Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia

Purpose: Aberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established. Experimental design: We compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative. Results: Dual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2. Conclusions: Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes

The mirror-neuron system and observational learning: Implications for the effectiveness of dynamic visualizations.

Van Gog, T., Paas, F., Marcus, N., Ayres, P., & Sweller, J. (2009). The mirror-neuron system and observational learning: Implications for the effectiveness of dynamic visualizations. Educational Psychology Review, 21, 21-30.Learning by observing and imitating others, has long been recognized as constituting a powerful learning strategy for humans. Recent findings from neuroscience research, more specifically, on the mirror-neuron system, begin to provide insight into the neural bases of learning by observation and imitation. These findings are discussed here, along with their potential consequences for the design of instruction, focusing in particular on the effectiveness of dynamic vs. static visualizations

The mirror-neuron system and observational learning: Implications for the effectiveness of dynamic visualizations.

Learning by observing and imitating others, has long been recognized as constituting a powerful learning strategy for humans. Recent findings from neuroscience research, more specifically, on the mirror-neuron system, begin to provide insight into the neural bases of learning by observation and imitation. These findings are discussed here, along with their potential consequences for the design of instruction, focusing in particular on the effectiveness of dynamic vs. static visualizations

Manual de procesos constructivos para pavimentos de carreteras de concreto hidráulico utilizando la pista Larreynaga (tramo mercado Mayoreo-Villa Dignidad)como modelo

Dicho documento se basa en la prolongación, Pista Larreynaga (Mercado Mayoreo - Villa Dignidad) construk]a de concreto hidráulico con el fin de implementar un manual de procesos constructivos para pavimentos de carreteras de concreto hidráulico, para que los futuros profesionales del área de la construcción a sii vez como los maestros, tengan al alcance de manera comprensible y clara un documento el cual les facilite y les brinde la información necesaria para seguir paso a paso de manera segura y precisa lo que es la construcción de carreteras de concreto hidráulico. Ya que este método se ha implementado cada vez más por la municipalidad de Managua, dentro de la capital y en diferentes departamentos con el fin de tener mejores vías de transporte con mayores capacidades, beneficios con un ahorro considerabLe en mantenimiento cada año. Este método de construcción brinda mayores beneficios, ya que tiene una vida útil mayor que la del astarto y no ne"ita de revestimiento ni sello de baches a causa del desgaste por el clima y el paso vehicular. Estos beneficios se darán siempre y cuando se sigan al pie de la letra las normas de construcción para la cual ki pista fue diseñada, a su vez de las notas generales de construcción que requiere para una construcción satisfactoria que cumpla con su objetivo, proporcionar mejores pistas para el usuario.Toda actividad, tiene un manual con los pasos a seguir y no cometer ningún tipo de errores, sin embargo hay que estar preparados para cada inconveniente o imprevisto que se presente durante la actividad. Este manual nos dará una gran ventaja para un mejor estudio o practica del lector, siguiendo paso a paso como debe de construirse una carretera de ooncrsto hidráulico, mostnando sus beneficios y los posibles imprevistos que se den dentro de la misma, que de inmediato deben de tomarse precauciones y solucionar lo más pronto posible. Por tanto este documento aborda las normas, especificaciones, ventajas,clasificación, diseño, concepto de lo que es el concreto hidráulico y como utilizarle correctamente para una buena construcción y así que esta cumpla con su objetivo para la cual fue diseñada

Urinary protein/creatinine ratio versus 24-hour proteinuria in the evaluation of lupus nephritis

