ENGLISH ABSTRACT: In this paper, we study a two-component continuous review inventory system. We assume that demand occurs according to a Poisson process and that a demand can be satisfied only if ...both the components are available in the inventory. Back-orders are not permitted. We assume that the lead-time distribution of one product is arbitrary and the other is exponential. Identifying the underlying process as a semi-regeneration process we find the stationary distribution of the inventory level, the performance measures such as mean stationary rate of number of lost demands, the demands and the reorders made. A numerical example illustrates the results. AFRIKAANSE OPSOMMING: Die artikel ondersoek 'n tweekomponent- deurlopende oorsigvoorraadstelsel. Daar word aanvaar dat aanvraag 'n Poissonproses is en dat aanvraag slegs bevredig kan word indien beide die komponente in die voorraad beskikbaar is. Agterstallige bestellings word nie toegelaat nie. Daar word aanvaar dat die lewertydverdeling van die een produk arbitrêr en die ander eksponensieël is. Indien die onderliggende proses as 'n semigenerasieproses geïdentifiseer word, kan die stasionêre verspreiding van die voorraadvlak bepaal word. Maatstawwe van vertoning soos mediaan- stasionêre koers van die hoeveelheid verlore aanvraag, die aanvraag en herbestellings wat gedoen is word bepaal. 'n Numeriese voorbeeld illustreer die resultate.
This study investigated the effects of music on responses to a specific listening environment. A stall offering advice on welfare issues was set up in a university cafeteria. A loudspeaker situated ...by the stall played four different types of music, which varied in their complexity and style, and the design also included a silent control condition. Two hundred and eighty-five subjects completed a questionnaire concerning their liking for the atmosphere in the cafeteria, how happy they would be to return to the cafeteria, their likelihood of visiting the advice stall and their liking for the music. Several behavioural measures were employed, although only a measure of the number of people visiting the stall yielded a sample of sufficient size for statistical analysis. The results indicated that responses to the listening environment were predictably associated with responses to the music, and these effects are considered in terms of the style and complexity of the music employed.
Development of the anti-CD20 antibody, rituximab, heralded the start of monoclonal antibody (mAb) therapy as an effective means of treating cancer. Despite its undoubted impact, clinical responses ...remain variable and cures are rarely achieved. Evidence from pre-clinical models and human trials indicates that mAbs primarily act through engaging low-affinity Fc gamma receptor (FcγR)-expressing effector immune cells. The low-affinity FcγR genes, FCGR2A, FCGR2B, FCGR2C, FCGR3A and FCGR3B, are located within a highly homologous 200 kb region at 1q23, which is the result of an ancestral segmental duplication event (Figure 1). The locus also contains numerous single nucleotide polymorphisms (SNPs), many of which can affect receptor affinity and/or function and are associated with differential responses following mAb immunotherapy. Moreover, the region contains extensive copy number variation (CNV) that also can affect the expression and function of these receptors, but its impact on mAb immunotherapy remains unknown.
To investigate the full impact of SNPs and CNV in the FcγR locus, we have optimised a number of sensitive and specific assays which are amenable to formalin fixed paraffin embedded (FFPE) material in order to apply them to clinical trial samples in a high-throughput manner. Initially we assessed the accuracy of established TaqMan and novel allele-specific (KASP) genotyping assays for FCGR2A-131H/R (rs1801274), FCGR3A-158F/V (rs396991) and FCGR2B-232I/T (rs1050501) SNPs by analysing 2085 DNA samples derived from peripheral blood lymphocytes (PBL) from a large, multi-centre cohort. Our data showed that although clear discrimination was possible at the FCGR2A-131H/R SNP, we needed additional selective Sanger sequencing to discriminate the FF/FV and IT/TT genotypes for the FCGR3A-158F/V and FCGR2B-232I/T SNPs, respectively. This difficulty in genotype discrimination in the cases of FCGR3A and FCGR2B is likely due to sequence homology with other genes and CNV in the gene regions which complicate assay design and interpretation of certain genotypes. Secondly, we applied a combined KASP genotyping and Sanger sequencing approach to matched PBL DNA and FFPE-extracted DNA from follicular lymphoma (FL) patients n=14 and showed that while FFPE material was more likely to fail genotyping, successfully genotyped cases were concordant with the matched genomic DNA samples. FFPE samples which failed to amplify PCR products of at least 100 bp using the BIOMED-2 multiplex PCR protocol were more likely to fail genotyping assays.
Finally, we assessed the ability of a multiplex ligation-dependent probe amplification (MLPA) assay to concurrently determine SNP genotype and CNV in the low-affinity FCGR locus in a cohort of 155 normal donors and DNA from seven matched PBL-/FFPE-derived FL cases. We employed a paralog ratio test (PRT) assay for FCGR3A and FCGR3B CNV confirmation. In our normal donors, MLPA and PRT results were concordant. 16% of normal donors harboured a deletion n=15 or duplication n=10 affecting the FCGR2C locus (A summary of regions of CNV is shown in Figure 1). CNV of FCGR3B was associated with variation at FCGR2C and no CNV was observed in FCGR2A and FCGR2B. CNV affecting FCGR3A was observed in 5% of donors with deletions and duplications in 4 and 5 donors, respectively. In the FFPE-derived DNA samples, we observed elevated variability in data quality that was most noticeable in probes targeting HSPA6, FCGR2C exon 4 and HSPA7. Poor quality data correlated with samples that failed to amplify at least the 100 bp PCR product using the BIOMED-2 multiplex PCR protocol. As such, the preclusion of HSPA6, FCGR2C exon 4 and HSPA7 probes and FFPE samples that failed to amplify any BIOMED-2 PCR product from the analysis permitted the production of high-quality MLPA data. Finally, we designed, and are currently optimising, a targeted re-sequencing platform (Haloplex, Agilent) to interrogate informative regions of the FcγR region, which includes those with unique sequence identify for CNV analysis, and those that include known SNPs.
