text:
Malignant B-cell clones are affected by both acquired genetic alterations and by inherited genetic variations changing the inflammatory tumour microenvironment.
We investigated 50 inflammatory response gene polymorphisms in 355 B-cell non-Hodgkin's lymphoma (B-NHL) samples encompassing 216 diffuse large B cell lymphoma (DLBCL) and 139 follicular lymphoma (FL) and 307 controls. The effect of single genes and haplotypes were investigated and gene-expression analysis was applied for selected genes. Since interaction between risk genes can have a large impact on phenotype, two-way gene-gene interaction analysis was included.
We found inherited SNPs in genes critical for inflammatory pathways; TLR9, IL4, TAP2, IL2RA, FCGR2A, TNFA, IL10RB, GALNT12, IL12A and IL1B were significantly associated with disease risk and SELE, IL1RN, TNFA, TAP2, MBL2, IL5, CX3CR1, CHI3L1 and IL12A were, associated with overall survival (OS) in specific diagnostic entities of B-NHL. We discovered noteworthy interactions between DLBCL risk alleles on IL10 and IL4RA and FL risk alleles on IL4RA and IL4. In relation to OS, a highly significant interaction was observed in DLBCL for IL4RA (rs1805010) * IL10 (rs1800890) (HR = 0.11 (0.02–0.50)). Finally, we explored the expression of risk genes from the gene-gene interaction analysis in normal B-cell subtypes showing a different expression of IL4RA, IL10, IL10RB genes supporting a pathogenetic effect of these interactions in the germinal center.
Citation: Nielsen KR, Steffensen R, Bendtsen MD, Rodrigo-Domingo M, Baech J, Haunstrup TM, et al. (2015) Inherited Inflammatory Response Genes Are Associated with B-Cell Non-Hodgkin's Lymphoma Risk and Survival. PLoS ONE 10(10): e0139329. https://doi.org/10.1371/journal.pone.0139329
Editor: Kristy L. Richards, Cornell University, UNITED STATES
Received: May 15, 2015; Accepted: September 11, 2015; Published: October 8, 2015
Copyright: © 2015 Nielsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are within the paper and its Supporting Information file. Gene expression data are deposited in the National Center for Biotechnology Information Gene Expression Omnibus repository (GSE56315).
Funding: These authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
Normal B-lymphocyte homeostasis requires survival and proliferation signals provided by cells in the lymph node microenvironment. In the case of B-cell non-Hodgkin's lymphoma (B-NHL) the malignant cells share some similarities with their normal B-cell counterpart linking the immunological inflammatory response to the growth potential of the malignant clone [1–3]. Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) accounts for the majority of B-NHL cases [4] and genetic analysis of the tumor microenvironment in these diseases has revealed different gene signatures associated to survival [5–7]. Functional single nucleotide polymorphisms (SNPs) affect the inflammatory microenvironment nesting malignant tumours [8]; however SNPs may also provide a direct effect on the malignant B-cells in the process of tumorigenesis [9]. Different genetic loci are associated with risk or outcome in B-NHL [10–14], amongst them most notably the IL4RA, IL6, IL10 and TNFA loci [15–21] and recently, genome wide association studies (GWAS) have suggested an effect of a number of other potential loci encoding inflammatory mediators [22,23]. The focus in most of the previous studies has primarily been on single gene effects, however disease susceptibility and prognosis in complex diseases such as B-NHL may not be caused by single genes but by genes interacting [24] as reported by a small number of investigators [10,25–30]. In the present paper we investigate the effect of single gene, haplotype and gene-gene interactions in different histological subtypes of B-NHL. We further suggest, that the biological effect of such interacting inflammatory response genes with germ line polymorphisms is of pathogenetic impact supported by the investigation of "risk genes" expression in normal B-cell compartments and lymphoma tissue [31,32].
Materials and Methods
Patients, controls and ethics statement
The current study included 355 B-NHL cases classified according to the World Health Organization (WHO) classification (216 DLBCL and 139 FL). Clinical data was abstracted from the Danish lymphoma database (LYFO) and from medical records. Follow-up information included type of treatment, International Prognostic Index (IPI) score and time to relapse. We included material from 307 healthy blood donors as previously described [33]. Research protocols were approved by the local scientific ethics committee of the North Denmark Region (approval numbers: N-20100059, N-20090018). The use of samples without informed consent was approved by the committee since the result did not result in any interventions and all samples were anonymized and de-identified prior to analysis. For details see S1 Text.
Sample preparation
Formalin-fixed paraffin-embedded (FFPE) bone-marrow aspirate were used for DNA extraction from all included patients. From controls, DNA were extracted from Ethylenediaminetetraacetic acid (EDTA) stabilised whole blood. For gene-expression analysis, normal lymph node tissue and DLBCL lymphoma cells were processed as previously described [34]. For details see S1 Text.
Genotyping was performed using a TaqMan OpenArray genotyping system from Applied Biosystems (ABI, Foster City, CA, USA). Seven SNPs were genotyped using custom-designed assays and 43 SNPs were genotyped using predesigned TaqMan SNP assays (see S1 Table for detailed assay information). The arrays were read using the OpenArray NT Imager and the allele calls and scatter plots were generated with the Biotrove OpenArray SNP Genotyping Analysis Software package version 1.0.3. The default threshold for the Quality value was set to 0.95. For details see S1 Text.
Analysis of gene expression profiles of normal and malignant lymphnodes
DLBCL lymphoma samples and and flow-sorted B-cell populations from Ficoll-purified mononuclear cells from human tonsils were hybridized to Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays (Affymetrix, Santa Clara, CA) as previously described [3]. The CEL files are deposited in the National Center for Biotechnology Information Gene Expression Omnibus repository (GSE56315)[3]. Gene expression profiles were analyzed using the statistical software system R, version 2.15.3. (http://www.r-project.org) and Bioconductor R-packages [35]. The CEL files were normalized by the just.rma function from the Bioconductor package affy, using customized cdf-files from brainarray [36], which summarized the probesets to ENGS symbols. The ENSG symbols were mapped to the HGNC symbols of interest by the function getBM from the Bioconductor package biomaRt.
Statistical analysis
Statistical analyses were carried out by the statistical software Stata Version 12.1 (Stata Corporation, College Station, TX, USA) and the statistical software system R, version 2.15.3. (http://www.r-project.org). PHASE 2.1 software (University of Chicago, USA) was used to construct haplotypes. Logistic regression analysis was used to estimate the association between odds of lymphoma and the single genotypes, alleles, haplotypes, and gene-gene interactions, respectively. Survival analysis for 10 year overall survival (OS) was used to analyse the effect of single SNPs, haplotypes, and gene-gene interactions between SNPs corresponding to different genes. Cox proportional hazards models adjusted for sex, age, IPI, and treatment was used for survival analysis. P-values below 0.05 were generally considered statistically significant. The purpose of performing gene-gene interaction analyses was to identify pairs of genes for which the interaction between them was significantly associated with the risk of getting lymphoma (performed by logistic regression) or significantly associated with the survival among lymphoma patients (performed by Cox regression). We performed the gene-gene interaction analyses by comparing the models with and without the interaction term using a likehood ratio test. Highly significant interactions were selected using the p-value from the likelihood ratio test corrected for the number of individual loci (31 loci) investigated why only interactions with a p-value of < 0.002 were considered significant. As possibly 9 combinations of genotypes exist for each pair of genes we have for the survival part reported hazard ratio estimates for each combination of genotypes with the combination of the most frequent homocygotes as reference. For the gene-expression data where a Bonferroni corrected p-value < 0.05 was considered significant.
Study population
The patient population consisted of 139 FL and 216 DLBCL patients with a median age of 63 years including 53% males. The median OS was 75.5 months (58.7 months for DLBCL and 101.7 months for FL). In this population, age (p < 0.0001) and IPI (p < 0.0001), but not sex (p = 0.39) were prognostic markers for OS. The control group consisted of 307 healthy blood donors. Of the controls 46% were males and the median age was 41 years.
Genotypes and their influence on B-NHL risk
For the IL6 (rs1800796) SNPs we observed a marginally significant deviation from Hardy-Weinberg equilibrium in the control group (p = 0.042, not corrected for multiple testing). Retesting did not suggest technical problems why this SNP was included in analysis. For the remaining 49 SNPs, no deviations from Hardy-Weinberg equilibrium were observed in the control group. Linkage analysis of the TNFA, IL1B and IL10 loci as expected revealed a high degree of linkage disequilibrium (LD) (see S1 Fig).
Table 1 summarizes the significant findings in the univariate analysis. Seven SNPs were solely associated with DLBCL; TAP2 (rs241447) odds ratio (OR)DLBCL = 0.61 (0.44–0.84), TLR9 (rs5743836) ORDLBCL = 0.66 (0.44–0.99), IL4 (rs2243248) ORDLBCL = 1.62 (1.00–2.63), IL2RA (rs2104286) ORDLBCL = 0.74 (0.55–0.98), FCGR2A (rs1801274) ORDLBCL = 1.37(1.07–1.77), TNFA (rs1800629) ORDLBCL = 1.46 (1.06–2.00), IL10RB (rs1058867) ORDLBCL = 0.68 (0.53–0.89). Four SNPs were associated solely with FL; GALNT12 (rs10987898) ORFL = 0.70 (0.49–1.00), IL12A (rs485497) ORFL = 0.71 (0.53–0.96), IL1B (rs1143627) ORFL = 0.65 (0.48–0.89), IL1B (rs16944) ORFL = 0.67 (0.49–0.92). Two SNPs in the TNFA locus were associated with both DLBCL and FL, the TNFA (rs1799724) and the TNFA (rs1799964). OR for all included SNPs are reported in S2, S3 and S4 Tables. Haplotype analysis did not add significant strength to the single gene analysis (data not shown).
