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Find video protocols related to scientific articles indexed in Pubmed.
Richter syndrome in chronic lymphocytic leukemia: updates on biology, clinical features and therapy.
Leuk. Lymphoma
PUBLISHED: 10-31-2014
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Abstract Richter syndrome (RS) or Richter transformation is the development of secondary aggressive lymphoma in the setting of underlying chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Most frequently CLL transforms into diffuse large B-cell lymphoma (90%) and rarely (10%) into Hodgkin lymphoma, termed Hodgkin variant of Richter syndrome (HvRS). RS is generally characterized by an aggressive clinical course and poor prognosis. In recent years, major advances have been made in understanding genetic events which relate to progression of CLL or transformation into RS. Better understanding of the molecular pathways has revealed that RS is not a single homogenous entity. The majority of cases are clonally related to the original CLL clone, while a minority develops from an unrelated clone. This review summarizes new data relating to the molecular biology and the genetic/epigenetic changes occurring during Richter transformation, and also considers the clinical features and therapy for both DLBCL-RS and Hodgkin variant-RS. leukemia, DLBCL, Hodgkin lymphoma.
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Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length.
Int. J. Cancer
PUBLISHED: 05-14-2014
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Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR?=?0.81; 95% CI: 0.72-0.92; p?=?0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy-free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR?=?1.19; 95% CI: 0.63-2.24; ptrend ?=?0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.
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Polymorphism of CD44 influences the efficacy of CD34(+) cells mobilization in patients with hematological malignancies.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-19-2014
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In the last decade, peripheral blood was the main source of hematopoietic stem cells (HSC) for autologous and allogeneic transplantation. The exact mechanisms of HSC mobilization are still not clear and the efficacy of the procedure is hardly predictable. Ligand-receptor interactions of adhesion molecules, such as SDF1/CXCR4, VLA4/VCAM-1, or CD44/osteopontin, play an important role in homing of HSC in the hematopoietic niche. There is some evidence that disruption of the ligand-receptor complex leads to the egress of HSCs to the peripheral blood. The aim of the present study was the evaluation of constitutive polymorphism of genes encoding cytokines and receptors present in the HSC niche and their impact on the efficacy of mobilization of HSCs in patients with hematological malignancies. We enrolled 110 patients (60 females and 50 males) in the study. The median age of the patients was 55 (range, 22 to 69) years. The group consisted of patients with multiple myeloma (n = 74), non-Hodgkin lymphoma (n = 19), Hodgkin lymphoma (n = 15), or acute myeloid leukemia (n = 2). The mobilization procedures comprised chemotherapy and subsequent granulocyte-colony stimulating factor (G-CSF) at a dose of 10 ?g/kg daily. The poor mobilizers group was defined according to Italian National Bone Marrow Transplant Registry criteria: patients with peak CD34(+) in the peripheral blood < 20/?L or total yield < 2 × 10(6) CD34(+) cells/kg body weight in maximum 3 aphereses. Genotyping was performed using standard PCR-based assays. The group of patients (N = 108) who achieved minimal threshold for collections (CD34(+) at least 10/?L) proceeded to apheresis. The median total yield of CD34(+) in this group was 5.6 × 10(6) cells/kg body weight, whereas the median number of cells collected during the first apheresis was 3.3 × 10(6) cells/kg body weight. Median number of days of G-CSF treatment before first apheresis was 10. Fifteen patients fulfilled the criteria for poor mobilizer. The group of poor mobilizers had higher frequency of TT genotype in rs13347 (CD44) gene (CC+ CT versus TT P = .047). Patients homozygous for T allele had a lower total yield of CD34(+) cells/kg body weight than the group with allele C (median, 3.7 × 10(6)/kg versus 5.8 × 10(6)/kg; P = .019) and a lower number of CD34(+) cells gathered during first apheresis (.95 × 10(6)/kg versus 3.3 × 10(6)/kg, P = .04). Multivariate logistic regression analysis revealed that the CD44 TT genotype was the only factor associated with 5-fold higher risk of poor mobilization (P = .037). Polymorphic variants of CXCR4 and VCAM-1 did not significantly influence the efficacy of HSCs mobilization in our group of patients. In conclusion, our results indicate that among investigated single nucleotide polymorphisms (SNPs), only CD44 rs13347 has an impact on the efficacy of HSCs mobilization in patients with hematologic malignancies. CD44 SNPs analysis may be helpful for predicting the poor mobilizers population who may benefit from newer modalities using adhesion molecules inhibitors.
