Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease.     

Spatiotemporal EEG/MEG source analysis based on a parametric noise covariance model

A method is described to incorporate the spatiotemporal noise covariance matrix into a spatiotemporal source analysis. The essential feature is that the estimation problem is split into two parts. First, a model is fitted to the observed noise covariance matrix. This model is a Kronecker product of a spatial and a temporal matrix. The spatial matrix models the spatial covariances by a function dependent on sensor distance. The temporal matrix models the temporal covariances as lag dependent. In the second part, sources are estimated given this noise model, which can be done very efficiently due to the Kronecker formulation. An application to real electroencephalogram (EEG) data shows that the noise model fits the data very well. Simulation results show that the resulting source estimates are more precise than those obtained from a standard analysis neglecting the noise covariance. In addition, the estimated standard errors of the source parameter estimates are far more precise than those obtained from a standard analysis. Finally, the source parameter standard errors are used to investigate the effects of temporal sampling. It is shown that increasing the sampling by a factor x, decreases the standard errors of all source parameters with the square root of x.     

Influx of immunoglobulins from the vascular compartment into a grafted cornea

PURPOSE: To determine the effect of a fresh corneal wound or a healed corneal scar on the immunodiffusion of immunoglobulins into the cornea. METHODS: F344 rats were immunized with human serum albumin (HSA) 1 week before an autologous rotational keratoplasty of the right cornea or 1 year after an autograft was performed. One group of rats also was treated with gentamicin-dexamethasone ointment in the grafted eye for 1 week after transplantation to reduce the postsurgical inflammatory signs. A serum sample was drawn every week and booster injections with HSA were given after 2 and 3 weeks. At various times after immunization, groups of rats were killed, blood and aqueous humor samples were taken, and the corneas of both eyes were removed. The corneas were divided into the graft or a 3-mm central button and the peripheral rim and weighed. The anti-HSA titer was determined in serum, aqueous humor, and both parts of the corneas. RESULTS: Up to 5 weeks after transplantation, the grafted cornea contained more anti-HSA immunoglobulins than did the control eye. One year postgrafting, no difference was seen. In the first weeks after keratoplasty, influx of anti-HSA from the peripheral into the central cornea was, however, neither obstructed nor enhanced. CONCLUSIONS: Surgical trauma in itself causes increased influx of anti-HSA immunoglobulins into the cornea. Within the cornea, a wound or a scar does not appear to be a barrier for centripetal immunoglobulin diffusion.     

A note on large-scale logistic prediction: using an approximate graphical model to deal with collinearity and missing data

Large-scale prediction problems are often plagued by correlated predictor variables and missing observations. We consider prediction settings in which logistic regression models are used and propose a novel approach to make accurate predictions even when predictor variables are highly correlated and only partly observed. Our approach comprises three steps: first, to overcome the collinearity issue, we propose to model the joint distribution of the outcome variable and the predictor variables using the Ising network model. Second, to render the application of Ising networks feasible, we use a latent variable representation to apply a low-rank approximation to the network’s connectivity matrix. Finally, we propose an approximation to the latent variable distribution that is used in the representation to handle missing observations. We demonstrate our approach with numerical illustrations.

     

Immune Checkpoints,Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.     

Regional labour market dynamics in the Netherlands

This article analyzes the response of regional labor markets in the Netherlands to region-specific labor demand shocks. Previous studies show remarkable differences in response between regions in European countries and regions in the United States. The analysis shows that, in Dutch regions, the speed of adjustment is similar to that of the US, but the primary adjustment mechanism is the same as in Europe. Whereas previous studies analyze only average patterns of all regions in a country, we also provide a more in-depth analysis of within country differences in labor market adjustment processes, thus showing remarkable differences between regions within the Netherlands.     

Effect of fruit ripeness and method of fruit drying on the extractability of avocado oil with hexane and supercritical carbon dioxide

BACKGROUND: Oil yield from avocado fruit may be influenced by fruit pre‐treatment and extraction method. Unripe and ripe avocado fruit pieces were deep‐frozen at ? 20 °C and either freeze‐dried or oven‐dried (80 °C). Oil yield from these samples was determined after extraction with hexane and supercritical carbon dioxide (SC‐CO₂). The fruit samples were examined using scanning electron microscopy before and after oil extraction. RESULTS: Average oil yield from ripe fruit (freeze‐dried and oven‐dried combined) was 72 g kg^?1 higher than from unripe fruit for SC‐CO₂ extracts and 61 g kg^?1 higher for hexane extracts. This may be due to enzymatic degradation of parenchyma cell walls during ripening, thus making the oil more available for extraction. Freeze‐dried samples had a mean oil yield 55 g kg^?1 greater than oven‐dried samples for SC‐CO₂ extracts and 31 g kg^?1 higher for hexane extracts. However, oil yields from ripe fruit (freeze‐dried and oven‐dried) subjected to hexane extraction were not significantly different. All hexane extracts combined had a mean oil yield 93 g kg^?1 higher than SC‐CO₂ extracts. CONCLUSION: SC‐CO₂ may be more selective and may create paths of least resistance through the plant material. Hexane, on the other hand, is less selective and permeates the whole plant material, leading to more complete extraction and higher oil yields under the experimental conditions. Copyright © 2007 Society of Chemical Industry