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General questionnaires are often used to assess quality of life in patients with spine metastases, although a disease-specific survey did not exist until recently. The Spine Oncology Study Group has developed an outcomes questionnaire (SOSG-OQ) to measure quality of life in these patients. However, a scoring system was not developed, and the questionnaire was not validated in a group of patients, nor was it compared with other general quality of life questionnaires such as the EuroQol 5 Dimensions (EQ-5D) questionnaire.
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The research was to appraise the utility of the patient-derived tumor xenografts (PDXs) as models of estrogen receptor positive (ER+HER2− and ER+HER2+) breast cancers. We compared protein expression profiles by Reverse Phase Protein Array (RPPA) in tumors that resulted in PDXs compared to those that did not. Our overall PDX intake rate for ER+ breast cancer was 9% (9/97). The intake rate for ER+HER2+ tumors (3/16, 19%) was higher than for ER+HER2− tumors (6/81, 7%). Heat map analyses of RPPA data showed that ER+HER2− tumors were divided into 2 groups by luminal A/B signature [protein expression of ER, AR, Bcl-2, Bim (BCL2L11), GATA3 and INPP4b], and this expression signature was also associated with the rate of PDX intake. Cell survival pathways such as the PI3K/AKT signaling and RAS/ERK pathways were more activated in the specimens that could be established as PDX in both classes. Expression of the ER protein itself may have a bearing on the potential success of an ER+ PDX model. In addition, HER2 and its downstream protein expressions were up-regulated in the ER+HER2+ patient tumors that were successfully established as PDX models. Moreover, the comparison of RPPA data between original and PDX tumors suggested that the selection/adaptation process required to grow the tumors in mice is unavoidable for generation of ER+ PDX models, and we identified differences between patient tumor samples and paired PDX tumors. A better understanding of the biological characteristics of ER+PDX would be the key to using PDX models in assessing treatment strategies in a preclinical setting.
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Genetic animal models of epilepsy are an important tool for further understanding the basic cellular mechanisms underlying epileptogenesis and for developing novel antiepileptic drugs. We conducted a comparative study of gene expression in the inferior colliculus, a nucleus that triggers audiogenic seizures, using two animal models, the Wistar audiogenic rat (WAR) and the genetic audiogenic seizure hamster (GASH:Sal). For this purpose, both models were exposed to high intensity auditory stimulation, and 60min later, the inferior colliculi were collected. As controls, intact Wistar rats and Syrian hamsters were subjected to stimulation and tissue preparation protocols identical to those performed on the experimental animals. Ribonucleic acid was isolated, and microarray analysis comparing the stimulated Wistar and WAR rats showed that the genomic profile of these animals displayed significant (fold change, |FC|≥2.0 and p<0.05) upregulation of 38 genes and downregulation of 47 genes. Comparison of gene expression profiles between stimulated control hamsters and stimulated GASH:Sal revealed the upregulation of 10 genes and the downregulation of 5 genes.
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Research indicates that high levels of sedentary behaviour (sitting or lying with low energy expenditure) are adversely associated with health. A key factor in improving our understanding of the impact of sedentary behaviour (and patterns of sedentary time accumulation) on health is the use of objective measurement tools that collect date and time-stamped activity information. One such tool is the activPAL monitor. This thigh-worn device uses accelerometer-derived information about thigh position to determine the start and end of each period spent sitting/lying, standing and stepping, as well as stepping speed, step counts and postural transitions. The activPAL is increasingly being used within field-based research for its ability to measure sitting/lying via posture. We summarise key issues to consider when using the activPAL in physical activity and sedentary behaviour field-based research with adult populations. It is intended that the findings and discussion points be informative for researchers who are currently using activPAL monitors or are intending to use them. Pre-data collection decisions, monitor preparation and distribution, data collection considerations, and manual and automated data processing possibilities are presented using examples from current literature and experiences from two research groups from the UK and Australia.