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Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia.
Leuk. Lymphoma
PUBLISHED: 11-14-2013
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Long-term outcomes following newer therapies for chronic lymphocytic leukemia (CLL) have rarely been reported. This article presents the results of the final analysis of the Polish Adult Leukemia Group PALG-CLL2 study performed 10 years from final patient enrollment. With the extended follow-up time, it was found that cladribine (2-CdA)-based combinations CMC (2-CdA, cyclophosphamide, mitoxantrone) and CC (2-CdA, cyclophosphamide) administered as first-line treatment of progressive CLL resulted in significantly longer progression-free survival, but similar overall survival compared to 2-CdA monotherapy. Furthermore, the risk of potentially fatal late adverse events including infections, autoimmune complications and, particularly, secondary neoplasms was comparable among patients treated with CMC, CC or 2-CdA. The results of our analysis support the importance of long-term outcome monitoring of randomized trials in CLL.
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ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium.
Oncol. Rep.
PUBLISHED: 01-24-2013
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There is strong epidemiologic evidence indicating that common genetic variability could be implicated in pancreatic cancer risk and, to date, various loci have been proposed. In particular, there is increasing evidence of the involvement of ABO gene variability and pancreatic cancer risk. In a large multicentric study of 1,028 pancreatic ductal adenocarcinoma cases and 2,257 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium, we investigated the suggested association with increased risk for carriers of single nucleotide polymorphisms (SNPs) determining the A or B allele in comparison with the O allele, which encodes for a non-functional enzyme. Since glycosyltransferase activity, encoded by ABO, is higher for the A1 variant compared with the A2 variant, we investigated the hypothesis that A1 carriers were at an increased risk of pancreatic cancer. In our analysis, carriers of the A1 were indeed at greater risk of developing the disease. In addition, we investigated the possible influence that genetic variability at the ABO locus may have in pancreatic cancer survival, but we observed no effect in our population.
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Polymorphisms in regulators of xenobiotic transport and metabolism genes PXR and CAR do not affect multiple myeloma risk: a case-control study in the context of the IMMEnSE consortium.
J. Hum. Genet.
PUBLISHED: 01-10-2013
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The exposure to pesticides and toxic compounds in xenobiotic transport and metabolism genes has been shown to affect risk of developing multiple myeloma (MM). Therefore, we hypothesized that genetic variations in xenobiotic transport and metabolism regulator genes PXR (NR1I2) and CAR (NR1I3) could determine a difference in MM susceptibility. Ten tagging single-nucleotide polymorphisms (SNPs) for PXR and seven for the CAR genes were selected and genotyped in 627 MM cases and 883 controls collected in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium. None of the 17 SNPs investigated showed significant association with MM risk either alone or when combined in haplotypes. Significant SNP-SNP interactions were not found, neither with 58 previously genotyped polymorphisms in ABC transporters. We can therefore exclude that common genetic variants in the xenobiotic transport and metabolism regulator genes PXR and CAR affect MM risk.
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Genetics and molecular epidemiology of multiple myeloma: the rationale for the IMMEnSE consortium (review).
Int. J. Oncol.
PUBLISHED: 08-29-2011
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There is strong evidence suggesting the presence of a genetic component in the aetiology of multiple myeloma (MM). However no genetic risk factors have been unequivocally established so far. To further our understanding of the genetic determinants of MM risk, a promising strategy is to collect a large set of patients in a consortium, as successfully done for other cancers. In this article, we review the main findings in the genetic susceptibility and pharmacogenetics of MM and present the strategy of the IMMEnSE (International Multiple Myeloma rESEarch) consortium in contributing to determine the role of genetic variation in pharmacogenetics and in MM risk.
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Common genetic variation at 15q25.2 impacts on chronic lymphocytic leukaemia risk.
Br. J. Haematol.
PUBLISHED: 05-09-2011
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A genome-wide association study of chronic lymphocytic leukaemia (CLL) suggested that common variants at 15q25.2 (rs783540) and 18q21.1 (rs1036935) influence CLL. To validate these associations and explore their relationship with CLL risk we genotyped case-control datasets from Poland, UK and Italy totalling 1428 cases and 1920 controls. Combined data from these and previously genotyped series (2503 cases and 5789 controls) provided evidence for an association between 15q25.2 and 18q21.1 loci and CLL risk (P(combined) = 1·10 × 10(-7) and 1·30 × 10(-5) respectively). These data provide further evidence for the involvement of common genetic variants in CLL risk and insight into the biological basis of disease development.
