Mifepristone Increases the Cytotoxicity of Uterine Natural Killer Cells by Acting as a Glucocorticoid Antagonist via ERK Activation

Background: Mifepristone (RU486), a potent antagonist of progesterone and glucocorticoids, is involved in immune regulation. Our previous studies demonstrated that mifepristone directly augments the cytotoxicity of human uterine natural killer (uNK) cells. However, the mechanism responsible for this increase in cytotoxicity is not known. Here, we explored whether the increased cytotoxicity in uNK cells produced by mifepristone is due to either anti-progesterone or anti-glucocorticoid activity, and also investigated relevant changes in the mitogen-activated protein kinase (MAPK) pathway. Methodology/Principal Findings: Uterine NK cells were isolated from decidual samples and incubated with different concentrations of progesterone, cortisol, or mifepristone. The cytotoxicity and perforin expression of uNK cells were detected by mitochondrial lactate dehydrogenase-based MTS staining and flow cytometry assays, respectively. Phosphorylation of components of the MAPK signaling pathway was detected by Western blot. Cortisol attenuated uNK cell-mediated cytotoxicity in a concentration-dependent manner whereas progesterone had no effect. Mifepristone alone increased the cytotoxicity and perforin expression of uNK cells; these effects were blocked by cortisol. Furthermore, mifepristone increased the phosphorylation of ERK1/2 in a cortisol-reversible manner. Specific ERK1/2 inhibitor PD98059 or U0126 blocked cortisol- and mifepristone-induced responses in uNK cells

International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee

Neuroblastoma serves as a paradigm for utilising tumour genomic data for determining patient prognosis and treatment allocation. However, before the establishment of the International Neuroblastoma Risk Group (INRG) Task Force in 2004, international consensus on markers, methodology, and data interpretation did not exist, compromising the reliability of decisive genetic markers and inhibiting translational research efforts. The objectives of the INRG Biology Committee were to identify highly prognostic genetic aberrations to be included in the new INRG risk classification schema and to develop precise definitions, decisive biomarkers, and technique standardisation. The review of the INRG database (n=8800 patients) by the INRG Task Force finally enabled the identification of the most significant neuroblastoma biomarkers. In addition, the Biology Committee compared the standard operating procedures of different cooperative groups to arrive at international consensus for methodology, nomenclature, and future directions. Consensus was reached to include MYCN status, 11q23 allelic status, and ploidy in the INRG classification system on the basis of an evidence-based review of the INRG database. Standardised operating procedures for analysing these genetic factors were adopted, and criteria for proper nomenclature were developed. Neuroblastoma treatment planning is highly dependant on tumour cell genomic features, and it is likely that a comprehensive panel of DNA-based biomarkers will be used in future risk assignment algorithms applying genome-wide techniques. Consensus on methodology and interpretation is essential for uniform INRG classification and will greatly facilitate international and cooperative clinical and translational research studies

Expression of Interest for a Novel Search for CP Violation in the Neutrino Sector: DAEdALUS

Submitted to the DUSEL DirectorateSubmitted to the DUSEL DirectorateDAEdALUS, a Decay-At-rest Experiment for delta_CP studies At the Laboratory for Underground Science, provides a new approach to the search for CP violation in the neutrino sector. The design utilizes low-cost, high-power proton accelerators under development for commercial uses. These provide neutrino beams with energy up to 52 MeV from pion and muon decay-at-rest. The experiment searches for aninu_mu to antinu_e at short baselines corresponding to the atmospheric Delta m^2 region. The antinu_e will be detected, via inverse beta decay, in the 300 kton fiducial-volume Gd-doped water Cherenkov neutrino detector proposed for the Deep Underground Science and Engineering Laboratory (DUSEL). DAEdALUS opens new opportunities for DUSEL. It provides a high-statistics, low-background alternative for CP violation searches which matches the capability of the conventional long-baseline neutrino experiment, LBNE. Because of the complementary designs, when DAEdALUS antineutrino data are combined with LBNE neutrino data, the sensitivity of the CP-violation search improves beyond any present proposals, including the proposal for Project X. Also, the availability of an on-site neutrino beam opens opportunities for additional physics, both for the presently planned DUSEL detectors and for new experiments at a future 300 ft campus

Cucurbitacin I Inhibits Cell Motility by Indirectly Interfering with Actin Dynamics

