45 research outputs found

    Use of an automated, integrated laboratory environment to enable predictive modeling approaches for identifying critical process parameters and controlling key quality attributes

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    An essential part of ensuring a high quality medicine is being able to reliably control Critical Quality Attributes (CQA’s). In the cell culture process, bioreactor conditions, feeds, cell state are some of the many variables that affect CQA’s. Out of this very large set of possible variables, the small subset of these (i.e., critical process parameters, or CPP’s) that have a large effect on the CQA’s must be identified and understood such that those CPP’s can be controlled to ensure quality product. Here, we demonstrate the use of predictive modeling techniques to supplement experimental bioreactor studies when defining critical process parameters (CPP’s) and generating process control strategies. Using predictive models to relate culture process conditions to CQA’s has the benefit of enabling both: 1) using model predictions to supplement experimental data when determining critical process parameters (CPP’s) and the resulting control strategy, and 2) active control of CQA’s based on model forecasts to achieve finer control of CQA’s. In order to support this predictive forecasting approach for bioreactor process definition and control, Bend Research has developed a new bioreactor laboratory environment that allows us to run the right experiments, take the right data, and determine which measurements are actually important in determining CQA’s, and to generate model predictions based on those data sets. Here we demonstrate the application of this new laboratory paradigm in practice, using galactosylation, an important product quality attribute, as the “CQA” of interest. We show how through using automated, perfusion-type systems identification experiments, combined with automated data-generation and reduction tools, we can generate a prediction of the effect of galactose feeding on product qualit

    CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer

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    Although only 1.5% of the human genome appears to code for proteins, much effort in cancer research has been devoted to this minimal fraction of our DNA. However, the last few years have witnessed the realization that a large class of non-coding RNAs (ncRNAs), named microRNAs, contribute to cancer development and progression by acting as oncogenes or tumor suppressor genes. Recent studies have also shown that epigenetic silencing of microRNAs with tumor suppressor features by CpG island hypermethylation is a common hallmark of human tumors. Thus, we wondered whether there were other ncRNAs undergoing aberrant DNA methylation-associated silencing in transformed cells. We focused on the transcribed-ultraconserved regions (T-UCRs), a subset of DNA sequences that are absolutely conserved between orthologous regions of the human, rat and mouse genomes and that are located in both intra- and intergenic regions. We used a pharmacological and genomic approach to reveal the possible existence of an aberrant epigenetic silencing pattern of T-UCRs by treating cancer cells with a DNA-demethylating agent followed by hybridization to an expression microarray containing these sequences. We observed that DNA hypomethylation induces release of T-UCR silencing in cancer cells. Among the T-UCRs that were reactivated upon drug treatment, Uc.160+, Uc283+A and Uc.346+ were found to undergo specific CpG island hypermethylation-associated silencing in cancer cells compared with normal tissues. The analysis of a large set of primary human tumors (n=283) demonstrated that hypermethylation of the described T-UCR CpG islands was a common event among the various tumor types. Our finding that, in addition to microRNAs, another class of ncRNAs (T-UCRs) undergoes DNA methylation-associated inactivation in transformed cells supports a model in which epigenetic and genetic alterations in coding and non-coding sequences cooperate in human tumorigenesis

    Antibiotic research and development: business as usual?

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    This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

    q2-FMT

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    q2-FMT is a software package with a suite of tools to enable microbiome researchers to quantify engraftment extent following Fecal Microbiota Transplant

    EL PARADOR ARISTON Y LA CASA SOBRE EL ARROYO. PROCESO CREATIVO Y TECNOLOGÍA | ACTAS - Jornadas de Investigación

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    Este trabajo tiene como una de las finalidades, apoyar  proyectos de puesta en valor  y contemplar su medio socio-temporal, es decir su entorno que le diera contexto. En un ambiente que lo caracteriza, sus aspectos amplios y relevantes. Es decir, aquellos que definimos como componedores, que configuran su inmanencia. Desde lo analítico, el proyecto de investigación, se vislumbra en su capacidad para generar  aplicaciones al intervenir, un área cultural, los cascos históricos y otros recortes territoriales naturales, donde el hombre ha dejado su impronta. A tal efecto, se trata de un estudio, para ser incorporado como un término conceptual, que tiene la potencialidad de ser tenido en cuenta en otra profundidad, en los planes estratégicos que contemplan el Patrimonio Cultural como una situación relevante atendiendo valores que son de otro orden. Las obras de los creadores Marcel Breuer (Parador Ariston) y Amancio Williams (Casa sobre el Arroyo), en Mar del Plata, Argentina, han marcado una huella profunda entre la forma de entender las relaciones artísticas entre Europa y Latinoamérica. Su original adaptación de elementos propios y su atención a las vanguardias (en una sociedad costumbrista y conservadora) puso un antes y un después del mismo modo como lo hiciera Oscar Niemeyer en Brasil

    PROPORCIONES ARMÓNICAS DE LA NATURALEZA EN EL ARTE ARQUITECTÓNICO, EN IMÁGENES. EL ARISTON DE BREUER | ACTAS - Jornadas de Investigación

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    La obra de Breuer, el Ariston, Mar del Plata, es una tardía y profunda huella en Latinoamérica bajo una concepción naturista muy particular dentro del Movimiento Moderno, el CIAM IV y dentro de los lineamientos de la Bauhaus en Berlín, con un antecedente que es la Kornhaus, de Carl Fieger (1929 - 1930). En función de que en 2019 se cumplen 100 años de la BAUHAUS hace que este tipo de obras sean ahora interpretadas bajo una visión analítica de imágenes concretas que eran y son cánones que resultan universales. De no haber existido la Escuela de la Bauhaus y de su diáspora, en 1933, el movimiento de local se convirtió en universal. En la actualidad las tecnologías digitales nos permiten un abordaje comunicacional en otra profundidad, tanto para personas con capacidad visual plena como para aquellos que presentan discapacidad visual gradual o total. El Ariston, en su ideación es pitagórica y Breuer como masón practicante nos deja una muy original versión de la Fleur de Vie, del Árbol de la Vida post Klimt, también como una Sacred Butterfly. Contiene elaborados elementos que compartiera con Catalano y Coire en un mensaje y un manifiesto muy expreso. Un ícono como éste marca una ruptura con la tradicional configuración espacial, de las arquitecturas como arte y por ende en estética. Sus cánones (patterns del tipo biofílico) se advierten luego en otros desarrollos, para el caso, en la Floralis de Catalano, Buenos Aires, 2002
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