquen and Neicorehue, two lake settlements with ceramics in the northeast of the dry pampa

Se presentan los resultados del estudio de artefactos líticos y cerámicos hallados en las márgenes de las lagunas Chadilauquen y Neicorehue (departamento Realico, La Pampa). Dado que los materiales fueron recuperados de superficie y carecen de resolución estratigráfica, para su análisis se aplicaron múltiples líneas de indagación interdisciplinaria: arqueológica, geológica, geomorfológica, petrográfica y tafonómica. Según el tipo de materia prima de los artefactos líticos se infieren las potenciales fuentes de aprovisionamiento, ya identificadas por otros investigadores en áreas aledañas. Respecto de la cerámica, se dan a conocer fechados AMS obtenidos a partir de la medición de fracciones del carbono identificado en los residuos orgánicos incluidos en la pasta. Los rangos temporales, los datos petrográficos y la impresión de cestería en la base de algunos tiestos, permiten comparar con hallazgos similares registrados en sitios arqueológicos de Santa Fe, Córdoba, San Luis y Mendoza. La integración de diferentes abordajes proporciona información significativa de los conjuntos arqueológicos de superficie recuperados en ambos sitios.The results obtained from the study of lithic and ceramic artifacts recovered on the edge of the Chadilauquen and Neicorehue lagoons (Department Realico, La Pampa) are presented. They are surface materials lacking stratigraphic resolution and for their analysis were applied multiple interdisciplinary lines of inquiry: archaeological, geological, petrographic, geomorphological and taphonomic. According to the type of raw material of the lithic artifacts, the potential sources of supply are inferred, already identified by other researchers in neighboring areas. Regarding ceramics, AMS dates obtained from measurements of the carbon contained in the samples are disclosed. The temporality range, the petrographic data and the impress of basketry in the recipient bases allow the comparison with findings recorded in archaeological sites of Santa Fe, Córdoba, San Luis and Mendoza. The integration of different approaches provides meaningful information of the archaeological surface collections that was recovered at both sites.Sociedad Argentina de Antropologí

Detecting Determinism in High Dimensional Chaotic Systems

A method based upon the statistical evaluation of the differentiability of the measure along the trajectory is used to identify in high dimensional systems. The results show that the method is suitable for discriminating stochastic from deterministic systems even if the dimension of the latter is as high as 13. The method is shown to succeed in identifying determinism in electro-encephalogram signals simulated by means of a high dimensional system.Comment: 8 pages (RevTeX 3 style), 5 EPS figures, submitted to Phys. Rev. E (25 apr 2001

Correlated Persistent Tunneling Currents in Glasses

Low temperature properties of glasses are derived within a generalized tunneling model, considering the motion of charged particles on a closed path in a double-well potential. The presence of a magnetic induction field B violates the time reversal invariance due to the Aharonov-Bohm phase, and leads to flux periodic energy levels. At low temperature, this effect is shown to be strongly enhanced by dipole-dipole and elastic interactions between tunneling systems and becomes measurable. Thus, the recently observed strong sensitivity of the electric permittivity to weak magnetic fields can be explained. In addition, superimposed oscillations as a function of the magnetic field are predicted.Comment: 4 page

Brazilian consensus meeting on stem cell transplantation: hemoglobinopathies comittee

Os distúrbios hereditários das hemoglobinas são as doenças genéticas mais frequentes do homem e mais difundidas no mundo, abrangendo sobretudo continentes como África, Américas, Europa e extensas regiões da Ásia. Estima-se que haja 270 milhões de portadores de hemoglobinopatias no mundo, dos quais 80 milhões são portadores de talassemia. Aproximadamente 60 mil crianças nascem anualmente no mundo com talassemia e 250 mil com anemia falciforme, dando uma frequência de 2,4 crianças afetadas para cada 1.000 nascimentos. No Brasil, a doenca falciforme é a doença hereditária monogênica mais comum, estimando-se que haja entre 20 a 30 mil pacientes portadores desta doenca. O transplante de células-tronco hematopoéticas alogênico (TCTH alo) é atualmente a única modalidade terapêutica capaz de curar pacientes com hemoglobinopatias. Neste artigo discutiremos os dados disponíveis na literatura e sugerimos os critérios para a indicação do TCTH nas hemoglobinopatias.Hemoglobinopathies are the most prevalent genetic diseases in man. Most cases are described in Europe, Africa and in the Americas. About 270 million hemoglobinopathy carriers are alive today with 80 million being carriers of thalassemia. We estimate that, throughout the world, about 60,000 children are born annually with thalassemia and 250,000 with sickle cell disease with an estimated frequency of 2.4 children in every 1000 births. Sickle cell disease is the most common monogenic hereditary disease in Brazil with a total of from 20,000 to 30,000 patients. Allogeneic stem cell transplantation is the only curative approach. Here we describe published data and propose criteria to indicate stem cell transplantation in thalassemia and sickle cell disease patients

Using Topological Statistics to Detect Determinism in Time Series

Statistical differentiability of the measure along the reconstructed trajectory is a good candidate to quantify determinism in time series. The procedure is based upon a formula that explicitly shows the sensitivity of the measure to stochasticity. Numerical results for partially surrogated time series and series derived from several stochastic models, illustrate the usefulness of the method proposed here. The method is shown to work also for high--dimensional systems and experimental time seriesComment: 23 RevTeX pages, 14 eps figures. To appear in Physical Review

Training Regulation-Based and Entrepreneurship-Based Approaches in Teaching Technology and Livelihood Education (TLE) Exploratory Courses in the K to 12 Program at Leyte Normal University

In education, there is a continuing search for methods, strategies, techniques and approaches that can best meet today’s challenges. The study sought to determine the appropriateness of the teaching approaches in TLE exploratory courses. These teaching approaches are the Entrepreneurial-based teaching approach and training regulations- based teaching approach. A Fish-bowl selection method was used in the study. Fifty (50) Integrated Laboratory School (ILS) pupils of grades 7 and 8 were the respondents including four (4) TLE teachers.  Four (4) themes emerged to contribute in the preference between the two teaching approaches.  These are the geographic location, family background, studying experiences and academic performance. The results further revealed that for the students it does not matter what specific approach is used as long as they enjoyed and fun during the class.