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Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study).
J. Clin. Oncol.
PUBLISHED: 03-08-2010
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PURPOSE Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. PATIENTS AND METHODS Patients received cladribine at 0.12 mg/kg combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (CC regimen) or fludarabine at 25 mg/m(2) combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (FC regimen), every 28 days for up to six cycles. The primary end point was complete response (CR) rate. Secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. RESULTS Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms. CONCLUSION Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.
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Current and emerging treatments for chronic lymphocytic leukaemia.
Drugs
PUBLISHED: 11-17-2009
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Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in Europe and North America. The disease is characterized by proliferation and accumulation of small CD5+ B cells in blood, lymph nodes, spleen, liver and bone marrow. The natural clinical course of CLL is highly variable, and chemotherapy is usually not indicated in early and stable disease. However, patients with progressive and more advanced CLL require treatment. For many years, chlorambucil with or without corticosteroids was used in previously untreated patients with CLL. More recently, purine nucleoside analogues (PNAs) [fludarabine, cladribine and pentostatin] have been included in treatment approaches for this disease, and chlorambucil is no longer the leading standard everywhere. Currently, this drug is rather recommended for the treatment of older, unfit patients with co-morbidities, especially in European countries. Significantly higher overall response (OR) and complete response (CR) rates in patients treated initially with PNAs than in those treated with chlorambucil or cyclophosphamide-based combination regimens have been confirmed in randomized, prospective, multicentre trials. Moreover, PNAs administered in combination with cyclophosphamide produce higher response rates, including CR and molecular CR, compared with PNA as monotherapy. Recent reports suggest that the administration of monoclonal antibodies (mAbs) can significantly improve the course of CLL. At present, two mAbs have the most important clinical value in patients with CLL. The first is rituximab, a human mouse antibody that targets CD20 antigens, and the second is alemtuzumab, a humanized form of a rat antibody active against CD52. Several recent reports suggest that in patients with CLL, rituximab combined with a PNA can increase the OR and CR rates compared with PNA or rituximab alone, with acceptable toxicity. In randomized trials, the combination of rituximab with fludarabine and cyclophosphamide (FC-R regimen) demonstrated higher rates of OR, CR and progression-free survival in patients with previously untreated and relapsed or refractory CLL than fludarabine plus cyclophosphamide (FC regimen). Several reports have confirmed significant activity with alemtuzumab in relapsed or refractory CLL, as well as in previously untreated patients. Recently, several new agents have been investigated and have shown promise in treating patients with CLL. These treatments include new mAbs, agents targeting the antiapoptotic bcl-2 family of proteins and receptors involved in mediating survival signals from the microenvironment, antisense oligonucleotides and other agents. The most promising are new mAbs directed against the CD20 molecule, lumiliximab and anti-CD40 mAbs. Oblimersen, alvocidib (flavopiridol) and lenalidomide are also being evaluated both in preclinical studies and in early clinical trials. In recent years, a significant improvement in haematopoietic stem cell transplantation (HSCT) procedures in patients with high-risk CLL has been observed. However, the exact role of HSCT, autologous or allogeneic, in the standard management of CLL patients is still undefined.
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ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer.
Int J Colorectal Dis
PUBLISHED: 04-16-2009
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The aim of this study was to determine the significance of three most common single-nucleotide polymorphisms (SNPs) of ABCB1 gene in the development of colorectal cancer and to estimate the influence of these SNPs to surviving patients treatment combination adjuvant therapy 5-fluorouracil/leucovorin. Haplotype structure of ABCB1 was analysed, and degree of linkage disequilibrium (LD) between SNPs of ABCB1 was estimated.
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Activity of cladribine combined with cyclophosphamide in frontline therapy for chronic lymphocytic leukemia with 17p13.1/TP53 deletion: report from the Polish Adult Leukemia Group.
Cancer
PUBLISHED: 03-11-2009
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The 17p13.1 deletion that causes loss of the p53-encoding TP53 gene is the most powerful predictor of a poor response to conventional therapy and shortened survival in patients with chronic lymphocytic leukemia (CLL). The results of this study have demonstrated that the cladribine and cyclophosphamide regimen may improve treatment results in this poor-risk patient population.
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Polymorphisms and haplotypes in the multidrug resistance 1 gene (MDR1/ABCB1) and risk of multiple myeloma.
Leuk. Res.