INTRODUCTION: The urinary protein/creatinine ratio has been used instead of 24-hour proteinuria in Nephrology practice for the follow-up of glomerular diseases, considering the advantages of collection and the low cost. However, there are still doubts as to its applicability both for an isolated evaluation and for the follow-up of patients with lupus nephritis. OBJECTIVE: To evaluate 24-hour proteinuria determinations and random urine samples, performing urinary creatinine correction and urinary protein/creatinine ratio in subjects with lupus nephritis. METHODS: 24-hour proteinuria and urinary protein/creatinine ratio were determined by conventional methods (automated Pyrogallol for proteinuria and alkaline picrate for creatinine). RESULTS: Seventy-eight urine samples of 41 patients diagnosed with systemic lupus erythematosus, according to the American Rheumatology Association, with lupus nephritis, were analyzed, and a good correlation between 24-hour proteinuria and urinary protein/creatinine ratio (r = 0.9010 and r² = 0.813) was observed. However, a poor correlation between random proteinuria (without creatinine correction) versus 24-hour proteinuria (r = 0.635 and r² = 0.403) or versus urinary protein/creatinine ratio (r = 0.754 and r² = 0.569) was seen. CONCLUSION: 24-hour proteinuria and urinary protein/creatinine ratio were useful in the follow-up of each case. However, we observed that the absolute values were different, which did not allow the replacement of one for the other during follow-up, especially when this result is used to define the activity of the disease. Based on these results, we suggest a period of intersection from one to the other (two to three determinations by both methods), and the choice of one marker for proteinuria follow-up, if necessary.INTRODUÇÃO: Tem-se defendido a utilização do índice urinário proteína e creatinina em substituição à determinação de proteinúria de 24 horas para acompanhamento de doenças glomerulares, considerando-se as vantagens de maior facilidade na coleta e o menor custo. Entretanto, há dúvidas quanto à pertinência de usar este índice tanto numa avaliação isolada como no seguimento de pacientes com nefrite lúpica. OBJETIVO: Avaliar as determinações de proteinúria de 24 horas e proteinúria em amostra isolada de urina, fazendo a correção pela creatinina urinária, relação proteinúria/creatininúria, em indivíduos com nefrite lúpica. MÉTODOS: Determinações de proteinúria de 24 horas e relação proteinúria/creatininúria por métodos convencionais (Pirogalol automatizado para proteinúria e picrato alcalino para creatinina). RESULTADOS: Foram comparadas 78 amostras de urina de 41 pacientes com diagnóstico de lúpus eritematoso sistêmico, segundo os critérios da Associação Americana de Reumatologia, com nefrite lúpica, constatando-se uma boa correlação entre proteinúria de 24 horas e relação proteinúria/creatininúria (r = 0,9010 e r² = 0,813). Não se observou, entretanto, uma boa correlação entre proteinúria em amostra isolada (sem correção pela creatinina urinária) versus aquela de 24 horas (r = 0,635 e r² = 0,403) ou versus relação proteinúria/creatininúria (r = 0,754 e r² = 0,569). CONCLUSÃO: Os marcadores de proteinúria de 24 horas e relação proteinúria/creatininúria isoladamente mostraram-se úteis no acompanhamento de cada caso. Porém, observou-se que os seus valores absolutos são diferentes, não possibilitando a substituição de um pelo outro ao longo do seguimento, particularmente quando este resultado é usado para definição de atividade da doença. Se necessário, sugere-se um período de intersecção (duas a três determinações pelos dois métodos) para mudança de um para outro e escolha de um único marcador preferencial para seguimento da proteinúria.Universidade Federal de São Paulo (UNIFESP) Setor de GlomerulopatiasHospital do Rim Laboratório CentralUNIFESP Setor de Glomerulopatias Laboratório de Glomerulopatias e Imunopatologia RenalUNIFESP, Setor de GlomerulopatiasUNIFESP, Setor de Glomerulopatias Laboratório de Glomerulopatias e Imunopatologia RenalSciEL

Intervertebral disc microbiome in Modic changes: Lack of result replication underscores the need for a consensus in low-biomass microbiome analysis

INTRODUCTION The emerging field of the disc microbiome challenges traditional views of disc sterility, which opens new avenues for novel clinical insights. However, the lack of methodological consensus in disc microbiome studies introduces discrepancies. The aims of this study were to (1) compare the disc microbiome of non-Modic (nonMC), Modic type 1 change (MC1), and MC2 discs to findings from prior disc microbiome studies, and (2) investigate if discrepancies to prior studies can be explained with bioinformatic variations. METHODS Sequencing of 16S rRNA in 70 discs (24 nonMC, 25 MC1, and 21 MC2) for microbiome profiling. The experimental setup included buffer contamination controls and was performed under aseptic conditions. Methodology and results were contrasted with previous disc microbiome studies. Critical bioinformatic steps that were different in our best-practice approach and previous disc microbiome studies (taxonomic lineage assignment, prevalence cut-off) were varied and their effect on results were compared. RESULTS There was limited overlap of results with a previous study on MC disc microbiome. No bacterial genera were shared using the same bioinformatic parameters. Taxonomic lineage assignment using "amplicon sequencing variants" was more sensitive and detected 48 genera compared to 22 with "operational taxonomic units" (previous study). Increasing filter cut-off from 4% to 50% (previous study) reduced genera from 48 to 4 genera. Despite these differences, both studies observed dysbiosis with an increased abundance of gram-negative bacteria in MC discs as well as a lower beta-diversity. Cutibacterium was persistently detected in all groups independent of the bioinformatic approach, emphasizing its prevalence. CONCLUSION There is dysbiosis in MC discs. Bioinformatic parameters impact results yet cannot explain the different findings from this and a previous study. Therefore, discrepancies are likely caused by different sample preparations or true biologic differences. Harmonized protocols are required to advance understanding of the disc microbiome and its clinical implications

Spatial and Temporal Variations of Microplastics within Humboldt Bay, California

This study aimed to quantify microplastic (MP) concentration and analyze the spatial and temporal variabilities of the concentrations during the tidal cycle in Humboldt Bay, California. To get an approximation of MP concentration, both water and sediment samples were taken at five different stations, twice during one tidal cycle. Sampling was conducted during two different cruises, on the 19th and 21st of September 2020. The samples were processed in the lab using a density separation procedure and filtration. MP concentrations in the different samples were determined using an average optical microscopy count. Comparison of the water column MP concentrations during ebb and flood tides shows higher concentrations during flood tide, 49.0 particles/L ± 32.37 (flood) vs 34.4 particles/L ± 16.32 (ebb), indicating that MPs are brought into Humboldt Bay from the ocean. The comparison of the MP concentrations during lower energy and higher energy conditions indicates that concentrations in the water column were elevated when there was greater tidal kinetic energy, approximated by the covariance of the measured velocity in North Bay Channel. This result was assumed to be caused by the strong tidal currents stirring up both sediments and the settled MPs into the water column. Due to lower tidal kinetic energy on the sediment sampling cruise day, we could not confirm that assumption. Water samples indicated that MPs are heterogeneously distributed in the bay, with higher concentrations found near the Entrance Channel and lower concentrations found further north in the bay. Sediment samples also indicate a heterogeneous distribution of MPs in the bay, with the lowest concentrations near the Entrance Channel, 15 particles/kg, where high tidal currents inhibit settling of particles