Metabolic scavenging by cancer cells: when the going gets tough, the tough keep eating

Cancer is fundamentally a disease of uncontrolled cell proliferation. Tumour metabolism has emerged as an exciting new discipline studying how cancer cells obtain the necessary energy and cellular ‘building blocks’ to sustain growth. Glucose and glutamine have long been regarded as the key nutrients fuelling tumour growth. However, the inhospitable tumour microenvironment of certain cancers, like pancreatic cancer, causes the supply of these nutrients to be chronically insufficient for the demands of proliferating cancer cells. Recent work has shown that cancer cells are able to overcome this nutrient insufficiency by scavenging alternative substrates, particularly proteins and lipids. Here, we review recent work identifying the endocytic process of macropinocytosis and subsequent lysosomal processing as an important substrate-acquisition route. In addition, we discuss the impact of hypoxia on fatty acid metabolism and the relevance of exogenous lipids for supporting tumour growth as well as the routes by which tumour cells can access these lipids. Together, these cancer-specific scavenging pathways provide a promising opportunity for therapeutic intervention

inTrack: High Precision Tracking of Mobile Sensor Nodes

Radio-interferometric ranging is a novel technique that allows for fine-grained node localization in networks of inexpensive COTS nodes. In this paper, we show that the approach can also be applied to precision tracking of mobile sensor nodes. We introduce inTrack, a cooperative tracking system based on radio-interferometry that features high accuracy, long range and low-power operation. The system utilizes a set of nodes placed at known locations to track a mobile sensor. We analyze how target speed and measurement errors affect the accuracy of the computed locations. To demonstrate the feasibility of our approach, we describe our prototype implementation using Berkeley motes. We evaluate the system using data from both simulations and field tests

Physical and functional fitness changes in older adults in response to a traditional training program and a Wii enhanced training program

The Wii Fit Plus Balance program has been recommended as an alternative training tool for older adults to improve physical and functional fitness. However, the effectiveness of the Wii Fit Plus in combination with traditional training approaches in older adults is unclear. PURPOSE: To compare changes in physical fitness measures in older adults (OA) engaging in two different training programs: 1) traditional exercises performed by the control group (CG) and 2) traditional exercises complemented by Wii balance games performed by the experimental group (EG). METHODS: 35 untrained OA (mean ± SD Age: 68.86 ± 6.13; BMI: 28.89 ± 5.32) with no exercise history were recruited and randomly assigned to either the CG or EG group. CG and EG programs both included cardio, strength, flexibility, and balance training exercises. However, subjects in the EG group performed additional balance exercises using Wii fit plus program. Both CG and EG subjects exercised twice per week for twelve weeks. Fitness assessments were based on standard procedures including the chair stand, gallon jug transfer, 8 foot up-and-go tests, as well as a long ramp walk and medicine ball throw tests. Data were collected at weeks 1, 6, and 12. Data analysis was conducted using the general linear mixed model with alpha level set at p\u3c0.05. RESULTS: A significant time effect was found for all fitness measures in both groups from week 1 to 6 (p\u3c0.001) and week 1 to 12 (p\u3c0.001). In general CG and EG subjects made 5.5% to 31.7% improvement from Week 1 to 6 and 8.1% to 52.5% improvement from Week 1 to 12. No significant group effects were observed between the CG and EG groups (p\u3e0.370). Also, no significant group by time interactions were observed for any of the fitness measures (p\u3e0.290). CONCLUSION: It appears that the use of the Wii Fit Plus Balance in conjunction with a traditional exercise program does not provide added significant fitness benefits for older adults. While additional fitness benefits are not evident, it appears that both a traditional exercise program alone and a traditional exercise program combined with the Wii Fit Plus Balance training may elicit significant fitness improvements

Macropinocytosis renders a subset of pancreatic tumor cells resistant to mTOR inhibition

Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach

A limit model for thermoelectric equations

We analyze the asymptotic behavior corresponding to the arbitrary high conductivity of the heat in the thermoelectric devices. This work deals with a steady-state multidimensional thermistor problem, considering the Joule effect and both spatial and temperature dependent transport coefficients under some real boundary conditions in accordance with the Seebeck-Peltier-Thomson cross-effects. Our first purpose is that the existence of a weak solution holds true under minimal assumptions on the data, as in particular nonsmooth domains. Two existence results are studied under different assumptions on the electrical conductivity. Their proofs are based on a fixed point argument, compactness methods, and existence and regularity theory for elliptic scalar equations. The second purpose is to show the existence of a limit model illustrating the asymptotic situation.Comment: 20 page

Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress

A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment

The Herbal Drug Melampyrum pratense

Melampyrum pratense L. (Koch) is used in traditional Austrian medicine for the treatment of different inflammation-related conditions. In this work, we show that the extracts of M. pratense stimulated peroxisome proliferator-activated receptors- (PPARs-)α and -γ that are well recognized for their anti-inflammatory activities. Furthermore, the extract inhibited the activation of the proinflammatory transcription factor NF-κB and induction of its target genes interleukin-8 (IL-8) and E-selectin in vitro. Bioassay-guided fractionation identified several active flavonoids and iridoids including melampyroside and mussaenoside and the phenolic compound lunularin that were identified in this species for the first time. The flavonoids apigenin and luteolin were distinguished as the main components accountable for the anti-inflammatory properties. Apigenin and luteolin effectively inhibited tumor necrosis factor α (TNF-α)-induced NF-κB-mediated transactivation of a luciferase reporter gene. Furthermore, the two compounds dose-dependently reduced IL-8 and E-selectin protein expression after stimulation with lipopolysaccharide (LPS) or TNF-α in endothelial cells (ECs). The iridoids melampyroside and mussaenoside prevented the elevation of E-selectin in LPS-stimulated ECs. Lunularin was found to reduce the protein levels of the proinflammatory mediators E-selectin and IL-8 in ECs in response to LPS. These data validate the ethnomedical use of M. pratense for the treatment of inflammatory conditions and point to the constituents accountable for its anti-inflammatory activity

Approximate conditional distributions of distances between nodes in a two-dimensional sensor network

When we represent a network of sensors in Euclidean space by a graph, there are two distances between any two nodes that we may consider. One of them is the Euclidean distance. The other is the distance between the two nodes in the graph, defined to be the number of edges on a shortest path between them. In this paper, we consider a network of sensors placed uniformly at random in a two-dimensional region and study two conditional distributions related to these distances. The first is the probability distribution of distances in the graph, conditioned on Euclidean distances; the other is the probability density function associated with Euclidean distances, conditioned on distances in the graph. We study these distributions both analytically (when feasible) and by means of simulations. To the best of our knowledge, our results constitute the first of their kind and open up the possibility of discovering improved solutions to certain sensor-network problems, as for example sensor localization