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  • 1
    Publication Date: 2016-08-02
    Description: Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo . Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage–induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes. Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894–902. ©2016 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2016-08-26
    Description: Crystal Growth & Design DOI: 10.1021/acs.cgd.6b01034
    Print ISSN: 1528-7483
    Electronic ISSN: 1528-7505
    Topics: Chemistry and Pharmacology , Geosciences , Physics
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  • 3
    Publication Date: 2016-05-17
    Description: A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation—thereby leaving signatures identical to classical selective sweeps—despite being neutral or deleterious to organismal fitness. We previously described R2d2 , a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number ( R2d2 HC ) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2 HC rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2 HC is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
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  • 4
    Publication Date: 2016-09-16
    Description: Purpose: WRN promoter CpG island hypermethylation in colorectal cancer has been reported to increase sensitivity to irinotecan-based therapies. We aimed to characterize methylation of the WRN promoter, determine the effect of WRN promoter hypermethylation upon expression, and validate a previous report that WRN promoter hypermethylation predicts improved outcomes for patients with metastatic colorectal cancer (mCRC) treated with irinotecan-based therapy. Experimental Design: WRN methylation status was assessed using methylation-specific PCR and bisulfite sequencing assays. WRN expression was determined using qRT-PCR and Western blotting. WRN methylation status was correlated with overall survival (OS) and progression-free survival (PFS) in 183 patients with mCRC. Among these patients, 90 received capecitabine monotherapy as first-line therapy, and 93 received capecitabine plus irinotecan (CAPIRI) therapy as part of the CAIRO phase III clinical trial. Results: WRN mRNA and WRN protein expression levels were low in colorectal cancer cell lines and in primary colorectal cancer and were largely independent of WRN methylation status. Patients with methylated WRN colorectal cancer had a shorter OS compared with patients who had unmethylated WRN colorectal cancer (HR = 1.6; 95% confidence interval [CI], 1.2–2.2; P = 0.003). Patients with unmethylated WRN showed a significantly longer PFS when treated with CAPIRI compared with capecitabine alone (HR = 0.48; 95% CI, 0.32–0.70; P = 0.0001). In contrast, patients did not benefit from adding irinotecan to capecitabine when WRN was methylated (HR = 1.1; 95% CI, 0.69–1.77; P = 0.7). Conclusions: WRN expression is largely independent of WRN promoter hypermethylation in colorectal cancer. Moreover, we could not validate the previous finding that WRN promoter hypermethylation predicts improved clinical outcomes of mCRC treated with irinotecan-based therapy and found instead the opposite result. Clin Cancer Res; 22(18); 4612–22. ©2016 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 5
    Publication Date: 2016-04-27
    Description: In vertebrates, numerous processes occur in a rhythmic manner. The hormonal signal reliably reflecting the environmental light conditions is melatonin. Nocturnal melatonin secretion patterns could be disturbed in pathophysiological states, including inflammation, Alzheimer’s disease, and depression. All of these states share common elements in their aetiology, including the overexpression of interleukin- (IL-) 1β in the central nervous system. Therefore, the present study was designed to determine the effect of the central injection of exogenous IL-1β on melatonin release and on the expression of the enzymes of the melatonin biosynthetic pathway in the pineal gland of ewe. It was found that intracerebroventricular injections of IL-1β (50 µg/animal) suppressed nocturnal melatonin secretion in sheep regardless of the photoperiod. This may have resulted from decreased synthesis of the melatonin intermediate serotonin, which may have resulted, at least partially, from a reduced expression of tryptophan hydroxylase. IL-1β also inhibited the expression of the melatonin rhythm enzyme arylalkylamine-N-acetyltransferase and hydroxyindole-O-methyltransferase. However, the ability of IL-1β to affect the expression of these enzymes was dependent upon the photoperiod. Our study may shed new light on the role of central IL-1β in the aetiology of disruptions in melatonin secretion.
    Print ISSN: 0962-9351
    Electronic ISSN: 1466-1861
    Topics: Medicine
    Published by Hindawi
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  • 6
    Publication Date: 2016-05-03
    Description: Author(s): Hadi Rajaei, Pranav Joshi, Kim M. J. Alards, Rudie P. J. Kunnen, Federico Toschi, and Herman J. H. Clercx Using measurements of Lagrangian acceleration in turbulent rotating convection and accompanying direct numerical simulations, we show that the transition between turbulent states reported earlier [e.g., S. Weiss et al. , Phys. Rev. Lett. 105 , 224501 (2010) ] is a boundary-layer transition between the… [Phys. Rev. E 93, 043129] Published Fri Apr 29, 2016
    Keywords: Fluid Dynamics
    Print ISSN: 1539-3755
    Electronic ISSN: 1550-2376
    Topics: Physics
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  • 7
    Publication Date: 2016-10-21
    Description: Rodents have important effects on contemporary human societies, sometimes providing a source of food but more often as agricultural pests, or as vectors and reservoirs of disease. Skeletal remains of rodents are commonly found in archaeological assemblages from around the world, highlighting their potential importance to ancient human populations. However, there are few studies of the interactions between people and rodents at such sites and most of these are confined to locations where rodents have formed a part of the recent diet. Here we compare the accumulation pattern of rodent remains from four locations within and adjacent to the renowned Neolithic site of Skara Brae, Orkney, showing that those within the settlement itself were the result of deliberate human activity. The accumulation and nature of burnt bones, incorporated over an extended period within deposits of household waste, indicate that rodents were used as a nutritional resource and may have been the subject of early pest control. We, therefore, provide the first evidence for the exploitation or control of rodents by the Neolithic inhabitants of Europe.
    Keywords: ecology, environmental science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 8
    Publication Date: 2016-10-20
    Description: Objectives We examine interactions among 3 factors that affect patient waits and use of overtime in outpatient clinics: clinic congestion, patient punctuality and physician processing rates. We hypothesise that the first 2 factors affect physician processing rates, and this adaptive physician behaviour serves to reduce waiting times and the use of overtime. Setting 2 urban academic clinics and an affiliated suburban clinic in metropolitan Baltimore, Maryland, USA. Participants Appointment times, patient arrival times, start of service and physician processing times were collected for 105 visits at a low-volume suburban clinic 1, 264 visits at a medium-volume academic clinic 2 and 22 266 visits at a high-volume academic clinic 3 over 3 distinct spans of time. Intervention Data from the first clinic were previously used to document an intervention to influence patient punctuality. This included a policy that tardy patients were rescheduled. Primary and secondary outcome measures Clinicians' processing times were gathered, conditioned on whether the patient or clinician was tardy to test the first hypothesis. Probability distributions of patient unpunctuality were developed preintervention and postintervention for the clinic in which the intervention took place and these data were used to seed a discrete-event simulation. Results Average physician processing times differ conditioned on tardiness at clinic 1 with p=0.03, at clinic 2 with p=10 –5 and at clinic 3 with p=10 –7 . Within the simulation, the adaptive physician behaviour degrades system performance by increasing waiting times, probability of overtime and the average amount of overtime used. Each of these changes is significant at the p〈0.01 level. Conclusions Processing times differed for patients in different states in all 3 settings studied. When present, this can be verified using data commonly collected. Ignoring these behaviours leads to faulty conclusions about the efficacy of efforts to improve clinic flow.
    Keywords: Open access, Health economics, Health services research
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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