111 research outputs found
Human P2X7 receptor causes cycle arrest in RPMI-8226 myeloma cells to alter the interaction with osteoblasts and osteoclasts
Multiple myeloma is a malignant expansion of plasma cells and aggressively affects bone health. We show that P2X7 receptor altered myeloma growth, which affects primary bone cells in vitro. Expression on six human myeloma cell lines confirmed the heterogeneity associated with P2X7 receptor. Pharmacology with 2â˛(3â˛)-O-(4-benzoylbenzoyl) adenosine 5â˛-triphosphate (BzATP) as agonist showed dose-dependent membranal pores on RPMI-8226 (p = 0.0027) and blockade with P2X7 receptor antagonists. Ca2+ influx with increasing doses of BzATP (p = 0.0040) was also inhibited with antagonists. Chronic P2X7 receptor activation reduced RPMI-8226 viability (p = 0.0208). No apoptosis or RPMI-8226 death was observed by annexin V/propidium iodide (PI) labeling and caspase-3 cleavage, respectively. However, bromodeoxyuridine (BrdU) labelling showed an accumulation of RPMI-8226 in the S phase of cell cycle progression (61.5%, p = 0.0114) with significant decline in G0/G1 (5.2%, p = 0.0086) and G2/M (23.5%, p = 0.0015) phases. As myeloma pathology depends on a positive and proximal interaction with bone, we show that P2X7 receptor on RPMI-8226 inhibited the myeloma-induced suppression on mineralization (p = 0.0286) and reversed the excessive osteoclastic resorption. Our results demonstrate a view of how myeloma cell growth is halted by P2X7 receptor and the consequences on myelomaâosteoblast and myelomaâosteoclast interaction in vitro
Single Nucleotide Polymorphisms in IL1B and the Risk of Acute Coronary Syndrome: A Danish Case-Cohort Study
BACKGROUND: Interleukin-1B (IL-1B) is a key pro-inflammatory cytokine that has been associated with the development of atherosclerosis and myocardial infarction. However, the prospective associations between functional single nucleotide polymorphisms (SNPs) in IL1B and incident acute coronary syndrome (ACS) have not been thoroughly investigated. The aims of this study were to examine the associations between individual SNPs in and SNP haplotypes of the promoter region of IL1B and incident ACS in a prospective study. Furthermore, we wanted to explore potential interactions with other risk factors for ACS on an additive scale. METHODOLOGY/PRINCIPAL FINDINGS: The present study was based on the Danish prospective study Diet, Cancer and Health comprising more than 57 000 participants aged 50-64 at baseline. During a median follow-up of 7.2 years we identified 989 cases of incident ACS (755 men and 234 women). All cases were validated by review of medical records, and information on covariates was collected by study technicians. The study was conducted according to a case-cohort study design including ACS cases and a sex-stratified sub cohort of 1663 participants drawn randomly from the entire cohort. Weighted Cox proportional hazard models with age as time axis were used in the statistical analyses. Individual IL1B SNPs, SNP haplotypes, or haplotype combinations were not significantly associated with incident ACS, and, likewise, we found no evidence of interaction on an additive scale between IL1B haplotypes and risk factors, respectively. CONCLUSIONS/SIGNIFICANCE: Genetic variation in the promoter region of IL1B may not be associated with incident ACS in men or women above the age of 50 years
A polygenic risk score for multiple myeloma risk prediction
There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53â4.69, p = 3.55 Ă 10â15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34â4.33, p = 1.62 Ă 10â13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population
Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups
<p>Abstract</p> <p>Background</p> <p>A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, <it>ERCC1</it>, <it>ERCC2</it>, and <it>PPP1R13L </it>(aka <it>RAI</it>) are related to DNA repair and cell survival, and one, <it>CD3EAP</it>, aka <it>ASE1</it>, may be related to cell proliferation. The whole region seems related to the cellular response to external damaging agents and markers in it are associated with risk of several cancers.</p> <p>Methods</p> <p>We downloaded the genotypes of all markers typed in the 19q13.3 region in the HapMap populations of European, Asian and African descent and inferred haplotypes. We combined the European HapMap individuals with a Danish breast cancer case-control data set and inferred the association between HapMap haplotypes and disease risk.</p> <p>Results</p> <p>We found that the susceptibility haplotype in our European sample had increased from 2 to 50 percent very recently in the European population, and to almost the same extent in the Asian population. The cause of this increase is unknown. The maximal proportion of overall genetic variation due to differences between groups for Europeans versus Africans and Europeans versus Asians (the F<sub>st </sub>value) closely matched the putative location of the susceptibility variant as judged from haplotype-based association mapping.</p> <p>Conclusion</p> <p>The combined observation that a common haplotype causing an increased risk of cancer in Europeans and a high differentiation between human populations is highly unusual and suggests a causal relationship with a recent increase in Europeans caused either by genetic drift overruling selection against the susceptibility variant or a positive selection for the same haplotype. The data does not allow us to distinguish between these two scenarios. The analysis suggests that the region is not involved in cancer risk in Africans and that the susceptibility variants may be more finely mapped in Asian populations.</p
Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients
Canadian Institutes of Health Research, Grant/
Award Number: 81274; Huntsman Cancer
Institute Pilot Funds; Leukemia Lymphoma
Society, Grant/Award Number: 6067-09; the
National Institute of Health/National Cancer
Institute, Grant/Award Numbers: P30
CA016672, P30 CA042014, P30 CA13148,
P50 CA186781, R01 CA107476, R01
CA134674, R01 CA168762, R01 CA186646,
R01 CA235026, R21 CA155951, R25 CA092049, R25 CA47888, U54 CA118948;
Utah Population Database, Utah Cancer
Registry, Huntsman Cancer Center Support
Grant, Utah State Department of Health,
University of Utah; VicHealth, Cancer Council
Victoria, Australian National Health and
Medical Research Council, Grant/Award
Numbers: 1074383, 209057, 396414;
Victorian Cancer Registry, Australian Institute
of Health and Welfare, Australian National
Death Index, Australian Cancer Database;
Mayo Clinic Cancer Center; University of Pisa
and DKFZThe authors thank all site investigators that contributed to the studies
within the Multiple Myeloma Working Group (Interlymph Consortium),
staff involved at each site and, most importantly, the study participants
for their contributions that made our study possible. This work was partially
supported by intramural funds of University of Pisa and DKFZ. This
work was supported in part by the National Institute of Health/National
Cancer Institute (R25 CA092049, P30 CA016672, R01 CA134674, P30
CA042014, R01 CA186646, R21 CA155951, U54 CA118948, P30
CA13148, R25 CA47888, R01 CA235026, R01 CA107476, R01
CA168762, P50 CA186781 and the NCI Intramural Research Program),
Leukemia Lymphoma Society (6067-09), Huntsman Cancer Institute
Pilot Funds, Utah PopulationDatabase, Utah Cancer Registry, Huntsman
Cancer Center Support Grant, Utah StateDepartment of Health, University
of Utah, Canadian Institutes of Health Research (Grant number
81274), VicHealth, Cancer Council Victoria, Australian National Health
and Medical Research Council (Grants 209057, 396414, 1074383), Victorian
Cancer Registry, Australian Institute of Health and Welfare,
Australian National Death Index, Australian Cancer Database and the
Mayo Clinic Cancer Center.Open Access funding enabled and organized
by ProjektDEAL.The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10(-7) either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.Canadian Institutes of Health Research (CIHR)
81274Huntsman Cancer Institute Pilot FundsLeukemia and Lymphoma Society
6067-09United States Department of Health & Human Services
National Institutes of Health (NIH) - USA
NIH National Cancer Institute (NCI)
P30 CA016672
P30 CA042014
P30 CA13148
P50 CA186781
R01 CA107476
R01 CA134674
R01 CA168762
R01 CA186646
R01 CA235026
R21 CA155951
R25 CA092049
R25 CA47888
U54 CA118948Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of UtahVicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council
1074383
209057
396414Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer DatabaseMayo Clinic Cancer CenterUniversity of PisaHelmholtz Associatio
SARS-CoV-2 antibody prevalence among homeless people and shelter workers in Denmark:a nationwide cross-sectional study
BACKGROUND: People experiencing homelessness (PEH) and associated shelter workers may be at higher risk of infection with âSevere acute respiratory syndrome coronavirus 2â (SARS-CoV-2). The aim of this study was to determine the prevalence of SARS-CoV-2 among PEH and shelter workers in Denmark. DESIGN AND METHODS: In November 2020, we conducted a nationwide cross-sectional seroprevalence study among PEH and shelter workers at 21 recruitment sites in Denmark. The assessment included a point-of-care test for antibodies against SARS-CoV-2, followed by a questionnaire. The seroprevalence was compared to that of geographically matched blood donors considered as a proxy for the background population, tested using a total Ig ELISA assay. RESULTS: We included 827 participants in the study, of whom 819 provided their SARS-CoV-2 antibody results. Of those, 628 were PEH (median age 50.8 (IQR 40.9â59.1) years, 35.5% female) and 191 were shelter workers (median age 46.6 (IQR 36.1â55.0) years and 74.5% female). The overall seroprevalence was 6.7% and was similar among PEH and shelter workers (6.8% vs 6.3%, pâ=â0.87); and 12.2% among all participants who engaged in sex work. The overall participant seroprevalence was significantly higher than that of the background population (2.9%, pâ<â0.001). When combining all participants who reported sex work or were recruited at designated safe havens, we found a significantly increased risk of seropositivity compared to other participants (OR 2.23, 95%CI 1.06â4.43, pâ=â0.02). Seropositive and seronegative participants reported a similar presence of at least one SARS-CoV-2 associated symptom (49% and 54%, respectively). INTERPRETATIONS: The prevalence of SARS-CoV-2 antibodies was more than twice as high among PEH and associated shelter workers, compared to the background population. These results could be taken into consideration when deciding in which phase PEH are eligible for a vaccine, as part of the Danish national SARS-CoV-2 vaccination program rollout. FUNDING: TrygFonden and HelseFonden. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-022-13642-7