In conclusion, we have evaluated a suite of assays for the genomic analysis of the FcγR locus that are scalable for application in large clinical trials of antibody therapy. This work will ultimately provide a detailed architecture of the region and establish the importance of FcγR genetics in predicting response to antibody therapeutics.
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No relevant conflicts of interest to declare.
In this paper we explore the relationships between the modelled climate of the Last Glacial Maximum (LGM) and that for doubled atmospheric carbon dioxide compared to the pre-industrial climate by ...analysing the output from an ensemble of runs from the MIROC3.2 GCM. Our results lend support to the idea in other recent work that the Antarctic is a useful place to look for historical data which can be used to validate models used for climate forecasting of future greenhouse gas induced climate changes, at local, regional and global scales. Good results may also be obtainable using tropical temperatures, particularly those over the ocean. While the greater area in the tropics makes them an attractive area for seeking data, polar amplification of temperature changes may mean that the Anatarctic provides a clearer signal relative to the uncertainties in data and model results. Our result for Greenland is not so strong, possibly due to difficulties in accurately modelling the sea ice extent. The MIROC3.2 model shows an asymmetry in climate sensitivity calculated by decreasing rather than increasing the greenhouse gases, with 80% of the ensemble having a weaker cooling than warming. This asymmetry, if confirmed by other studies would mean that direct estimates of climate sensitivity from the LGM are likely to be underestimated by the order of half a degree. Our suspicion is, however, that this result may be highly model dependent. Analysis of the parameters varied in the model suggest the asymmetrical response may be linked to the ice in the clouds, which is therefore indicated as an important area for future research.
SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, ...selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.
The in vivo hollow fiber assay, in which semipermeable hollow fibers filled with tumor cells, are implanted into animals, was originally developed to screen for anticancer compounds before assessment ...in more complex tumor models. To enhance screening, evaluation of anticancer drugs, we have applied optical imaging technology to this assay. To demonstrate that tumor cells inside hollow fibers can communicate with the host mice, we have used fluorescence imaging in vivo, CD31 immunostaining ex vivo to show that angiogenesis occurs around cell-filled hollow fibers by 2 weeks after subcutaneous implantation. Bioluminescence imaging has been used to follow the number of luciferase-expressing tumor cells within implanted hollow fibers; proliferation of those cells was found to be significantly inhibited by docetaxel, irinotecan. We also used bioluminescence imaging of hollow fibers to monitor the nuclear factor κB (NFκB) pathway in vivo; NFκB activation by lipopolysaccharide, tumor necrosis factor-α was evaluated in tumor cell lines genetically engineered to express luciferase controlled by an NFκB-responsive element. These results demonstrate that optical imaging of hollow fibers containing reporter tumor cells can be used for the rapid, accurate evaluation of antitumor activities of anticancer drugs, for measurement of molecular pathways.
Abstract
Purpose: To determine the agreement between expert readers on mammographic findings and calcification patterns.
Materials and Methods: Ten academic radiologists from 5 centers reviewed 250 ...de-identified mammographic cases without prior exams which were previously assessed as BI-RADS 4 or 5 with subsequent pathologic diagnosis by percutaneous or surgical biopsy. For benign cases diagnosed by percutaneous biopsy, 1 year of benign or negative imaging follow-up was required. Using standardized forms, each radiologist assessed the presence of any suspicious mammographic findings (microcalcifications, asymmetry (1-vew), focal asymmetry (2-view), architectural distortion), and the morphology (none, round/punctate, amorphous, coarse heterogeneous, fine pleomorphic, fine linear branching) and distribution (none, diffuse, regional, grouped, linear, segmental) of any identified microcalcifications. Agreement between radiologists for presence/absence of findings, morphology, and distribution of calcifications was determined by calculating the Kappa (k) coefficient with 95% confidence interval (95% CI). The kappa coefficient proposed strength of agreement is ≤0 = poor, .01-.20 = slight, .21-.40 = fair, .41-.60 = moderate, .61-.80 = substantial, and .81-1 = almost perfect, as established by Landis and Koch.1
Results: Of the 250 lesions, 156 (62%) were benign and 94 (38%) malignant. Agreement among the 10 expert readers was strongest for recognizing the presence/absence of calcifications (k = 0.82, 95% CI: 0.80-84), “almost perfect”). There was substantial agreement among the readers for the identification of a mass (k = 0.67, 95% CI: 0.66-69), whereas agreement was fair for the presence of a focal (2-view) asymmetry (k = 0.21, 95% CI: 0.1900.23) or architectural distortion (k = 0.28, 95%CI: 0.26-0.30). Agreement for asymmetries (1-view) was slight (k = 0.09, 95%CI: 0.08-0.11). Among the 6 categories of microcalcification distribution and morphology, reader agreement was moderate (distribution k = 0.60, 95%CI:0.59-0.61; morphology k = 0.51, 95%CI: 0.50-0.52).
Conclusion: When asked to characterize suspicious mammographic findings, this sampling of 10 expert academic breast imagers across 5 centers revealed varying strength of agreement for different findings, ranging from slight to almost perfect. Strongest agreement (“almost perfect”) was found for identifying the presence or absence of microcalcifications, although agreement drops to moderate when readers are asked to specify microcalcification morphology and distribution.
1 Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics.1977;33:159-174.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-01-06.
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