468 research outputs found
Mitochondrial dysfunction is an early indicator of doxorubicin-induced apoptosis
AbstractGeneration of reactive oxygen species and mitochondrial dysfunction has been implicated in doxorubicin-induced cardiotoxicity. This study examined pro-apoptotic mitochondrial cell death signals in an H9C2 myocyte rat cell line and in isolated rat heart mitochondria exposed to doxorubicin. Mitochondrial and cellular viability were assessed using an MTT viability assay (formazan product formed by functional mitochondrial dehydrogenases) and calcein AM dye (fluoresces upon cleavage by cytosolic esterases). Mitochondrial dysfunction followed by cell death was observed using nM concentrations of doxorubicin. Significant doxorubicin-induced cell death was not apparent until after 6 h following doxorubicin exposure using the calcein AM assay. The involvement of apoptosis is evidenced by an increase in TUNEL (terminal (TdT)-mediated dUTP-biotin nick end labeling)-positive nuclei following doxorubicin treatment. Furthermore, doxorubicin administered to isolated mitochondria induced a rapid increase in superoxide production, which persisted for at least 1 h and was followed by increased cytochrome c efflux. In addition, caspase-3 activity was increased with doxorubicin administration in the H9C2 myocyte cell line. An oxidant-mediated threshold of mitochondrial death may be required for doxorubicin-induced apoptosis
A theoretical look at ensemble-based optimization in reservoir management
Ensemble-based optimization has recently received great attention as a potentially powerful technique for life-cycle production optimization, which is a crucial element of reservoir management. Recent publications have increased both the number of applications and the theoretical understanding of the algorithm. However, there is still ample room for further development since most of the theory is based on strong assumptions. Here, the mathematics (or statistics) of Ensemble Optimization is studied, and it is shown that the algorithm is a special case of an already well defined natural evolution strategy known as Gaussian Mutation. A natural description of uncer-tainty in reservoir management arises from the use of an ensemble of history-matched geological realizations. A logical step is therefore to incorporate this uncertainty description in robust life-cycle production optimization through the expected objective function value. The expected value is approximated with the mean over all geological realizations. It is shown that the frequently advocated strategy of applying a different control sample to each reservoir realization delivers an unbiased estimate of the gradi-ent of the expected objective function. However, this procedure is more variance prone than the deterministic strategy of applying the entire ensemble of perturbed control samples to each reservoir model realization. In order to reduce the variance of the gradient estimate, an importance sampling algorithm is proposed and tested on a toy problem with increasing dimensionality.acceptedVersio
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Associations of Weight Change With Changes in Calf Muscle Characteristics and Functional Decline in Peripheral Artery Disease.
Background Among people with lower extremity peripheral artery disease, obesity is associated with faster functional decline than normal weight. The association of weight loss with functional decline in peripheral artery disease is unknown. Methods and Results Adults with an ankle-brachial index <0.90 were identified from Chicago-area hospitals in 2002-2004. Weight and 6-minute walk distance were measured annually. Weight change categories were weight loss or gain (≥5 pounds/year at ≥1 visit) or stable (weight change <5 pounds at each visit). Participants reported whether weight loss was "intentional" or "unintentional." Calf muscle area was measured with computed tomography every 2 years. Associations of weight change with changes in calf muscle area and 6-minute walk distance were analyzed using mixed-effects models and adjusted for age, body mass index, ankle-brachial index, physical activity, and other confounders. Among 389 participants, mean ankle-brachial index was 0.63±0.16, mean age was 74.5±7.8, and mean body mass index was 28.1±5.1 kg/m2. Over 3.23±1.37 years, muscle area declined more in adults with intentional weight loss versus stable or gain (pair-wise comparisons, P<0.001). Intentional weight loss was associated with less annual decline in 6-minute walk distance than weight gain (intentional loss, 3.7 m; stable, -14.0 m; gain, -28.5 m; unintentional loss, -20.8 m; pair-wise comparison intentional loss versus gain, P=0.003). Conclusions Despite a greater loss of calf muscle area, adults with peripheral artery disease who intentionally lost ≥5 pounds experienced less functional decline than those who gained weight. A randomized trial is needed to establish whether benefits of weight loss in peripheral artery disease outweigh potential adverse effects
The metabolic landscape browser:a novel tool for understanding pan-cancer metabolic processes through variance in gene expression data
The metabolic landscape browser:a novel tool for understanding pan-cancer metabolic processes through variance in gene expression data
Wear behavior of a microhybrid composite vs. a nanocomposite in the treatment of severe tooth wear patients:A 5-year clinical study
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Robust metabolic transcriptional components in 34,494 patient-derived cancer-related samples and cell lines
BACKGROUND: Patient-derived bulk expression profiles of cancers can provide insight into the transcriptional changes that underlie reprogrammed metabolism in cancer. These profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in biopsies of tumor lesions. Hence, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. However, consensus independent component analyses (c-ICA) can capture statistically independent transcriptional footprints of both subtle and more pronounced metabolic processes. METHODS: We performed c-ICA with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues, and cell lines. Gene set enrichment analysis with 608 gene sets that describe metabolic processes was performed to identify the transcriptional components enriched for metabolic processes (mTCs). The activity of these mTCs was determined in all samples to create a metabolic transcriptional landscape. RESULTS: A set of 555 mTCs was identified of which many were robust across different datasets, platforms, and patient-derived tissues and cell lines. We demonstrate how the metabolic transcriptional landscape defined by the activity of these mTCs in samples can be used to explore the associations between the metabolic transcriptome and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment. CONCLUSIONS: To facilitate the use of our transcriptional metabolic landscape, we have provided access to all data via a web portal (www.themetaboliclandscapeofcancer.com). We believe this resource will contribute to the formulation of new hypotheses on how to metabolically engage the tumor or its (immune) microenvironment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40170-021-00272-7
Usefulness of preclinical models for assessing the efficacy of late-life interventions for sarcopenia
Caloric restriction and physical exercise have proven beneficial against age-associated changes in body composition and declining physical performance; however, little is known regarding what benefit these interventions might have when initiated late in life. The study of mimetics of diet and exercise and the combination thereof may provide additional treatments for a vulnerable elderly population; however, how and when to initiate such interventions requires consideration in developing the most safe and efficacious treatment strategies. In this review, we focus on preclinical late-life intervention studies, which assess the relationship between physical function, sarcopenia, and body composition. We provide a conceptual framework for the ever-changing definition of sarcopenia and a rationale for the use of an appropriate rodent model of this condition. We finish by providing our perspective regarding the implications of this body of work and future areas of research that may also contribute to the ultimate goal of extending healthspan. © 2011 The Author
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