Cucurbitacins are plant natural products that inhibit activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway by an unknown mechanism. They are also known to cause changes in the organization of the actin cytoskeleton. actin depolymerization experiments, cucurbitacin I had no effect on the rate of actin filament disassembly at the nanomolar concentrations that inhibit cell migration. At elevated concentrations, the depolymerization rate was also unaffected, although there was a delay in the initiation of depolymerization. Therefore, cucurbitacin I targets some factor involved in cellular actin dynamics other than actin itself. Two candidate proteins that play roles in actin depolymerization are the actin-severing proteins cofilin and gelsolin. Cucurbitacin I possesses electrophilic reactivity that may lead to chemical modification of its target protein, as suggested by structure-activity relationship data. However, mass spectrometry revealed no evidence for modification of purified cofilin or gelsolin by cucurbitacin I.Cucurbitacin I results in accumulation of actin filaments in cells by a unique indirect mechanism. Furthermore, the proximal target of cucurbitacin I relevant to cell migration is unlikely to be the same one involved in activation of the JAK2/STAT3 pathway

Implication of long-distance regulation of the HOXA cluster in a patient with postaxial polydactyly

Apparently balanced chromosomal inversions may lead to disruption of developmentally important genes at the breakpoints of the inversion, causing congenital malformations. Characterization of such inversions may therefore lead to new insights in human development. Here, we report on a de novo inversion of chromosome 7 (p15.2q36.3) in a patient with postaxial polysyndactyly. The breakpoints do not disrupt likely candidate genes for the limb phenotype observed in the patient. However, on the p-arm the breakpoint separates the HOXA cluster from a gene desert containing several conserved noncoding elements, suggesting that a disruption of a cis-regulatory circuit of the HOXA cluster could be the underlying cause of the phenotype in this patient

Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

BACKGROUND: Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. METHODS/DESIGN: The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment. DISCUSSION: The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life

Vision and visual history in elite-/near-elite level cricketers and rugby-league players

Background: The importance of optimal and/or superior vision for participation in high-level sport remains the subject of considerable clinical research interest. Here we examine the vision and visual history of elite/near-elite cricketers and rugby-league players. Methods: Stereoacuity (TNO), colour vision, and distance (with/without pinhole) and near visual acuity (VA) were measured in two cricket squads (elite/international-level, female, n=16; near-elite, male, n=23) and one professional rugby-league squad (male, n=20). Refractive error was determined, and details of any correction worn and visual history were recorded. Results: Overall, 63% had their last eye-examination within 2 years. However, some had not had an eye examination for 5 years, or had never had one (near-elite-cricketers: 30%; rugby-league players: 15%; elite-cricketers: 6%). Comparing our results for all participants to published data for young, optimally-corrected, non-sporting adults, distance VA was ~1 line of letters worse than expected. Adopting α=0.01, the deficit in distance-VA deficit was significant, but only for elite-cricketers (p0.02 for all comparisons). On average, stereoacuity was better than in young adults, but only in elite-cricketers (p<0.001; p=0.03, near-elite-cricketers; p=0.47, rugby-league -players). On-field visual issues were present in 27% of participants, and mostly (in 75% of cases) comprised uncorrected ametropia. Some cricketers (near-elite: 17.4%; elite: 38%) wore refractive correction during play but no rugby-league player did. Some individuals with prescribed correction choose not to wear it when playing. Conclusion: Aside from near stereoacuity in elite-cricketers, these basic visual abilities were not better than equivalent, published data for optimally-corrected adults. 20-25% exhibited sub-optimal vision, suggesting that the clearest possible vision might not be critical for participation at the highest levels in the sports of cricket or rugby-league. Although vision could be improved in a sizeable proportion of our sample, the impact of correcting these, mostly subtle, refractive anomalies on playing performance is unknown

