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71.
PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS
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Gilberto S. Almeida Carlo M. Bawn Martin Galler Ian Wilson Huw D. Thomas Suzanne Kyle Nicola J. Curtin David R. Newell Ross J. Maxwell 《NMR in biomedicine》2017,30(9)
Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (1H‐MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD+) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild‐type (WT) and PARP1 knock‐out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. 1H‐MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD+ levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD+ levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD+ levels in the temozolomide‐treated group. The combination of rucaparib and temozolomide did not prevent the NAD+ depletion caused by temozolomide treatment. The 1H‐MRS results show that NAD+ levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD+ would be valuable. 相似文献
72.
W. Kyle Simmons Jason A. Avery Joel C. Barcalow Jerzy Bodurka Wayne C. Drevets Patrick Bellgowan 《Human brain mapping》2013,34(11):2944-2958
Relatively discrete experimental literatures have grown to support the insula's role in the domains of interoception, focal exteroceptive attention and cognitive control, and the experience of anxiety, even as theoretical accounts have asserted that the insula is a critical zone for integrating across these domains. Here we provide the first experimental demonstration that there exists a functional topography across the insula, with distinct regions in the same participants responding in a highly selective fashion for interoceptive, exteroceptive, and affective processing. Although each insular region is associated with areas of differential resting state functional connectivity relative to the other regions, overall their functional connectivity profiles are quite similar, thereby providing a map of how interoceptive, exteroceptive, and emotional awareness are integrated within the insular cortex. Hum Brain Mapp 34:2944–2958, 2013. © 2012 Wiley Periodicals, Inc. 相似文献
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The fidelity of gradient waveforms in MRI pulse sequences is essential to the acquisition of images and spectra with minimal distortion artefacts. Gradient waveforms can become nonideal when eddy currents are created in nearby conducting structures; however, the resultant magnetic fields can be characterised and compensated for by measuring the spatial and temporal field response following a gradient impulse. This can be accomplished using a grid of radiofrequency (RF) coils. The RF coils must adhere to strict performance requirements: they must achieve a high sensitivity and signal‐to‐noise ratio (SNR), have minimal susceptibility field gradients between the sample and surrounding material interfaces and be highly decoupled from each other. In this study, an apparatus is presented that accomplishes these tasks with a low‐cost, mechanically simple solution. The coil system consists of six transmit/receive RF coils immersed in a high‐molarity saline solution. The sensitivity and SNR following an excitation pulse are sufficiently high to allow accurate phase measurements during free‐induction decays; the intrinsic susceptibility matching of the materials, because of the unique design of the coil system, results in sufficiently narrow spectral line widths (mean of 19 Hz), and adjacent RF coils are highly decoupled (mean S12 of ?47 dB). The temporal and spatial distributions of eddy currents following a gradient pulse are measured to validate the efficacy of the design, and the resultant amplitudes and time constants required for zeroth‐ and first‐order compensation are provided. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
75.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as an increasingly important pathogen, causing infections in persons who have no significant healthcare exposures. Persons with human immunodeficiency virus (HIV) infection have been disproportionately affected by CA-MRSA, with increased colonization and infection documented. Several factors are likely involved in the increased CA-MRSA burden observed among HIV-infected patients, including immune factors as well as healthcare and community exposures. Proposed community exposures that have been associated with increased CA-MRSA risk include substance abuse, incarceration, geographic area of residence, and social networks. This article explores these associations and reviews the current knowledge of the epidemiology, pathogenesis, clinical manifestations, and treatment of CA-MRSA in HIV-infected persons. 相似文献
76.
Thrombotic thrombocytopenic purpura in a postoperative patient taking cephalexin responding to plasmapheresis: A case report and review of cephalosporin‐induced TTP
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The clinical presentation of thrombotic thrombocytopenic purpura (TTP) is often atypical delaying diagnosis and treatment. A number of drugs have been implicated in the development of TTP, including cyclosporine, tacrolimus, clopidogrel, and quinine. To our knowledge, only three cases of cephalosporin‐induced TTP have been described, with two of these cases occurring with these use of cephalexin. We herein describe a case of TTP occurring in a postoperative patient taking cephalexin, requiring plasmapheresis. Following plasmapheresis, the patient's mental status and platelet count significantly improved. J. Clin. Apheresis 31:473–475, 2016. © 2015 Wiley Periodicals, Inc. 相似文献
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Alison Lee Kyle Brauer Boone Ira Lesser Marcy Wohl Stacy Wilkins Carlton Parks 《The Clinical neuropsychologist》2013,27(3):303-308
To our knowledge, no investigations have been undertaken to determine whether depression impacts performance on two commonly used tests to detect malingering of cognitive symptoms, the Rey 15-item Memorization Test and the Rey Dot Counting Test. This is a critical issue because of the high rate of depressive symptoms in patients with neurological conditions. It was hypothesized that depressed individuals, especially those with more severe depression, might be at risk for failing the tests, because these patients exhibit mild deficits in mental speed, visual perceptual/spatial skills, and visual memory, abilities required for successful completion of the malingering tests. However, examination of test performance in 64 older participants with major depression generally revealed very low false positive rates for most test scores, and severity of depression was unrelated to test scores. These results add to accumulating data supporting the validity of these cognitive malingering tests by documenting few false positive identifications. 相似文献
79.
Traumatic brain injury (TBI) is a major public health problem that significantly impacts young adults. Since severe TBI patients lack decision-making capacity, the providers and patient surrogates are often faced with the challenging task of deciding whether to continue with aggressive life-prolonging care or to transition to comfort-focused care with an expected outcome of natural death. The assumption is often made that aggressive care is appropriate for young patients who suffer severe TBI despite the high likelihood of a poor outcome. However, the young community''s attitude towards goals of care after severe TBI has not been studied. A questionnaire-based survey study on young healthy adults was conducted to assess their attitude towards aggressive care after a hypothetical case of severe TBI. Logistic regression analysis was performed to determine the factors associated with the decision to favor aggressive care. Among a total of 120 community-dwelling young adults (mean age: 19±1 years) who were surveyed, 79 (66%) were willing to live with severe motor disability, 78 (65%) were willing to live with expressive aphasia, and 53 (44%) were willing to live with receptive aphasia. Despite being presented with a high likelihood of long-term moderately severe-to-severe disability, 65 of the 115 respondents (57%) favored aggressive care. A willingness to live with receptive aphasia was the only independent factor that predicted aggressive care (OR 2.50, 95% CI: 1.15 to 5.46). Even among the young adults, preference of care was divided between aggressive and conservative approaches when presented with a hypothetical case of severe TBI. 相似文献
80.