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X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder induced by a mutation in the ABCD1 gene, which causes the accumulation of very long-chain fatty acids in tissue and plasma. Oxidative stress may be a hallmark of X-ALD. In the plasma of X-ALD patients with different forms of the disease, characterized by high levels of C24:0 and C26:0, we observed the presence of oxidative stress revealed by decreased levels of GSH, α-tocopherol, and docosahexaenoic acid (DHA). We showed that oxidative stress caused the oxidation of cholesterol and linoleic acid, leading to the formation of cholesterol oxide derivatives oxidized at C7 (7-ketocholesterol (7KC), 7β-hydroxycholesterol (7β-OHC), and 7α-hydroxycholesrol (7α-OHC)) and of 9- and 13-hydroxyoctadecadienoic acids (9-HODE, 13-HODE), respectively. High levels of 7KC, 7β-OHC, 7α-OHC, 9-HODE and 13-HODE were found. As 7KC induces oxidative stress, inflammation and cell death, which could play key roles in the development of X-ALD, the impact of 7KC on the peroxisomal status was determined in microglial BV-2 cells. Indeed, environmental stress factors such as 7KC could exacerbate peroxisomal dysfunctions in microglial cells and thus determine the progression of the disease. 7KC induces oxiapoptophagy in BV-2 cells: overproduction of H2O2 and O2−, presence of cleaved caspase-3 and PARP, nuclear condensation and/or fragmentation; elevated [LC3-II/LC3-I] ratio, increased p62 levels. 7KC also induces several peroxisomal modifications: decreased Abcd1, Abcd2, Abcd3, Acox1 and/or Mfp2 mRNA and protein levels, increased catalase activity and decreased Acox1-activity. However, the Pex14 level was unchanged. It is suggested that high levels of 7KC in X-ALD patients could foster generalized peroxisomal dysfunction in microglial cells, which could in turn intensify brain damage.
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In multiple sclerosis (MS) a process of white matter degradation leading to demyelination is observed. Oxidative stress, inflammation, apoptosis, necrosis and/or autophagy result together into a progressive loss of oligodendrocytes. 7-ketocholesterol (7KC), found increased in the cerebrospinal fluid of MS patients, triggers a rupture of RedOx homeostasis associated with mitochondrial dysfunctions, aptoptosis and autophagy (oxiapoptophagy) in cultured murine oligodendrocytes (158N). α-tocopherol is able to mild the alterations induced by 7KC partially restoring the cellular homeostasis. In presence of 7KC, the amount of adherent 158N cells was decreased and oxidative stress was enhanced. An increase of caspase-3 and PARP degradation (evidences of apoptosis), and an increased LC3-II/LC3-I ratio (criterion of autophagy), were detected. These events were associated with a decrease of the mitochondrial membrane potential (ΔΨm) and by a decrease of oxidative phosphorylation revealed by reduced NAD+ and ATP. The cellular lactate was higher while pyruvate, citrate, fumarate, succinate (tricarboxylic acid (TCA) cycle intermediates) were significantly reduced in exposed cells, suggesting that an impairment of mitochondrial respiratory functions could lead to an increase of lactate production and to a reduced amount of ATP and acetyl-CoA available for the anabolic pathways. The concentration of sterol precursors lathosterol, lanosterol and desmosterol were significantly reduced together with satured and unsatured long chain fatty acids (C16:0 − C18:0, structural elements of membrane phospholipids). Such reductions were milder with α-tocopherol. It is likely that the cell death induced by 7KC is associated with mitochondrial dysfunctions, including alterations of oxidative phosphorylation, which could result from lipid anabolism dysfunctions, especially on TCA cycle intermediates. A better knowledge of mitochondrial associated dysfunctions triggered by 7KC will contribute to bring new information on the demyelination processes which are linked with oxidative stress and lipid peroxidation, especially in MS.
