SDRS—an algorithm for analyzing large-scale dose–response data

Summary: Dose–response information is critical to understanding drug effects, yet analytical methods for dose–response assays cannot cope with the dimensionality of large-scale screening data such as the microarray profiling data. To overcome this limitation, we developed and implemented the Sigmoidal Dose Response Search (SDRS) algorithm, a grid search-based method designed to handle large-scale dose–response data. This method not only calculates the pharmacological parameters for every assay, but also provides built-in statistic that enables downstream systematic analyses, such as characterizing dose response at the transcriptome level

Robust high-dimensional precision matrix estimation

The dependency structure of multivariate data can be analyzed using the covariance matrix $\Sigma$. In many fields the precision matrix $\Sigma^{-1}$ is even more informative. As the sample covariance estimator is singular in high-dimensions, it cannot be used to obtain a precision matrix estimator. A popular high-dimensional estimator is the graphical lasso, but it lacks robustness. We consider the high-dimensional independent contamination model. Here, even a small percentage of contaminated cells in the data matrix may lead to a high percentage of contaminated rows. Downweighting entire observations, which is done by traditional robust procedures, would then results in a loss of information. In this paper, we formally prove that replacing the sample covariance matrix in the graphical lasso with an elementwise robust covariance matrix leads to an elementwise robust, sparse precision matrix estimator computable in high-dimensions. Examples of such elementwise robust covariance estimators are given. The final precision matrix estimator is positive definite, has a high breakdown point under elementwise contamination and can be computed fast

Detecção de doença residual mínima em crianças com leucemia linfoblástica aguda por citometria de fluxo

The detection of minimal residual disease (MRD) is an important prognostic factor in childhood acute lymphoblastic leukemia (ALL) providing crucial information on the response to treatment and risk of relapse. However, the high cost of these techniques restricts their use in countries with limited resources. Thus, we prospectively studied the use of flow cytometry (FC) with a simplified 3-color assay and a limited antibody panel to detect MRD in the bone marrow (BM) and peripheral blood (PB) of children with ALL. BM and PB samples from 40 children with ALL were analyzed on days (d) 14 and 28 during induction and in weeks 24-30 of maintenance therapy. Detectable MRD was defined as > 0.01% cells expressing the aberrant immunophenotype as characterized at diagnosis among total events in the sample. A total of 87% of the patients had an aberrant immunophenotype at diagnosis. On d14, 56% of the BM and 43% of the PB samples had detectable MRD. On d28, this decreased to 45% and 31%, respectively. The percentage of cells with the aberrant phenotype was similar in both BM and PB in T-ALL but about 10 times higher in the BM of patients with B-cell-precursor ALL. Moreover, MRD was detected in the BM of patients in complete morphological remission (44% on d14 and 39% on d28). MRD was not significantly associated to gender, age, initial white blood cell count or cell lineage. This FC assay is feasible, affordable and readily applicable to detect MRD in centers with limited resources.A detecção de doença residual mínima (DRM) é um importante fator prognóstico na leucemia linfóide aguda (LLA) infantil e fornece informações sobre a resposta ao tratamento e o risco de recaída. Entretanto, os altos custos das técnicas utilizadas limitam seu uso nos países em desenvolvimento. Desta forma, realizamos um estudo prospectivo para avaliar a citometria de fluxo (CF), utilizando três fluorescências e um painel limitado de anticorpos monoclonais, como método de detecção de DRM em medula óssea (MO) e sangue periférico (SP) de crianças com LLA. Amostras de MO e SP de 40 crianças portadoras de LLA foram analisadas nos dias (d)14 e d28 da indução e nas semanas 24-30 da terapia de manutenção. Foram consideradas como DRM+ as amostras que apresentaram > 0,01% das células com o fenótipo aberrante (FA). Oitenta e sete por cento dos pacientes apresentaram FA ao diagnóstico. No d14, 56% das amostras de MO e 43% do SP apresentaram DRM. No d28, foi detectada DRM em 45% e 31% das amostras de MO e SP, respectivamente. A porcentagem de DRM na MO foi similar à do SP nos casos de LLA-T, mas aproximadamente dez vezes maior na LLA de precursor-B. Foi detectada DRM na MO de 44% e 39% dos pacientes que estavam remissão morfológica nos d14 e d28, respectivamente. Não foi demonstrada associação significante entre a presença de DRM e sexo, idade, leucometria inicial e linhagem celular. Esta técnica de detecção de DRM por CF é relativamente barata e pode ser aplicada em centros com recursos limitados

Comparison of serum and bronchoalveolar lavage fluid sialic acid levels between malignant and benign lung diseases

BACKGROUND: It is known that tissue and serum sialic acid levels may be altered by malignant transformation. In this study, sialic acid levels were determined in bronchoalveolar lavage fluid (BAL) and serum in two groups of patients with lung cancer and non-malignant diseases of the lung. METHODS: Colorimetric methods were used for determination sialic acid in serum and in BAL samples. Flexible bronchoscopy was used to obtain the latter. RESULTS: Sialic acid levels in bronchoalveolar lavage fluid and serum did not show any statistically significant difference between subjects with malignant and the non-malignant lung diseases (p > 0.05). Sialic acid levels were also unrelated to the stage and localization of the tumor (p > 0.05). CONCLUSIONS: Sialic acid levels do not appear to be a good marker for discriminating malignant from non-malignant diseases of the lung

Characterization of LiMn2O4 cathodes by electrochemical strain microscopy

Electrochemical strain microscopy (ESM) is a scanning probe microscopy (SPM) method in which the local electrodiffusion is probed via application of AC voltage to the SPM tip and registration of resulting electrochemical strain. Here, we implemented ESM to measure local strain in bulk LiMn2O4 cathodes of a commercial Li-battery in different states of charge to investigate distribution of Li-ion mobility and concentration. Ramped AC ESM imaging and voltage spectroscopy were used to find the most reliable regime of measurements allowing separating and diminishing different contributions to ESM. This is not a trivial task due to complex geometry of the sample and various obstacles resulting in less predictable contributions of different origins into ESM response: electrostatic tip surface interactions, charge injection, electrostriction, and flexoelectricity. Understanding and control of these contributions is an important step towards quantitative interpretation of ESM data