For DLBCL, we observed significant interaction between combinations of IL10 (rs1800796) * IL4RA (rs1801275) (p = 0.0002), IL10 (rs1800896) * IL1RN (rs2637988) (p = 0.001), and TNFA (rs1799964) * TLR9 (rs5743836) (p = 0.0018) and for FL; IL4RA (rs1805011) * IL4 (rs2243248) (p = 0.0002), IL1B (rs1143627) * MBL2 (rs12780112) (p = 0.0014) and the CTLA4 (rs231775) * IL4RA (rs1805010) (p = 0.0018).
Survival analysis
Univariate 10 year OS analysis of all cases revealed significant association with five SNPs (see Table 2). For DLBCL five SNPs were significantly related to OS; TAP2 (rs241447) hazard ratio (HR)GG = 3.17 (1.21–8.32), MBL2 (rs7096206) HRCG = 1.47 (1.02–2.13), IL5 (rs2069812) HRTT = 1.94 (1.12–3.39), CX3CR1 (rs373379) HRTT = 2.01 (1.13–3.57), and IL12A (rs485497) HRAA = 1.76 (1.06–2.90) (see Table 3). For the FL subgroup two SNPs was associated with survival; CHI3L1 (rs4950928) HRCG = 2.04 (1.17–3.54) and CX3CR1 (rs3732379) HRTT = 4.21 (1.67–10.61) (See Table 4). Figs 1–6 provides Kaplan-Meier estimates of the most notable associations. TNFA haplotype analysis revealed a deleterious effect of the (rs1799964, rs1799724, rs1800629) CCG haplotype for combined FL and DLBCL and DLBCL alone but not for the FL group alone (HRB-NHL = 1.62 (1.14–2.31), HRDLBCL = 1.74 (1.14–2.66)). HR for all included SNPs are reported in S5, S6 and S7 Tables.
The model is adjusted for sex, IPI and treatment.
The model is adjusted for sex, IPI and treatment.
The model is adjusted for sex, IPI and treatment.
Gene-gene interactions analysis revealed several gene combinations significantly related to adjusted OS. For DLBCL; IL4RA (rs1805010) * IL10 (rs1800890) (p = 0.00021), FCGR2A (rs1801274) * IL1RN (rs419598) (p = 0.0003), IL10 (rs1800896) * IL4RA (rs1805010) (p = 0.0004), IL10 (rs1800896) * IL1RA (rs419598) (p = 0.0006), TNFRSF1B (rs1061622) * IL10 (rs1800890) (p = 0.0008), TNFRSF1B (rs1061622) * MBL2 (rs7096206) (p = 0.0009), CX3CR1 (rs373379) * IL12RB1 (rs2305742) (p = 0.0011), IL10 (rs1800872) * IL2 (rs2069762) (p = 0.001) and IL10 (rs1800871) * IL4RA (rs1805010) (p = 0.001). Analysis of the FL subgroup revealed interactions for the IL1RN (rs2637988) * IL4 (rs2243248) (p = 0.0004), TNFRSF1B (rs1061622) * IL2RA (rs2104286) (p = 0.0006)). HR for specific genotype combinations is reported in S8, S9 and S10 Tables.
Gene expression analysis in normal B-cell subsets and DLBCL lymphoma cells
We selected the most significant genes from the gene-gene interaction analysis and analyzed the expression of these genes in the normal lymph node B-cell hierarchy and DLBCL lymphoma cells. We explored genes related to the IL-4 and IL-10 cytokines; Figs 7–10 illustrates differences in expression between normal germinal centre (GC) B-cells (defined as centrocytes (CC) and centroblasts (CB)) and non-GC subtypes (naïve (N), plasmablasts (PB), memory (M) B-cells) and DLBCL cells using Bonferroni corrected p-values. The IL10 gene (Fig 7) and the IL10RB (Fig 8) gene were up regulated in DLBCL cells when compared to normal GC subtypes. The increased expression of IL10 was only seen in DLBCL cells whereas increased IL10RB expression could also be shown in pre- and post germinal center subpopulations. The IL4 gene was equally expressed in all normal B-cell subpopulations (Fig 9) whereas the expression in DLBCL cells was slightly down regulated, a similar expression profile was seen for the IL4R gene (Fig 10) however this gene was also found to be down regulated in post GC subpopulations.
The asterisk represents significant difference in expression after Bonferroni correction (*** = p < 0.001, ** = p< 0.01, * = p < 0.05). Gene expression is presented on a log2 scale. Lymphoma: DLBCL B-cells, N: Naïve B-cells, CC: Centrocytes, CB: Centroblasts, PB: Plasmablasts, M: Memory B-cells.
, The asterisk represents significant difference in expression after Bonferroni correction (*** = p < 0.001, ** = p< 0.01, * = p < 0.05). Gene expression is presented on a log2 scale. Lymphoma: DLBCL B-cells, N: Naïve B-cells, CC: Centrocytes, CB: Centroblasts, PB: Plasmablasts, M: Memory B-cells.
The asterisk represents significant difference in expression after Bonferroni correction (*** = p < 0.001, ** = p< 0.01, * = p < 0.05). Gene expression is presented on a log2 scale. Lymphoma: DLBCL B-cells, N: Naïve B-cells, CC: Centrocytes, CB: Centroblasts, PB: Plasmablasts, M: Memory B-cells.
The asterisk represents significant difference in expression after Bonferroni correction (*** = p < 0.001, ** = p< 0.01, * = p < 0.05). Gene expression is presented on a log2 scale. Lymphoma: DLBCL B-cells, N: Naïve B-cells, CC: Centrocytes, CB: Centroblasts, PB: Plasmablasts, M: Memory B-cells.
DLBCL and FL share a common dependence of the inflammatory tumor microenvironment for their proliferation and growth [7] however we generally observed a specific association with disease risk supporting DLBCL and FL being two different diseases with respect to genetic risk factors.
Interleukins (IL) and toll-like receptors (TLR) play a major role in B-cell differentiation and proliferation. The TNFA gene have been intensively studied and in accordance with others, including the large pooled Interlymph study and a recent GWAS study including largely the same patients [10,37] we found the TNFA (rs1800629) A allele associated with increased risk of DLBCL (OR = 1.46 (1.06–2.00)). The functional IL1B (rs1143627) C allele and IL1B (rs16944) A allele were associated with a decreased risk of FL but not DLBCL, a trend for an association with the IL1B gene was observed in the Interlymph study [10], however substantial difference was observed between the included cohorts.[10] The IL10RB (rs1058867) SNP was earlier investigated in a pooled study [12] reporting an association with FL; results we failed to confirm, whereas we observed a significant association in DLBCL where a decreased risk was shown for DLBCL carries of the G allele. Inappropriate TLR9 activation has been reported in malignant B-cells [38] and we observed a decreased risk of B-NHL (OR = 0.67) and DLBCL (OR = 0.66) for carriers of the TLR9 (rs5743836) C allele. This was in agreement with observations by Carvalho et al. [39] and suggests a role for TLR signalling in lymphomagenesis.
Among other notable findings, the (rs241447) SNP in the TAP2 gene, coding for a HLA-II associated transport protein [40], was significantly associated with decreased risk of DLBCL, OR = 0.61 (0.44–0.84). Vijai et al. reported an adjacent SNP in the TAP2 gene to be associated with risk of DLBCL and FL, a finding confirmed by Cerhan et al. [23,40]. The cumulative findings emphasize the possible importance of genetic variation in the HLA-II region and further evaluation of the TAP2 gene in larger cohorts is awaited. The GALNT12 gene is linked to pathological aberrant glycosylation, and was associated with outcome in FL in a recent GWAS [41] study including 244 FL cases. We observed a decreased risk of FL for carries of the GALNT12 (rs10987898) G allele whereas there was no apparent effect on DLBCL risk, supporting a specific role for this gene in the pathogenesis of FL and emphasising the need to explore this gene in relation to the glycosylation patterns in FL B-cells. Another intensively studied locus [13,15,42] is the FCGR2A gene. The FCGR2A gene encodes a low affinity Immunoglobulin-G (IgG) receptor (FcγRIIa) and genetic variation affects inflammatory cytokine production [43]. The association between the FCGR2A (rs1801274) SNP and DLBCL was also confirmed in our population (OR = 1.37 (1.07–1.77)) whereas the association with FL was not statistically significant (OR = 0.76 (0.57–1.01)).