PUBLISHED: 02-28-2009
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MDR1(ABCB1) gene encodes for P-glycoprotein (P-gp, MDR1, ABCB1), an ATP-binding cassette superfamily member involved in the transport of xenobiotics. Here, we investigated whether common MDR1 single nucleotide polymorphisms (1236C>T, 2677G>A/T and 3435C>T) affect predisposition to multiple myeloma. Genotyping was performed in 111 myeloma patients and 96 controls by PCR-based assays. Haplotypes were inferred using PHASE algorithm. We found comparable allele and genotype frequencies among myeloma patients and controls. Moreover, patient and control groups did not differ regarding MDR1 haplotype distribution (p=0.18). In conclusion, our results do not support major influence of MDR1 variants on the risk of myeloma in Caucasians.
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CD38 gene polymorphisms contribute to genetic susceptibility to B-cell chronic lymphocytic leukemia: evidence from two case-control studies in Polish Caucasians.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-24-2009
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Given the recent findings on the importance of CD38 signaling in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), we hypothesized that single nucleotide polymorphisms (SNP) in the CD38 gene may be related to B-CLL risk. We evaluated two potentially functional CD38 SNPs, intronic rs6449182 (184C>G) and missense rs1800561 (418C>T, Arg140Trp) in two hospital-based case-control studies (study A and validation study B). Genotyping was done using PCR-based assays in a total of 460 Polish Caucasian patients with B-CLL and 503 age-matched and gender-matched controls. We found that frequencies of both variant alleles (rs6449182 G and rs1800561 T) were significantly higher in B-CLL. In study A, logistic regression analysis revealed an association between B-CLL and genotypes: rs6449182 CG [odds ratio (OR), 3.57; 95% confidence interval (95% CI), 2.4-5.3], rs6449182 GG (OR, 5.2; 95% CI, 2.36-11.5), and rs1800561 CT (OR, 6.72; 95% CI, 1.5-30.1), although no homozygous rs1800561 TT genotype was detected in either study. These results were confirmed in study B, which showed an association between B-CLL and genotypes rs6449182 CG (OR, 4.00; 95% CI, 2.7-6.0), rs6449182 GG (OR, 12.84; 95% CI, 4.3-38.7), and rs1800561 CT (OR, 10.12; 95% CI, 1.3-81.6), and in the combined analysis of both studies. We also observed that rs6449182 G carriers had more advanced clinical stage (P=0.002) and tended to be younger at diagnosis (P=0.056). Furthermore, we found higher CD38 transcript levels and higher proportions of CD38-positive cells in carriers of rs6449182 G and rs1800561 T alleles (P<0.05 for all comparisons). In conclusion, our data show that CD38 SNPs may affect CD38 expression and contribute to the increased risk of B-CLL carcinogenesis.
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Evaluation of circulating endothelial cells as noninvasive marker of angiogenesis in patients with chronic lymphocytic leukemia.
Leuk. Lymphoma
PUBLISHED: 01-07-2009
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An increased angiogenesis has been documented in bone marrow and lymph nodes of patients with chronic lymphocytic leukemia (CLL). There is accumulating evidence that circulating endothelial cells (CECs) play an important role in angiogenesis. The aim of our study was to compare the number of CECs in peripheral blood of CLL patients and healthy donors and to correlate these numbers with bone marrow microvessel density (MVD) and known prognostic factors in CLL. Proportions of resting CECs (rCECs), activated CECs (aCECs), apoptotic CECs (apoCECs) and circulating precursor endothelial cells (CPECs) were estimated by flow cytometry in 104 untreated CLL patients and 29 healthy blood donors. The MVD was analysed in the bone marrow biopsy in 21 CLL patients and 11 controls using the hot spot analysis of vessels density (x200 HPS). We found significantly higher numbers of CPECs, rCECs, aCECs and apoCECs in CLL patients than in healthy controls (p < 0.001 for all comparisons). Furthermore, the rCECs number was higher in advanced versus low clinical stage CLL (median 17.5 cells/microL vs. 13.5 cells/microL, p = 0.05). The MVD was significantly higher in the bone marrow of CLL patients when compared with controls (p = 0.016). However, we did not find any correlation between MVD and different CECs populations. In conclusion, the number of CECs is increased in CLL and correlates with stage of the disease, but does not seem to directly reflect the intensity of neovascularisaton in the bone marrow.
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Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium.
Dig Liver Dis
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Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going.
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Comprehensive investigation of genetic variation in the 8q24 region and multiple myeloma risk in the IMMEnSE consortium.
Br. J. Haematol.
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Genome-wide association studies (GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma (MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant (P = 0·0022) association between rs2456449 and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.