Ethnicity and incidence of Hodgkin lymphoma in Canadian population

<p>Abstract</p> <p>Background</p> <p>Research has shown that ethnicity is a significant predictor of Hodgkin lymphoma (HL). Variations in cancer incidence among ethnic groups in the same country can lead to important information in the search for etiological factors. Other risk factors important in the etiology of HL are medical history and exposure to pesticides. In this report we investigated the association between ethnicity and HL in the presence of medical history, and exposure to pesticides.</p> <p>Methods</p> <p>The data resulting from a matched population-based case-control study conducted in six provinces of Canada (Ontario, Quebec, Manitoba, Saskatchewan, Alberta, and British Columbia) was analyzed to determine whether or not there was any association between ethnicity and incidence of HL when adjusted for personal medical history and pesticide exposure. Information on ethnicity, personal medical history, and pesticide exposure was collected by questionnaires via mail on 316 men diagnosed with HL; and on 1506 controls. A conditional logistic regression was utilized and results were presented as odds ratios and 95% confidence intervals.</p> <p>Results</p> <p>In our study population, the distribution of ethnic groups was: 38.5% North American, 15% British, 8.4% Western European, 8.2% Eastern European, 1.7% Asian, 1.4% Scandinavian and 27% of other ethnic origin. Compared to North Americans (i) the risk of HL was greater among the Eastern European descendents (Odds Ratio (OR_adj): 1.82; 95% confidence interval (CI): 1.02, 3.25) and Western European (OR_adj: 1.62; 95% CI: 0.95–2.76) descent population (borderline significance at 5% level); and (ii) the risk of HL was lower in Asian descents. Diagnosis with measles (OR_adj: 0.72, 95% C.I.: 0.53–0.98) and/or positive history of allergy desensitization shots (OR_adj: 0.55, 95% C.I.: 0.30–0.99) were negatively associated with the incidence of HL, while diagnosis with acne (OR_adj: 2.12, 95% C.I.: 1.19–3.78), shingles (OR_adj: 2.41, 95% C.I.: 1.38–4.22) and positive family history of cancer (OR_adj: 1.93, 95% C.I.: 1.40–2.65) increased the risk of HL. Exposure to individual herbicide dichlorprop showed an increased risk of HL (OR_adj: 6.35, 95% C.I.: 1.56–25.92).</p> <p>Conclusion</p> <p>In Canada, compared to North Americans descendents, the risk of HL was significantly greater among the Eastern European and Western European descent population. Our results related to association between ethnicity and HL support the findings reported by other researchers. Our data showed that subjects who were diagnosed with measles or had allergy desensitization shots negatively associated with the incidence of HL; and other medical conditions, ever diagnosed with acne, and positive family history of cancer were positively associated with the incidence of HL.</p

Vision in high-level football officials

YesOfficiating in football depends, at least to some extent, upon adequate visual function. However, there is no vision standard for football officiating and the nature of the relationship between officiating performance and level of vision is unknown. As a first step in characterising this relationship, we report on the clinically-measured vision and on the perceived level of vision in elite-level, Portuguese football officials. Seventy-one referees (R) and assistant referees (AR) participated in the study, representing 92% of the total population of elite level football officials in Portugal in the 2013/2014 season. Nine of the 22 Rs (40.9%) and ten of the 49 ARs (20.4%) were international-level. Information about visual history was also gathered. Perceived vision was assessed using the preference-values-assigned-to-global-visual-status (PVVS) and the Quality-of-Vision (QoV) questionnaire. Standard clinical vision measures (including visual acuity, contrast sensitivity and stereopsis) were gathered in a subset (n = 44, 62%) of the participants. Data were analysed according to the type (R/AR) and level (international/national) of official, and Bonferroni corrections were applied to reduce the risk of type I errors. Adopting criterion for statistical significance of p<0.01, PVVS scores did not differ between R and AR (p = 0.88), or between national- and international-level officials (p = 0.66). Similarly, QoV scores did not differ between R and AR in frequency (p = 0.50), severity (p = 0.71) or bothersomeness (p = 0.81) of symptoms, or between international-level vs national-level officials for frequency (p = 0.03) or bothersomeness (p = 0.07) of symptoms. However, international-level officials reported less severe symptoms than their national-level counterparts (p<0.01). Overall, 18.3% of officials had either never had an eye examination or if they had, it was more than 3 years previously. Regarding refractive correction, 4.2% had undergone refractive surgery and 23.9% wear contact lenses when officiating. Clinical vision measures in the football officials were similar to published normative values for young, adult populations and similar between R and AR. Clinically-measured vision did not differ according to officiating level. Visual acuity measured with and without a pinhole disc indicated that around one quarter of participants may be capable of better vision when officiating, as evidenced by better acuity (≥1 line of letters) using the pinhole. Amongst the clinical visual tests we used, we did not find evidence for above-average performance in elite-level football officials. Although the impact of uncorrected mild to moderate refractive error upon officiating performance is unknown, with a greater uptake of eye examinations, visual acuity may be improved in around a quarter of officials.Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2013