When we analyzed 10 year OS, we observed an association between the CHI3L1 (rs4950928) C allele and a worse outcome in FL (CG genotype compared to the CC genotype)—the rare GG genotype group was unfortunately small and did not add sufficient information as presented the Kaplan-Meier plot (Fig 1). The CHI3L1 gene encodes the pro-inflammatory YKL-40 protein [44] and we have previously reported circulating levels of YKL-40 to be associated with dismal outcome in NHL [45] and the existence of the functional (rs4950928) SNP in the CHI3L1 gene affecting serum-YKL-40 [33], however to the best of our knowledge the CHI3L1 gene have not previously been investigated in this setting. The SELE gene encodes the selectin-E molecule expressed on endothelial cells known to promote metastasis [46]; the SELE (rs5361) SNP was found to be associated with OS in FL and DLBCL in a recent study [47] and we found an equal effect on the combined DLBCL and FL cohort, however, the effect was not obvious when analyzed at specific diagnostic entity levels. IL12A (rs485497) (Fig 2) was associated with decreased risk in FL, as well as outcome in DLBCL and we also confirmed the earlier suggested association between B-NHL outcome and the CX3CR1 gene [47] (Fig 3) and we did observe a novel association between the IL5 (rs2069812), encoding B-cell growth factor IL-5 [48], and outcome of DLBCL ((HR = 1.94 (1.12–3.39)) for carriers of the TT genotype, Fig 4). Surprisingly, we observed a DLBCL specific association between the TAP2 (rs241447) gene in GG genotype and decreased OS however the G allele is significantly associated with decreased risk of DLBCL (OR = 0.61 (0.44–0.84)) we do not have an explanation for this findings, but it could suggest that this protein could play a different role in disease initiation and response to treatment (Fig 5). The suggested effect are however in line with the general believe of genes in the HLA-II region of chromosome 6p as one of the most interesting areas in the genome in relation to B-cell lymphomas and our findings of a possible relation to OS in DLBCL must encourage to further studies of this region. The MBL2 gene has been studied in a number of malignant and infectious diseases with conflicting results. The MBL2 (rs7096206) is associated with risk of hepatocellular carcinoma [49] and febrile neutropenia [50] however the genotype have not been studied in relation to NHL [51]. Whether the effect of this genotype on DLBCL survival (Fig 6) is related to disease progression or increased risk of infectious complication needs to be investigated in future studies.
Growing evidence suggest, that inflammatory mediators act in networks why co-occurrence of genotypes -gene-gene interaction -analysis needs to be considered in complex diseases as B-NHL [24,52]. Of most notable interest, was a highly significant interaction between two risk alleles; IL10 (rs1800872) and IL4RA (rs1801275). IL-4 and IL-10 play a major role in the GC reaction, B-cell proliferation is enhanced by IL-10 in the presence of IL-4 and both cytokines are involved in the class switch recombination process [53–55]. We further explored gene-gene interactions in relation to FL and DLBCL specific OS. Most notably, we discovered a highly significant (p = 0.0002) interaction between IL10 (rs1800890) and IL4RA (rs1805010) in DLBCL. Carriers of IL10 (rs1800890) AA in combination with the IL4RA (rs1805010) AA genotype had a significantly improved outcome (HR = 0.11 (0.20–0.50)). Several SNPs in the IL4, IL4R and IL10 genes has been proposed associated with outcome in earlier studies [20]. Analysis of the effect of these individual genes have been somewhat contradictory however the results of attempts to include these loci in multi-gene models [47], including ours, argues for a combined effect of these loci not readily identified in a single gene model emphasizing the interaction between these cytokines to be of importance and in need of exploration in future studies. For FL the most notable effect of gene-gene interactions was seen for interaction between the IL1RN (rs2637988) and IL4 (rs2243248) (p = 0.0004). As it was the case for DLBCL, a SNP related to the IL-4 cytokine was involved in gene-gene interactions in the FL group. We did explore survival estimates for gene-gene combinations (S8, S9 and S10 Tables), however risk estimates are imprecise since the number of events in each group was small.
In order to study the functional aspect of these genes in the B-cell hierarchy, we combined the SNP study with analysis of gene expression in normal B-cell subpopulations and DLBCL lymphoma cells. We restricted the analysis to the most notable genes from the gene-gene expression analysis which suggested a prominent effect of IL-4 and IL-10 related genes. Increased expression of IL-10 related genes has earlier been shown in chronic lymphocytic leukaemia (CLL) and in Waldenström's macroglobulinemia [56]. We found a up regulation of the IL10 and the IL10RB gene in DLBCL cells when compared to normal GC B-cell subpopulations supporting the hypothesis that this cytokine/receptor could play a role for the survival of germinal centre derived lymphomas, as supported by the earlier findings in CLL [56] and further supporting the protective effect of the low producer IL10 (rs1800872) AA genotype as well as the protective effect of the IL10RB (rs1058867) G allele [10,12]. The IL4 gene was slightly down regulated in DLBCL cells when compared to all normal B-cell subpopulations whereas the IL4R gene was down regulated in post GC B-cell subpopulations suggesting that these genes could be important at different stages of the stepwise oncogenetic process [57] and further suggesting that such genes with oncogenetic potential may be important in the multi step process of malignant transformation even if they are not found to be expressed in malignant tissue [9]. These findings needs to explored further by investigating the expression of these genes in the different B-cell subpopulation thought to be the cell of origin of the investigated B-cell malignancy [31,58]. The functional properties of these pathways obviously needs further investigation; as an example, the functional properties of IL4 gene and the distal IL10 promotor variations still remains largely unknown and so does the combined effect of these interactions on protein level [59]. Our study holds some limitations providing a possible bias. We do acknowledge that the sample size in our study was too small for in depth investigation of gene-gene interactions making our risk estimates less precise. We however do encourage that the findings from our exploratory investigation of gene-gene interactions is investigated in a larger cohort, preferably a multicenter study. The age distribution in the control group and patient group was not identical and the sample material differed between groups. We found no association between age and genotypes within the groups and we included a cohort with no reported BM involvement, however these differences between groups still could have introduced bias to our results.
We analysed 50 SNPs in inflammatory response genes with respect to risk and outcome in B-NHL. We reported a significant association between thirteen SNPs and risk and reported seven SNPs associated with outcome. Moreover we here suggest a gene-gene interaction effect in relation to risk and survival and when we combined these findings with gene expression analysis in normal and malignant B-cells we suggest that these inherited variations could play a role at different stages of the multi step process of B-cell oncogenesis. These findings further strengthened the discovered association between interacting key inflammatory response genes and B-lymphoma and we propose further studies exploring the functional aspects of these interactions. As for earlier studies on genetics in lymphoma, our results were not always consistent with findings in other B-NHL cohorts. This can be a result of sample size as well as ethnical differences between study populations [51] although we have a well defined, ethnically homogenous population with a long follow up period. Despite limitations of our study, we believe that our findings confirms some of the earlier reported findings and adds new knowledge to the immunogenetics as an important factor in relation to risk and outcome in B-NHL.
Supporting Information
S1 Fig. LD plots for the TNFA, IL-1 and IL-10 loci.
S1 Table. Assay information 50SNPs genotyped in 31 genes.
S2 Table. Association between SNPs and B-NHL risk
S3 Table. Association between SNPs and DLBCL risk.
S4 Table. Association between SNPs and risk of FL
S5 Table. Assoication between SNPs and 10 year overall survival for B-NHL. The model is adjusted for sex, IPI and treatment.
S6 Table. Assoication between SNPs and 10 year overall survival for DLBCL. The model is adjusted for sex, IPI and treatment.
S7 Table. Assoication between SNPs and 10 year overall survival for FL. The model is adjusted for sex, IPI and treatment.
S8 Table. Gene-gene interactions in relation to overall survival in all patients
S9 Table. Gene-gene interactions in relation to overall survival in DLBCL
S10 Table. Gene-gene interactions in relation to overall survival in FL
S1 Text. Supplementary methods.
Author Contributions
Conceived and designed the experiments: KRN HEJ. Performed the experiments: KRN RS AS KSB JSB KD. Analyzed the data: KRN MDB MRD MB. Contributed reagents/materials/analysis tools: KRN RS HEJ. Wrote the paper: KRN MDB MRD HEJ JSB KD JB MB PJ TMH RS KSB AS.
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- 19. Lech-Maranda E, Baseggio L, Bienvenu J, Charlot C, Berger F, Rigal D, et al. Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma. Blood. 2004;103: 3529–34. pmid:14701701
- 20. Kube D, Hua T-D, von Bonin F, Schoof N, Zeynalova S, Klöss M, et al. Effect of interleukin-10 gene polymorphisms on clinical outcome of patients with aggressive non-Hodgkin's lymphoma: an exploratory study. Clin Cancer Res. 2008;14: 3777–84. pmid:18559596
- 21. Cerhan JR, Ansell SM, Fredericksen ZS, Kay NE, Liebow M, Call TG, et al. Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma. Blood. 2007;110: 4455–63. pmid:17827388
- 22. Smedby KE, Foo JN, Skibola CF, Darabi H, Conde L, Hjalgrim H, et al. GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma. PLoS Genet. 2011;7: e1001378. pmid:21533074
- 23. Cerhan JR, Fredericksen ZS, Novak AJ. A Two-Stage Evaluation of Genetic Variation in Immune and Inflammation Genes with Risk of Non-Hodgkin Lymphoma Identifies New Susceptibility Locus in 6p21.3 Region. 2012;
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- 26. Forrest MS, Skibola CF, Lightfoot TJ, Bracci PM, Willett EV, Smith MT, et al. Polymorphisms in innate immunity genes and risk of non-Hodgkin lymphoma. Br J Haematol. 2006;134: 180–3. pmid:16740140
- 27. Nieters A, Beckmann L, Deeg E, Becker N. Gene polymorphisms in Toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk. Genes Immun. 2006;7: 615–24. pmid:16971956
- 28. Lu Y, Abdou AM, Cerhan JR, Morton LM, Severson RK, Davis S, et al. Human leukocyte antigen class I and II alleles and overall survival in diffuse large B-cell lymphoma and follicular lymphoma. ScientificWorldJournal. 2011;11: 2062–70. pmid:22125456
- 29. Cerhan JR, Wang S, Maurer MJ, Ansell SM, Geyer SM, Cozen W, et al. Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival. Blood. 2007;109: 5439–46. pmid:17327408
- 30. Habermann TM, Wang SS, Maurer MJ, Morton LM, Lynch CF, Ansell SM, et al. Host immune gene polymorphisms in combination with clinical and demographic factors predict late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era. Blood. 2008;112: 2694–702. pmid:18633131
- 31. Johnsen HE, Bergkvist KS, Schmitz A, Kjeldsen MK, Hansen SM, Gaihede M, et al. Cell of origin associated classification of B-cell malignancies by gene signatures of the normal B-cell hierarchy. Leuk Lymphoma. 2013; 1–10.