Polymorphisms in NFkB, PXR, LXR and risk of colorectal cancer in a prospective study of Danes
<p>Abstract</p> <p>Background</p> <p>Transcription factors and nuclear receptors constitute a link between exposure to heterocyclic amines and polycyclic aromatic hydrocarbons from meat and tobacco smoke and colorectal cancer (CRC) risk. The aim of this study was to investigate if polymorphisms in nuclear factor kappa-B, pregnane X receptor, and liver X receptor were associated with risk of CRC, and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use.</p> <p>Methods</p> <p>The polymorphisms nuclear factor kappa-B (<it>NFkB, NFKB1) </it>-94 insertion/deletion ATTG (rs28362491), pregnane X receptor (<it>PXR, NR1I2) </it>A-24381C (rs1523127), C8055T (rs2276707), A7635G (rs6785049), liver X receptor (<it>LXR-β, NR1H3) </it>C-rs1405655T, T-rs2695121C were assessed together with lifestyle factors in a nested case-cohort study of 378 CRC cases and 756 random participants from the Danish prospective Diet, Cancer and Health study of 57,053 persons.</p> <p>Results</p> <p>Carriers of <it>NFkB </it>-94deletion were at 1.45-fold higher risk of CRC than homozygous carriers of the insertion allele (incidence rate ratio (IRR) = 1.45, 95% confidence interval (95% CI): 1.10-1.92). There was interaction between this polymorphism and intake of red and processed meat in relation to CRC risk. Carriers of <it>NFkB </it>-94deletion were at 3% increased risk pr 25 gram meat per day (95% CI: 0.98-1.09) whereas homozygous carriers of the insertion were not at increased risk (p for interaction = 0.03). <it>PXR </it>and <it>LXR </it>polymorphisms were not associated with CRC risk. There was no interaction between use of nonsteroid antiinflammatory drugs (NSAID) or smoking status and <it>NFkB</it>, <it>PXR </it>or <it>LXR </it>polymorphisms.</p> <p>Conclusions</p> <p>A polymorphism in <it>NFkB </it>was associated with CRC risk and there was interaction between this polymorphism and meat intake in relation to CRC risk. This study suggests a role for NFkB in CRC aetiology.</p
Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group
This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes
Consequences Of On-Track Competition In Railways By Use Of Simulations
Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne
Polymorphisms within autophagy-related genes as susceptibility biomarkers for multiple myeloma: a meta-analysis of three large cohorts and functional characterization
Functional data used in this project have been meticulously catalogued and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/, accessed on 12 February 2020) using the MOLGENIS open-source platform for scientific data.Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the
bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains,
resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a
dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development,
but also ensuring MM cell survival and promoting resistance to treatments. To date no studies
have determined the impact of genetic variation in autophagy-related genes on MM risk. We
performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and
6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms
(SNPs; p < 1 Ă 10â9) with immune responses in whole blood, peripheral blood mononuclear
cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy
donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46,
IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 Ă 10â4â5.79 Ă 10â14).
Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations
of vitamin D3 (p = 4.0 Ă 10â4), whereas the IKBKErs17433804 SNP correlated with the number of
transitional CD24+CD38+ B cells (p = 4.8 Ă 10â4) and circulating serum concentrations of Monocyte
hemoattractant Protein (MCP)-2 (p = 3.6 Ă 10â4). We also found that the CD46rs1142469 SNP corre lated with numbers of CD19+ B cells, CD19+CD3â B cells, CD5+ IgDâ cells, IgMâ cells, IgDâIgMâ
cells, and CD4âCD8â PBMCs (p = 4.9 Ă 10â4â8.6 Ă 10â4
) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels
of CD4+EMCD45RO+CD27â cells (p = 9.3 Ă 10â4
). These results suggest that genetic variants within
these six loci influence MM risk through the modulation of specific subsets of immune cells, as well
as vitamin D3â, MCP-2â, and IL20-dependent pathways.This work was supported by the European Unionâs Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), ConsejerĂa de TransformaciĂłn EconĂłmica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de CĂĄncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB).This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)âproject UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)
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