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This empirical paper investigates the relevance of long-run risks associated with uncertainty shocks to future growth prospects (news about future prospects) for explaining the risk-pricing of oil stocks. An econometric method that incorporates dynamic factor analysis is used for estimating the pricing equation of oil stocks. The results indicate that oil investors care about long-run risks associated with future growth prospects. Long-run risks account for almost half of the total risk-premium of oil stocks. Long-run risks associated with future growth prospects are significantly shaped by latent factors related to the labor market, the price indices, and financial markets. Moreover, our estimated model captures some historical events including the oil crisis of the seventies, the economic crisis of the mid-eighties, the stock market crash of 1987, and the economic crises of 1998 and 2000.
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The U.S. Strategic Petroleum Reserve (SPR) was established in 1975 to mitigate major oil supply disruptions and to deter the use of energy as a geopolitical “weapon.” However, policies towards the utilization of strategic oil stocks have varied under different presidencies and the SPR has often not been used in sufficient quantity or soon enough to avoid the negative economic consequences that can follow oil supply outages. Economic theory suggests that the existence of public stockpiles of commodities will alter inventory management practices of private market participants. This paper models private crude oil storage in the United States and estimates the private storage response to presidential announcements regarding the SPR. We investigate the incidence of different kinds of announcement events including releases and test sales from the SPR, announced changes in fill rates, and changes of presidency and how these events impact private land-based storage in the United States by region (PADD) as well floating storage. We find significant substitution between private and public stocks for crude oil and find that announcement events are associated with observable changes in private inventory levels, with implications for public policy choices and geopolitical strategies.
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Mitochondrial dysfunctions and oxidative stress are involved in several non demyelinating or demyelinating neurodegenerative diseases. Some of them, including multiple sclerosis (MS), are associated with lipid peroxidation processes leading to increased levels of 7-ketocholesterol (7KC). So, the eventual protective effect of dimethylfumarate (DMF), which is used for the treatment of MS, was evaluated on 7KC-treated oligodendrocytes, which are myelin synthesizing cells. To this end, murine oligodendrocytes 158N were exposed to 7KC (25, 50μM) for 24h without or with DMF (1, 25, 50μM). The biological activities of DMF associated or not with 7KC were evaluated by phase contrast microscopy, crystal violet and MTT tests. The impact on transmembrane mitochondrial potential (ΔYm), O2− and H2O2 production, apoptosis and autophagy was measured by microscopical and flow cytometric methods by staining with DiOC6(3), dihydroethidine and dihydrorhodamine 123, Hoechst 33342, and by Western blotting with the use of specific antibodies raised against uncleaved and cleaved caspase-3 and PARP, and LC3-I/II. DMF attenuates the different effects of 7KC, namely: cell growth inhibition and/or loss of cell adhesion, decrease of ΔΨm, O2− and H2O2 overproduction, PARP and caspase-3 cleavage, nuclear condensation and fragmentation, and activation of LC3-I into LC3-II. The ability of DMF to attenuate 7KC-induced reactive oxygen species overproduction, apoptosis, and autophagy on oligodendrocytes reinforces the interest for this molecule for the treatment of MS or other demyelinating diseases.
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In this paper, we focus on joint regression and classification for Alzheimer’s disease diagnosis and propose a new feature selection method by embedding the relational information inherent in the observations into a sparse multi-task learning framework. Specifically, the relational information includes three kinds of relationships (such as feature-feature relation, response–response relation, and sample-sample relation), for preserving three kinds of the similarity, such as for the features, the response variables, and the samples, respectively. To conduct feature selection, we first formulate the objective function by imposing these three relational characteristics along with an ℓ2,1-norm regularization term, and further propose a computationally efficient algorithm to optimize the proposed objective function. With the dimension-reduced data, we train two support vector regression models to predict the clinical scores of ADAS-Cog and MMSE, respectively, and also a support vector classification model to determine the clinical label. We conducted extensive experiments on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to validate the effectiveness of the proposed method. Our experimental results showed the efficacy of the proposed method in enhancing the performances of both clinical scores prediction and disease status identification, compared to the state-of-the-art methods.
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