- 32. Rasmussen T, Haaber J, Dahl IM, Knudsen LM, Kerndrup GB, Lodahl M, et al. Identification of translocation products but not K-RAS mutations in memory B cells from patients with multiple myeloma. Haematologica. 2010;95: 1730–7. pmid:20511669
- 33. Nielsen KR, Steffensen R, Boegsted M, Baech J, Lundbye-Christensen S, Hetland ML, et al. Promoter polymorphisms in the chitinase 3-like 1 gene influence the serum concentration of YKL-40 in Danish patients with rheumatoid arthritis and in healthy subjects. Arthritis Res Ther. 2011;13: R109. pmid:21714862
- 34. Bergkvist KS, Nyegaard M, Bøgsted M, Schmitz A, Bødker JS, Rasmussen SM, et al. Validation and implementation of a method for microarray gene expression profiling of minor B-cell subpopulations in man. BMC Immunol. 2014;15: 3. pmid:24483235
- 35. Gentleman RC, Gentleman RC, Carey VJ, Carey VJ, Bates DM, Bates DM, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5: R80. pmid:15461798
- 36. Dai M, Wang P, Boyd AD, Kostov G, Athey B, Jones EG, et al. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res. 2005;33: 1–9.
- 37. Cerhan JR, Berndt SI, Vijai J, Ghesquières H, McKay J, Wang SS, et al. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet. 2014;46.
- 38. Bourke E, Bosisio D, Golay J, Polentarutti N, Mantovani A. The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Blood. 2003;102: 956–63. pmid:12689944
- 39. Carvalho A, Cunha C, Almeida AJ, Osório NS, Saraiva M, Teixeira-Coelho M, et al. The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma. Genes Immun. 2012;13: 197–201. pmid:21866115
- 40. Vijai J, Kirchhoff T, Schrader K a, Brown J, Dutra-Clarke AV, Manschreck C, et al. Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies. PLoS Genet. 2013;9: e1003220. pmid:23349640
- 41. Gibson TM, Wang SS, Cerhan JR, Maurer MJ, Hartge P, Habermann TM, et al. letters Inherited genetic variation and overall survival following follicular lymphoma. 2012; 724–726.
- 42. Hosgood HD, Purdue MP, Wang SS, Zheng T, Morton LM, Lan Q, et al. A pooled analysis of three studies evaluating genetic variation in innate immunity genes and non-Hodgkin lymphoma risk. Br J Haematol. 2011;152: 721–6. pmid:21250972
- 43. Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AE, de Haas M. Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood. 1997;90: 1109–14. Available: http://www.ncbi.nlm.nih.gov/pubmed/9242542 pmid:9242542
- 44. Johansen JS, Schultz NA, Jensen BV. Plasma YKL-40: a potential new cancer biomarker? Future Oncol. 2009;5: 1065–82. pmid:19792974
- 45. El-Galaly TC, Bilgrau AE, Gaarsdal E, Klausen TW, Pedersen LM, Nielsen KR, Bæch J, Bøgsted M, Dybkær K, Johansen JS, J H. Circulating TNF α and YKL-40 level is associated to remission status following salvage therapy in relapsed non-Hodgkin lymphoma. Leuk Lymphoma. 2015; 10.31.
- 46. Läubli H, Borsig L. Selectins promote tumor metastasis. Semin Cancer Biol. 2010;20: 169–77. pmid:20452433
- 47. Aschebrook-Kilfoy B, Zheng T, Foss F, Ma S, Han X, Lan Q, et al. Polymorphisms in immune function genes and non-Hodgkin lymphoma survival. J Cancer Surviv. 2012;6: 102–14. pmid:22113576
- 48. Takatsu K. Interleukin 5 and B cell differentiation. Cytokine Growth Factor Rev. 1998;9: 25–35. Available: http://www.ncbi.nlm.nih.gov/pubmed/9720754 pmid:9720754
- 49. Eurich D, Boas-Knoop S, Morawietz L, Neuhaus R, Somasundaram R, Ruehl M, et al. Association of mannose-binding lectin-2 gene polymorphism with the development of hepatitis C-induced hepatocellular carcinoma. Liver Int. 2011;31: 1006–1012. pmid:21733090
- 50. Van der Bol JM, de Jong FA, van Schaik RH, Sparreboom A, van Fessem MA, van de Geijn FE, et al. Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia. Oncologist. 2010;15: 1063–1072. pmid:20930093
- 51. Nielsen KR, Steffensen R, Haunstrup TM, Bødker JS, Dybkær K, Baech J, et al. Inherited variation in immune response genes in follicular lymphoma and diffuse large B-cell lymphoma. Leuk Lymphoma. 2015; 1–10.
- 52. Gascoyne RD, Rosenwald A, Poppema S, Lenz G. Prognostic biomarkers in malignant lymphomas. Leuk Lymphoma. 2010;51 Suppl 1: 11–9. pmid:20658955
- 53. Kay NE, Pittner BT. IL-4 biology: impact on normal and leukemic CLL B cells. Leuk Lymphoma. 2003;44: 897–903. pmid:12854886
- 54. Pound JD, Gordon J. Maintenance of human germinal center B cells in vitro. Blood. 1997;89: 919–928. pmid:9028323
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- 56. Gutiérrez NC, Ocio EM, de Las Rivas J, Maiso P, Delgado M, Fermiñán E, et al. Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals. Leukemia. 2007;21: 541–9. pmid:17252022
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Ready for Bake Off? We are!
It's that time of year again, when we all go baking crazy - because our beloved Bake Off is back! Whether you are inspired by Paul's bread challenges, Prue's pastry prowess or you simply LOVE Cake, we are always on hand with the tools you need, as well as any advice you may need!Read More

subset: commoncrawl


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A student of the Usman Institute of Technology's (UIT) and his team won the DICE VIC 2017 for their 'Home Tuition' project and got into NEST I/O. Mohammad Saad Iqbal came up with the project idea keeping in view the higher fees at the coaching centres.… Read the rest
Author Archives: Siddiqi
London Court of International Arbitration finds the Djiboutian Government's Seizure of Doraleh Terminal Illegal
An Arbitral Tribunal of the London Court of International Arbitration ("LCIA") today confirmed the illegitimacy of the Government of Djibouti's action of seizing control of the Doraleh Container Terminal from DP World. The LCIA Tribunal has ruled that Doraleh Container Terminal's Concession Agreement "remains valid and binding notwithstanding Law 202 and the 2018 Decrees".… Read the rest
Pakistan's liquid foreign reserves position
The total liquid foreign reserves held by the country stood at US$17,079.7million on 27July 2018.The break-up of the foreign reserves position is as under:-
- Foreign reserves held by the State Bank of Pakistan: US$10,349.7million
- Net foreign reserves held by commercial banks : US$6,730.0million
- Total liquid foreign reserves :US$17,079.7 million
During the week ending 27July2018,SBP's reserves increased by US$1,339million to US$10,350million, due to official inflows.… Read the rest
Jazz Introduces affordable prepaid bundle for Hajis
For the first time ever, Jazz has introduced a prepaid bundle offer for Hajis, whereby they can call their loved ones back home without having to worry about affordability. Called the Saudi Bundle, the offer includes incoming and outgoing call charges of PKR 15/min – more affordable and hassle free than the visitor SIMs available in Saudi Arab.… Read the rest
MCB Bank announces financial results for 1HFY 2018
The Board of Directors of MCB Bank Limited, met under the Chairmanship of Mian Mohammad Mansha, on August 01, 2018 to review the performance of the Bank and approve the financial statements for the half year ended June 30, 2018.
During the six months' period ended June 30, 2018, MCB Bank Limited reported Profit Before Tax (PBT) of Rs.… Read the rest
6th Pak China Business Forum – Industrial Expo 2018
COMSATS University Islamabad, Lahore Campus is organizing the 6th Pak China Business Forum – Industrial Expo 2018. This was possible after successfully organizing this event in five consecutive years, from 2012 to 2015 in Islamabad, and in Lahore during 19 to 22 March, 2016 at Expo Centre.… Read the rest
FLAVA sponsors Gilgit-Baltistan Girls Football League 2018
Pakistan's most nutritious and delicious flavored milk brand Flava sponsored Gilgit-Baltistan Girls Football League 2018. Gilgit-Baltistan Girls Football League is an initiative founded by two young and energetic sisters Karishma Inayat and Sumaira Inayat in the year 2016 to establish a football league solely for young girls from Gilgit-Baltistan.… Read the rest
A tribute to Muhammad Rafi
Houseful musical session "Rafi Ki Yadein" observed on the evening of 31st July at Arts Council of Pakistan Karachi where hundreds gathered to pay tribute to the late legendary singer Muhammad Rafi on his 38th death anniversary.
Saleem Shehzad, legendary play back singer and the focal attraction of the evening, said that today's era is a period of chaos and it is a great deal to conduct such a marvelous session to honor the late classical singers during such horrific times.… Read the rest
Jazz, KPITB and World Bank to further digitalization in KPK
Jazz has embarked on a journey to further digitalize Khyber Pakhtunkhwa (KP) in partnership with Khyber Pakhtunkhwa Information Technology Board (KPITB) and the World Bank. This will see the mobile operator invest resources in the province's 'Durshal' program and empowerment of youth through employable digital skills under the KPITB 'Youth Employment Program'.… Read the rest
ICAP announces CFAP, MSA and Final Examination results
The Institute of Chartered Accountant of Pakistan has announced the results of Certified Finance and Accounting Professional (CFAP), Multi Subject Assessment (MSA) and Final Examination held in June 2018. As many as 318 candidates qualified CFAP/Final Examination whereas 2265 candidates have obtained permanent credit.… Read the rest


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How DJI Drones can Save You Time, Stress, and Money in Fisherville KY 40023
A DJI spokesman from America also acquired in touch with us late on Friday evening (3 August) to dispute our assertion that DJI beams sensitive facts back again to China. He pointed us to an announcement issued through the firm final yr, which claims: "Some modern news tales have claimed DJI routinely shares shopper information and drone movie with authorities in China, wherever DJI is headquartered. This is fake. A junior DJI staffer misspoke all through an impromptu job interview with reporters."
DJI's products and solutions blend Superior engineering with dynamic designs. Because 2006, they've been turning heads with their intensive array of drones. We are able to't look at DJI without having mentioning the Phantom collection.
Quadcopter Price … Drone Phantom
Electronics Stores in Fisherville, Kentucky 40023
Drones for Sale in Fisherville Kentucky
Fisherville KY - BingNews Search results
Mary Wilburn Chisholm
She is survived by her daughter & son-in-law, Donna & Marshall MacDonald of Fort Worth, Texas, and her son and daughter-in-law, John, Jr. & Brenda ("Cricket") Chisholm of Fisherville, Kentucky, grandc...
Family will continue Hinsdale OTB after owner's death
His daughter, Karen Gaddy of Fisherville, Ky., is the new owner. Gaddy said she and her father actively discussed her taking the reins of the business, also called Hinsdale Harness. But she said she h...
Third CityJam concert of the season set for Thursday night
The other members are Bob Willis of North Vernon, the lead vocalist who portrays Tom Petty; John Byrne of Indianapolis, lead guitarist; and Aaron Montgomery of Fisherville, Kentucky, drums. "We do it ...
The Future Of Floyds Fork: Louisville Works to Balance Nature Preservation With Development
The Fisherville Area Neighborhood Association and the Friends ... parts where the state does not recommend coming in contact with the water. Here's how the Kentucky Environmental Quality Commission de...
Homearama features the latest in home construction and design
Fisherville, Ky. (WDRB) - For the last 51 years, Homearama has displayed custom-built new homes in the Greater Louisville area. Catalpa Farms in Fisherville is the latest subdivision in Jefferson Coun...


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Create browser game java count timePekerjaan
saya butuh fungsi CI dimana fungsi tersebut dapat mengintegrasikan devices ACR120u, Mingtech-MRF35, HID-Omnikey ke browser agar dapat membaca smartcard id. jika anda tertarik , harap mencantumkan bagaimana anda menyelesaikan permasalahan ini, dan bagaimana caranya testingnya .
Customize NopCommerce utk bisa diakses dari Mobile Browser (IPhone, Android) menggunakan template yang sudah ada. Skill Bootstrap, CSS, JQuery diperlukan. Kustomisasi pembayaran dan penghitungan biaya pengiriman menggunakan JNE. Untuk mengetahui lebih detail mengenai NOPCommerce bisa kunjungi websitenya di [login untuk melihat URL]
HELLO, I DEVELOP A WEBSITE: [login untuk melihat URL] THE WEBSITE I DEVELOP IN GOOGLE CHROME. BUT WE HAVE FEW PROBLEM IN CROSS BROWSERS (SOME FEATURES ARE NOT PERFORMING CORRECTLY) FOR EXAMPLE, YOU CAN SEE SOME PROBLEMS IN FIREFOX AS PER ATTACHEMNTS ARE YOU FAMILIAR WITH APTANA ? OUR PROGRAMER USE APTANA. OUR FTP DETAIL: 1. dev_design@[login untuk melihat URL], password : Votemenot123, ser...
I neet to fullfill the attached file excel. JOB TO BE DONE From 01/01/2018 to 30/06/2018 Facebook 4 profiles need to be counted in terms of: - number of post - for each post need to be counted the engagement: nr of likes, reactions, comments, sharing the 2 numbers need to be fullfilled in the excel as the example Instagram 15 profiles as for facebook - number of post - for each post need to be...
I need a browser extension (Chrome - compatible with both Mac and Windows) that allows user to search instagram (IG), save select posts and related content to file and apply metadata to the collected assets for organization. - user needs to activate the extension with email address - user can save #hashtags and @usernames to create "saved searches"
Currently working on a browser game that simulates real politics, economics and diplomacy.
Want a personal project management browser based (at least Chrome, Safari, Mozilla and Edge supported) responsive site built, where the user can login and setup customizable tasks & goals, for multiple members. And track them. Based on the login, each member will see their set of relevant tasks, dashboards etc. With a reward module. I am open to/prefer
Hi I need MS Access developer who can make ms access web browser which will work without emulation.
Count numbers in a plain text file
curl php simulation browser login facebook and get token, cookie
Hi I need MS Access Web browser control that uses default browser rather than the MS ActiveX control. More details will be shared via chat.
Need a program that will capture the time in and time out, while at the same time count the number of times a circuit opens, When you hit the time out button the time will stop and send the number of minutes / hours and the count of the times open via odbc to a db2 database This will have to use raspberry pi Using either PHP or Pyton
please message me if you are experienced with python, working with scripts, general things along that line. and we can talk more
i want a browser like uc browser
Hello, We would like to run WhatsApp on pc using Arc welder please if you know how to do that please bid on this project and if you do not know it then try it in your pc if you are able to do it then please bid. please watch this youtube video for your reference: [login untuk melihat URL]
The game is similar to the game [login untuk melihat URL] on ios. I just need one level and the ability to have multiplayer (10 players max). Art can be simple colored spheres. Further details to be discussed after this.
We require to have freezing popup with alert on updated browsers. When ever the page is live, ...updated browsers. When ever the page is live, it should not let the person to close the page anyhow by clicking it to any closing option for the live browser. Only feature which should let the browser to close, is to have force quit through task manger.
We require to have freezing popup with alert on updated browsers. When ever the page is live, ...updated browsers. When ever the page is live, it should not let the person to close the page anyhow by clicking it to any closing option for the live browser. Only feature which should let the browser to close, is to have force quit through task manger.
Looking for an experienced JS developer to help fix an internet Explorer bug that we are facing. We have identified the issues below that we need help to resolve: - SVG's are squished in IE 11 and below. (now fixed) -- Inserting the inline SVG code to [login untuk melihat URL] (this is to fix issues with img tags scaling .svg files wrong in IE) then removes all animations from ScrollMagic....
We need to validate 200K urls manually. So need a custom web browser where we can paste 50/100 urls at a time, and the program will load them in browser in multiple sub-windows. We will close active URLs window and copy all dead/error URLs to clipboard. The browser will load only texts, not images. We just need to see the url/website is active/functional
Hi! I need a plugin/extension that can access with people's permission their cookies on their browser. Send me details about what you require from me for this task & your price. Thanks! rahatrafi
Hi! I need a extension/addon that can access with people's permission their cookies on their browser. Send me details that you require from me for this task & your price. Thanks! rahatrafi
Web Browser Inventory Management with mobile scanning functionality. Similar to Viper. Needs: Mobile Web Browser Dashboard (with four user relationships) Dashboard User Information Admin -Should be able to generate usernames and passwords for all levels. -This dashboard should display current inventory of each office, manager, & agent by
We would like to create a Chrome Browser Extension - That is similar to [login untuk melihat URL] from its look & feel and installation process - When writing text in a text field on a website, the Extension should extract the written text and send it to our rest API - Our API will send back a value between 0 and 1 for the text - The text written, should take a
ENGLISH: I need a php script that will calculate word count for a docx file uploaded by user. The script should work with all type of docx files regardless the formatting of the document. If there are images in the docx file, script should count the words perfectly, ignoring image. The word count must be exactly the same like the number showed in ms
Requirements - Design and implement a basic Wiki 1. By definition a Wiki is, "A website on which users collaboratively modify content and structure directly from the web browser" 2. Underlying technology/language is up to you 3. Must have robust unit test code written for testing server code. 4. Must support adding new pages 5. Must support editing
I have a browser app and the app was rejected in google play console reason is (device and network violates) so this app was slove problem and upload to publish
i need someone make my website have notification feature. just like facebook . like when you open yo...need someone make my website have notification feature. just like facebook . like when you open your browser .sometime on top right of the browser have a box notice you from facebook. so my website user can see my website notification all the time .
Project detail is in [login untuk melihat URL]
I have and landing page design need to fix in safari Browser landing page : [login untuk melihat URL]
I have and landing page thats build with [login untuk melihat URL] I use a code for Form field shipping data this is the landing page [login untuk melihat URL] you ...[login untuk melihat URL] I use a code for Form field shipping data this is the landing page [login untuk melihat URL] you see the shipping date thats not working on safari Browser
...- up to you. Around the building there should be the correct streets and surroundings. Once the 3D model is done we have to put the 3D in to an Internet browser. When seen in Internet browser In Safari, Chrome, Firefox, Internet Explorer etc. I want to view the 3D building, to have the option to to zoom in and out and to rotate around the building
...viewable in browser and on mobile device Menu choices should always be displayed at the top of every screen (#8 under Purpose below) Purpose The prupose of the site is to give non-technical investors a portal site where they can 1. get information on how to purchase a specific crypto currency (not purchase through this site) 2. Create an Account
Looking to build a keyboard app like Swiftkey for Android/IOS with vanilla word suggestions. The focus will be on text features and logging users' text into a database at the backend, and is enabled on only a few apps. Minimal user interface. Should scale to a few thousand users. Similar plugin for Chrome without word suggestions, only logs text posted in textboxes, is enabled on a few websi...
Listen song from dedicated sever to any browsers using ip and port. windows server. I have alredy soft lunch song on ip and port. i just listen on server. I would like from any browser listen song with ip of server an d port
Listen song from dedicated sever to any browsers using ip and port. windows server. I have alredy soft lunch song on ip and port. i just listen on server. I would like from any browser listen song with ip of server an d port
Listen song from dedicated sever to any browsers using ip and port. windows server
A really simply PHP project. We need the total count of unreconciled transactions from all accounts in our Xero financial software using their API. Literally just require a total number of transactions as an integer using PHP, and likely cURL.
I need a time...pause and technical problems. Now my problem is when i refresh page timer doesn't count the time between refreshing and loading page (i lose 1-3s). Timer should have features to count time when button start is clicked, when page is refresh timer to not stop and time to be saved on database. Format of timer needed to be is hh:mm:ss.
...no/service/[login untuk melihat URL] In this service there a function called GetUsersSip [login untuk melihat URL] I want to count users with a SIP_Username Count SIP_Username NOT NULL You need to create a Mysql DB with two tables. One table for the customer. And one table for the output. Customer table fields: customerID Customer Link Username
Check this site: [login untuk melihat URL] Need the button to be clicked when the site load. Should work in the most used browser. Only bid on it if you can do it. I want to see a test before you win the project: Only bid if you got a working example.
wanting to count the series to java enoder and solvable, and make it work in charm mode liek suing
My project use webview using swift 4 programming languages. I need pull to refresh function and open pdf file on external browser. the code already done but need to alter it.
Hi, Im looking for web based coder who can code web browser and who can work with ms access.
Hi, Im looking for a good coder who is experience with MS Access. I want MS Access web browser control. More details will be shared via chat.
Looking for people who know what I am talking about.
We have 510 urls that we need to increase view count on. Each IP hit counts as 1 so we need about 150 to 200 ips to visit each url


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Personal Statement
I pride myself in attending local and statewide seminars to stay current with the latest techniques, and treatment planning....more
I pride myself in attending local and statewide seminars to stay current with the latest techniques, and treatment planning.
More about Dr. Rajan Babu
Dr. Rajan Babu is a trusted Gastroenterologist in Peravallur, Chennai. You can visit him at Dr. Rajan Babu@Abhijay Hospital Pvt Ltd in Peravallur, Chennai. Don't wait in a queue, book an instant appointment online with Dr. Rajan Babu on Lybrate.com.
Lybrate.com has an excellent community of Gastroenterologists in India. You will find Gastroenterologists with more than 27 years of experience on Lybrate.com. You can find Gastroenterologists online in Chennai and from across India. View the profile of medical specialists and their reviews from other patients to make an informed decision.
Lybrate.com has an excellent community of Gastroenterologists in India. You will find Gastroenterologists with more than 27 years of experience on Lybrate.com. You can find Gastroenterologists online in Chennai and from across India. View the profile of medical specialists and their reviews from other patients to make an informed decision.
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Asked for male, 75 years old from South Goa
I have trouble of rectum prolex on account of I have horrible time to pass my stools in the morning. Every night at bed time I take one measure of Cremadiet dissolved in glass of water and one tablespoon of cremmafin even that I am not getting any relief. Can Doctor suggest any alternate medication?
MBBS, M S General Surgery ,
General Surgeon, Chandigarh
hi u need to take a combination of medicines first take much of high fibre diet stop meat and chicken take plenty of fluids take tab dulcolax one tab in morning syrup cremaffin 3 tablespoon at night with 3 table spoon of isapgol at night with two tab of dulcolax at night . then in the next morning u will be olrite
Asked for Male, 22 years
Hi, From left side belly ,tissue gets pain up to left leg that's is so pain even now no diagnosed in x ray.Please suggest me something.
MBBS, PG-Diploma In Clinical Pathology
General Physician, Sri Ganganagar
Pain in the lower right hand side of the abdomen can have several different causes. The cause that must be looked into first is appendicitis. Although you are not in the right age group, and your pain is not typical, appendicitis must by ruled out. This is because it is the one cause of pain in this area which can be very dangerous to your health. Once appendicitis has been ruled out, then your doctor should seek out other possible causes of your pain. Since your hysterectomy was only partial, you still should have an ovary in that area. Ovarian cysts can cause this type of pain. If your ovary is still attached to its connective tissue, it is possible for it to twist on itself, disrupting its blood flow, and causing pain. The latter possibility is less likely. These two possible causes can be evaluated by abdominal ultrasound and may even be done in the doctor's office. Since these possible causes fall under multiple specialties, you should first see your primary care physician. He or she can take a more detailed history of your symptoms and perform a thorough abdominal exam. Your doctor may need to order some imaging (ultrasound or CT scan) of your abdomen depending on the results of your physical exam.
Asked for male, 25 years
Hi I am having ulcers for 6 years now, sometimes I don't feel pain like burning, remaining time I feel it so badly. What's the cure? I mean a total cure. I really don't want ulcer again.
MBBS, MD - General Medicine
General Physician, Delhi
Take t. Sompraz 40 mg 1-0-0 x 6 weeks (30 min before breakfast) ulcer will heal over a period of time.
Health Query
MBA (Healthcare & Hospital Administration), MBA (Healthcare), PG Diploma in Cosmatology and PG Diploma in advanced skin & Laser
Homeopath, Vapi
Drinking alcohol will aggravate your ulcer, also it destroys your stomach protective covering, if you want to live long n healthy life, you must avoid alcohol.
Asked for female, 26 years old from Bangalore
I m 23 years old. 2 days back I had constipation and when I passed the stool It was very hard. And as it passed I felt a very sharp pricking pain and irritation in the anal area. The next morning I passed stools but I even saw 2-3 tiny drops of pinkish red blood. It was definitely not my periods. It wasn't coming out from urine also, so I guess it must be from anal area only. Even now wen I pass stools there is sharp pricking pain and itching that persists for 10-15 mins even after bowel movements. There is no blood in stool. But when I pass stools it turns the toilet water fully brown. I will visit a doctor in person within a day now. But just wanted to confirm whether this is serious? Is it like anal / colon cancer or something?
Fellowship in Minimal Access Surgery, MS - General Surgery, MBBS, FICS
General Surgeon, Delhi
You might have sustained a small cut/abrasion in the anal mucosa~ `(ref. Anal fissure) avoid straining at defecation. Avoid constipation. Take plenty of fibre rich diet, liquids and fruits. You may take some laxative at bed time for few days. Wash the area with plenty of warm water at least twice a day. If it persists please consult a surgeon.
Health Query
BAMS.MD.( Ayurved)
You take Kutakghanvati 2-2 ------------------------- 1x 2 with Kutakarisht 25 ml + Water 25 ml2 hrs before meal morning n evening.
Asked for female, 44 years old from Hoshiarpur
My mother has liver hemangioma and we have Diagnosed it by The consult of a doctor and then By CT SCAN OF ABDOMEN AND BREAST. They told us that it can't be operated because it had become large 15cm and cannot be removed. The hemangioma os in liver and surgeon told us that I will not grow further and it may be liver transplanted. She had sometimes problem abdominal and back pain before diagnosis. So Please help and is there any cure for this disease in homeopathy or Ayurveda.
Homeopath, Kolkata
Yes there is a answer in Homeopathy for her hemangioma this requires a continuous treatment for some time.. You need to consult me for that.
Asked for male, 21 years old from Ambala
I suffer from pain in my lower abdomen whenever I have meals. It lasts for short time but occurs consistently. Mostly occurs after breakfast. Medicines do no good! All the tests (examinations) show that there is no problem at all. What should I do?
General Physician, Cuttack
1. It could be due to gastric/duodenal ulcer, h. Pylori infection, gerd (gastro oesophageal reflux disease). 2. Take bland diet. Avoid spicy food, 3. Take one capsule of omez daily in the morning before break fast for 4 week. 4. If no relief, do upper gi endoscopy after consulting gastro enterologist and follow the advice and treatment.
Health Query
Hi. I am 20 years old. I am feeling burn in my stomach from three days and my lips is every time drying. So. What shall I do. please tell me.
Homeopath, Faridabad
Hi,Gas and acidity is the result of constipation and indigestion.Take homoeopathic medicine to get relief:-1. Gastrobin (WSG), 10 drops+ 1/2 cup of water, half an hour before meals, 3 times a day. *Lycopodium 30, 3 drops once daily in the morning for 7 days. 2. Natrum phos 6x, 4 tablets at a time, 3 times a day 10 mins. after meals. 3. Drink 10 to 12 glasses of water daily. 4. Drink two cups of coconut water daily. 5. . Avoid heavy spicy and oily food , pickles. Revert me after 7 days.
Asked for male, 18 years old from Ulhasnagar
I am having a severe motions from 5 days, and whatever I am eating is going waste, I t doesn't look like it is been digested.
Ayurveda, Bangalore
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I have a question about tax returns for children. If my child earned income and received a W-2, do we need to file a dependent tax return?
Regarding tax returns for children, your dependent child's earned income doesn't go on your return and you can still claim your child as a dependent if the other dependency rules apply. Your child must file his or her own dependent tax return as a dependent to claim his or her own W-2 income if:
- Your child meets the filing requirements.
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Iconclude two things about George C. Scott: (1) He likes to work, and (2) he likes to be kept entertained while working. To satisfy the first thirst, he has agreed to roar, swagger, and contentedly smirk his way through two parts in "Sly Fox," doing swan dives into canopied beds as the trickster who pretends to be dying in order bilk his equally mercenary friends out of their wives and fortunes (yes, playwright‐gagman Larry Gelbart is fiddling around with Ben Jonson's "Volpone"), and riding herd on an unruly courtroom as a judge with a passion for throwing the book at people (he does throw it at one poor culprit, and big fat volume it is). To satisfy the second craving, he bas surrounded himself with a small menagerie of character comedians who might as well have their Tonys mailed to them right now and who undoubtedly would keep Mr. Scott in stitches if he weren't so infernally busy that he's left with little time to look at them. Maybe he got his kicks watching them. mug during rehearsals.
If this suggests that the evening's most boisterous comedy comes from the stumblebums who are trying curry favor with a master conniver rather than from conniver Scott himself, it is meant to. Actually, the jokes the occasion are split down the middle, or perhaps along a bias. About a third of them have an academic echo them, ss though our present author had tried to salvage sonething of the real Ben Jonson without quite succeeding in blowing the dust off the old boy; the remaining two‐thirds are pure or impure (in the sense of lascivious) Gelbart, and, it must be said, these are better for present purposes. It, so happens that Mr. Scott, pumping the plot along, given most of the neo‐Jonsonisms, and there isn't really much he can do with "Living is all that keeps me from dying" or, glancing at the bottles that litter his night‐table, "It's enough medicine to make you sick." He becomes something of a wheelhorse, then, pushing hard from behind, but where could find better?
It's when Mr. Gelbart takes full liberty, or license, to devise shtick for the likes of Jack Gilford, Bob Dishy, and Hector Elizondo that what was once rather cerebral verse becomes sumptuous contemporary vaudeville. Mr. Gilford dissolves into positively ectoplasmic awe at the sight of the treasures he may one day inherit, mouth frozen open into a pumpkin grin, the very curls that creep from beneath his headgear quivering in sensuous delight. Otherwise, he is not very responsive: with his hand halfway down a wicked wench's bosom, he falls quite asleep. It's hard to say whether he looks more like Ed Wynn playing Scrooge or somebody's mother‐in‐law as drawn by George: Price, but he's evocative, very evocative.
Bob Dishy is even more spectacularly greedy as maniacally jealous husband who can nonetheless be wheedled into bartering away the favors of his pretty young spouse (Trish Van Devere, and choice in the courtroom scene, where she is the square root of innocence); Mr. Dishy looks like a Quaker, sounds like a memory of Lbti Holtz, and is in such poor command of his eyeballs that you feel they are rolling clockwise and counterclockwise (‐rice. I think they are. Presented with an opportunity play a scene with Mr. Elizondo, he snatches at it, and at Mr. Elizondo, as though Damon had just found Pythias and had literally decided to glue himself to him.
Strictly speaking, Mr. Elizondo does not work as his fellow clowns do. He's deft, darting, deadpan, matter‐of‐factly mussing Mr. Scott's already matted hair as Mr. Scott decides that "It's time for my morning suffering," asking questions without question marks because he knows the answers beLorehand, sidestepping all.issues and swiftly slipping up stairwells; not so much to stand above the action as beside it. Servant to a wily master, he's the quiet one; his detachment is as dry as his footwork is droll. But whenContinue reading the main story
it is time to spar with Mr. Dishy, hurl himself into a slapstick routine that sets two plotters to alternately embracing each other and then wildly clawing loose, the timing so impeccable that broad comedy very nearly turns into maddened billet. Under Arthur Penn's direction, stunning stuff.
James Gallery has some splendid outbursts as a Chief of Police who assaults women on sight because he has been sexually deprived ("My wife died yesterday, and it's been hell!") and, of course, Mr. Scott neglects nothing workable that comes his way. He is especially felicitous when waxing sentimental, dwelling with great gratitude on Mr. Elizondo's eternal willingness to drink, lie and whore with him. "You are the son I never had," he concludes, smiling his rubbery, avuncular, sublimely untrustworthy sMile.
In short, when "Sly Fox" is funny it's very, very funny, and when it's not all that funny, it's still okay.
This is obviously the season to be jolly at the expense of what are customarily called classics. A question, some times a subtle one, is precisely now much dirt should done them.
If I remember correctly, when George Abbott was pa‐trier to the Rodgers‐Hart musicalization of Shakespeare's ? ? ly of Errors," he kept exactly one line of the original ? nd to make things sassier, had a clown pop out the portals to point out to the audience just which line it was. "Shakespeare!" the clown cried triumphantly, and we all knew we'd paid our dues now and could go back to playing hob with the plot and hooky from our English teachers while some funny people improvised "The Boys From Syracuse" at random.
In the post‐rock musical version of "Twelfth Night" (there having once been a very good rock version called "Your Own Thing"), Mr. Abbott once again had his adroit directorial hand at the ready. But this time, as librettist for the already departed "Music Is," he kept both too much and too little of what Shakespeare wrote. Virtually the entire lunatic plot was intact, but skeletonized. And quite a few the original lines were there, but mainly the straight ones. "This is Illyria, lady" was easy to keep: it was plain, prosy exposition, and after that terrible shipwreck Viola simply had to come to shore somewhere.
In addition to the merely ;nformative material, some early 17th‐century comedy turned up, albeit nervously. The Fool's "Many a good hanging prevents a bad marriage," together with the 12 or 16 lines that follow, put in an appearance, and I suppose no one was ever going to part with the reliable laugh that comes when Olivia, at last unveiling herself. asks if she isn't peachy to look at only to get Viola's impertinently qualified agreement, "If God did all."
The quip had been slightly tampered with, in a possibly significant way. At the St. James the tall and spunky Viola (Catherine Cox) said "If God did it all" and that little added "it" told us, more or less, what was going on. The lyricism had been excised, the rhythm flattened out in favor of a quick clarity. Presumably Richard Adler's melodies would make up for the lost music. But we'd been given just enough of the narrative and the characters and the sounds that used to come from them to want more the same, or less. Less would have given the show freedom to make its own jokes, as "Volpone" plainly does. More would have fleshed out what had been started. Caught between.
Mr. Adler's songs didn't make the necessary difference, and "Music Is" came out skinny both ways, old and new. One very pleasant tune, "Please Be Human," served two lovers quite nicely (Joel Higgins as a robustly agreeable Sebastian and Sherry Mathis as an Olivia who looked as though a Disney animator had drawn her), but it arrived very late in the proceedings. And choreographer Patricia Birch had made a splendid galop—filled with dizzying spins, Music Hall high‐kicks, clapped hands and delightfully discreet bumps — out of an Offenbachish first‐act finale, "Blind Man's Buff." But most of the tunes were casuals (they didn't seem to have endings, somehow) and Will Holt's lyrics ran to quatrains on the order of "I don't know about you/I scarcely know your name/Yet I know that life without you/ Would never be the same." And so, after an 'hour or so of increasing disappointment, you wound up sitting like patience on a monument, not quite smiling at grief.Continue reading the main story


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How does the non-profit economy affect entrepreneurship?
November 20, 2011 Editor 0
How does the non-profit economy affect entrepreneurship?
Sandrine Emin; Nathalie Schieb-Bienfait
International Journal of Entrepreneurship and Small Business, Vol. 14, No. 4 (2011) pp. 456 – 477
How and on what basis can we can analyse the entrepreneurial process in the non-profit sector? This article is based on a critical discussion of four paradigms value creation, innovation, business opportunity and creation of organisation analysed by Verstraete and Fayolle (2005). We examine how these four paradigms can help analyse social entrepreneurship. We suggest that the non-profit sector challenges these four paradigms of entrepreneurship. They suffer from limitations due to assumptions that are not compatible with the non-profit sector. Lastly we conclude that a new set of assumptions should be introduced to provide new insight into social entrepreneurship.
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Re-reading entrepreneurship in the hidden economy: commercial or social entrepreneurs? Syngenta Thoughtseeders launched to maximize innovation potential for global agricultural solutions
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On election night on Nov. 6, as returns showed Barack Obama winning, victory honks sounded in cities around the U.S. Compared to 2008, however, the mood still seemed somber, and the hope mostly absent. The president's new theme, "forward," raised more questions than answers: where's the country going, and who's leading? Pundits were clear that… Read more »
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Freedom Socialist Letters to the editor December 2012
ELECTION 2012 Great candidates It was so good to vote for two people I know for president and vice president, Stephen and Christina. To vote for socialists. To vote for community activists. To vote for a gay man and a long time union activist and community organizer. To vote for a woman of color. To… Read more »
Socialist feminist presidential campaign: bringing race and gender issues to the fore
Let's consider. The forest of laws keeping minor parties off U.S. ballots just keeps thickening; all the major media act like alternative candidates don't exist; and the price tag for being seen as any kind of "serious" contender just keeps going up. All in all, the Democratic and Republican two-party lock on the U.S. ballot… Read more »
Freedom Socialist Party candidates buoyed by strong response to socialist message
Stephen Durham "They ran on fear; we ran on belief in the potential of the working class" On July 14, 2012, former hotel workers' union activist Durham visits a picket to support locked-out employees of New York City utility Con Edison. Photo credit: Dave Schmauch / FS It doesn't take a rocket scientist to see… Read more »
La gran división: La contienda presidencial de EEUU es un reflejo de la creciente polarización de la sociedad
¿Quién va ganando? Al escribir estas líneas, del lado del Partido Demócrata, la máxima operadora política, Hillary Clinton, se enfrenta al teóricamente "independiente" Bernie Sanders, el socialista del sistema. Del lado republicano, la competencia principal existe entre dos hombres que nunca han ocupado cargos políticos: el grosero, crudo misógino y racista Donald Trump, multimillonario gracias… Read more »
The role of socialists in the union movement today
This article is an edited and updated version of a talk given by Alison Thorne at a Freedom Socialist Party (FSP) meeting on 31 August 2005. Thorne is a workplace delegate in the Community and Public Sector Union (CPSU) and an activist in the rank and file caucus, Members First. CPSU workplace delegate, Alison Thorne,… Read more »
Victorian State election November 30, 2002 – A Radical Woman hits the Socialist Alliance Campaign Trail in Lara
When I was first approached to seek preselection as a Socialist Alliance (SA) candidate for the Victorian State elections I was filled with trepidation. How was I going to cope with being thrown into the spotlight? But then I remembered that I am a member of Radical Women and could not allow silly fears to… Read more »


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i worked their for three days.Then power went out on my 3rd night the supervior told all spanish speaking people what was going on not us English speaking people what was going on so i quit. I believe that was way wrong and disrespectful to me as an American.
Fruitland, ID Schwans
YP - The Real Yellow PagesSM - helps you find the right local businesses to meet your specific needs. Search results are sorted by a combination of factors to give you a set of choices in response to your search criteria. These factors are similar to those you might use to determine which business to select from a local Yellow Pages directory, including proximity to where you are searching, expertise in the specific services or products you need, and comprehensive business information to help evaluate a business's suitability for you. "Preferred" listings, or those with featured website buttons, indicate YP advertisers who directly provide information about their businesses to help consumers make more informed buying decisions. YP advertisers receive higher placement in the default ordering of search results and may appear in sponsored listings on the top, side, or bottom of the search results page.
1. Schwan's
200 N Pennsylvania AveFruitland, ID 83619
We found1results
avoid this place for employment. i worked in the rain after being told we would be off when it rained. when i interviewed, i said i couldn't work on sundays. the communication is bad, the management has the demeanor of prison guards, and you will need to ask if you are working past 40 hours... cause no one tells you. they just assume you want to work everyday. the equipment is old and run down, and jerryrigged. i was told to operate equipment that i had no training or license for, and the thought that people may be operating heavy outdoor industrial equipment without any formal official certification is just alarming. Take a Spanish class before you go too, cause you will be at a severe disadvantage if you only speak English. But, my advice would be DON'T WORK AT DICKINSON TO BEGIN WITH!


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Turmeric Indian Restaurant
Daisy Hill QLD
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25% discount for dine in or take away Fri & Sat* 2 for 1 Buy one main course curry & get one free. Dinner only. Tuesday, Wednesday & Thursday. Dine in only. Bookings essential.
About Turmeric Indian Restaurant
Turmeric Indian Restaurant creates authentic North and South Indian dishes. They import the most exotic and flavourful spices to create magic. Be it Samosas and Chicken Tikka Masala to egg kotthu parota, palak chaat and mango brulee, you will lose your heart to them.
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*Not valid with 2 for 1 dinner or dinner packs. One Shop A Docket per customer. Not to be used in conjunction with any other offer, 2 for 1 nights, events or dinner packs.
- 7, Allamanda Dr, Daisy Hill, 4127, QLD


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We are Crowe Malaysia, one of the top 10 accounting firms in Malaysia. We are looking to hire a copywriter to write articles about the finance and accounting industry. Thus, we would prefer individuals with knowledge and expertise in writing in the related fields.
I want to create professional finance ppt which will show to potential high net worth investors, I will need to demonstrate our partnered hedge fund and fund manager's profile and ability to manage a large amount of money, the business we are doing is fund of fund. I will provide some material for you, and you will also need to do some research on the
Hi There, I am looking for experience website developer specialised incodegnitor code. I have a ready made project that require some modifications. Requirements: You must have prior experience in Fintech project and ready to share your relevant portfolio. Have worked with Bitcoin Should be reliable and quick to deliver. Reply - with subject line 'Yes I can' if you do not your applic...
...Complies with federal, state, and local financial legal requirements by studying existing and new legislation, enforcing adherence to requirements, and advising management on needed actions. • Prepares special financial reports by collecting, analysing, and summarizing account information and trends. • Maintains customer confidence and protects operations
I want freelancer who can complete finance work for me according to requirements
I m looking for accounting and finance tutors/specialists to create content in pdf format
daily, weekly & monthly collection finance software
I need a freelancer for some business plan finance excel stuff
...different logo's that I use, just to give you inspiration. (a .jpg file with the 3 different logo's and also the 3 .ai files for you to work with if needed) The company is about teaching people about Finance & Investing and how to deal with money etc. Think about things like financial freedom, giving seminars, investing, financial matters, city skyline
...providing general assistance with various projects as needed. Key Responsibilities: • Assist with Accounts Payable processing. • Act as the point person for the Concur tool. • Process new partner setups and changes. • Assist with the unclaimed property process. • Assist Accounting and Finance personnel in the resolution of accounting related issues
I need a tutor for corporate Finance. I also need a person who has good experience in Ratio Analysis of banking financial reports. I need a serious and hard working persons if u r tutor then write Tutor at top . if u r ratio analysis expert then write Ratio Analysis expert
Hi there, We are an agency that promotes investment products and services through email marketing. We're looking for someone who has experience in writing content for investment/ financial related email marketing and is able to work with us on a weekly basis. You must be able to put together email campaigns based on current offers provided to get the maximum amount of email opens and click...
I am looking to build a team of Free...tools, big data analytics, content marketing and online marketing. We are now looking to build a team of passionate freelance writers. You can be experienced in Travel, Finance, Business, HR, IT, interview articles as well as website copy-writing. Student writers are also welcome to apply for suitable projects.
...points: About the movie: • Review of the movie explaining what issue it is dealing with. • Each movie report must explain in detail a minimum of 5 "ideas/concepts/topics in finance" that the movie covers. Each movie report needs to be 2-3 pages long. However, you need to submit a single file for the entire project containing reports for all three movies
Yahoo has a message board for each stock ticker. for example here for Apple Inc. AAPL. [login to view URL] Once logged in with Yahoo one can post a message in the comment box. I need a script to be able to post a message for stock ticker XYZ using some yahoo credentials/account. Script needs to be able to run from commandline (ie. php -f [login to view URL])
I need a Accounting expert required with Finance knowledge expert for my current project. If you have knowledge please bid. Details will be shared in message with the selected freelancers. CA with certificate and stamp preferred
...following: 1. Setting up the System base currency to South African Rand (ZAR) so it updates all other currencies to cost based on the ZAR price through the standard Yahoo Finance Integration already present. 2. Ability to create new Realtime ChanSip, PJSip and IAX accounts that FREE PBX can connect to without needing to re-load A2Billing. (DB Accounts)


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July 24-july 31st. We had booked our hotel 6 months ago to ensure we had a seamless and stress free vacation and our requests accommodated. However it was a disaster for the first 3 days we were there. It wasn't until I had escalated my...More
"Ask for a room with a toilet that is functioning and the TV is working."
"Ask for a corner room they are larger and the room with the swim out pool is nice for the weekend"
"For an intimate experience, book a room in the adults-only area of the resort. Very quiet"