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Find video protocols related to scientific articles indexed in Pubmed.
The SIPA1 -313A>G polymorphism is associated with prognosis in inoperable non-small cell lung cancer.
Tumour Biol.
PUBLISHED: 07-11-2014
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Polymorphism in signal-induced proliferation-associated 1 (SIPA1) gene may contribute to the development of metastasis in human cancers. In this preliminary study, we examined the association of the SIPA1 -313A>G (rs931127) polymorphism with overall survival (OS) and progression-free survival (PFS) in 351 inoperable patients with non-small cell lung cancer (NSCLC) treated with radiotherapy or radiochemotherapy (curative or palliative). The GG homozygotes had significantly shorter PFS under codominant and recessive models in all patients (hazard ratio (HR) 1.47, p?=?0.035, and HR 1.47, p?=?0.022, respectively) and in advanced stage subgroup (HR 1.49, p?=?0.037, and HR 1.48, p?=?0.023, respectively). The GG genotype was also associated with reduced OS and PFS (codominant model: HR 2.41, p?=?0.020, and HR 2.34, p?=?0.020, respectively; recessive model: HR 2.16, p?=?0.026, and HR 2.18, p?=?0.022, respectively) in radiotherapy alone subgroup. Moreover, the SIPA1 -313GG was identified as an independent adverse prognostic factor for PFS in the cohort. Our results indicate, for the first time, that the SIPA1 -313A>G may have a prognostic role in unresected NSCLC making it a potential predictor of poor survival due to earlier progression.
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HSPA2 is expressed in human tumors and correlates with clinical features in non-small cell lung carcinoma patients.
Anticancer Res.
PUBLISHED: 06-13-2014
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It has been shown that HSPA2 protein, a testis-enriched member of HSPA/HSP70 family, is important for cancer cell growth and metastasis. However, the status of HSPA2 expression in tumors and its clinical/prognostic significance are obscure. Herein we aimed to investigate the expression of HSPA2 in various types of tumors and to determine the possible clinical and prognostic significance of HSPA2 in non-small cell lung carcinoma (NSCLC).
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Influence of genetic polymorphisms on biomarkers of exposure and effects in children living in Upper Silesia.
Mutagenesis
PUBLISHED: 07-18-2013
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This article is a follow-up to our previous molecular epidemiology studies on the DNA damage in children from the Upper Silesia region of Poland. It is expected that metabolic and DNA repair gene polymorphisms may modulate individual susceptibility to environmental exposure. In this study, we investigate the association between polymorphisms of metabolising (CYP2D, EPHX1, GSTM1, GSTP1, GSTT1, NAT2) and DNA repair (XPD, XRCC1, XRCC3) genes and selected biomarkers of exposure and effect such as levels of 1-hydroxypyrene (1-OHP) and urinary mutagenicity, aromatic DNA adducts, sister chromatid exchange (SCE) and micronuclei (MN) in 74 children. Both 1-OHP concentration and urinary mutagenicity tested by TA98+S9 were significantly higher in individuals with EPHX1 (exon 4) Arg/Arg genotype than in individuals with other genotype. The EPHX1 (exon 3) significantly affected urinary mutagenicity tested with strain YG1024+S9. The urinary mutagenicity in individuals with Tyr/Tyr homozygotes was lower than in individuals with Tyr/His and His/His (1057±685 vs. 1432±1003 revertants/mol creatinine). XRCC3 Met/Met genotype was associated with significantly higher levels of 1-OHP in urine compared with only The/Met genotype. The PAH-DNA adduct levels in the subgroup with GSTM1 null genotype was 2-fold higher than in individuals with GSTM1 active (7.06±5.12 vs. 13.14±9.81 adduct/10(8) nucleotides). The mean level of aromatic DNA adducts in children with deletion of the GSTT1 gene was significantly higher compared with individuals with that gene present (8.03±6.23 vs. 14.66±10.70 adduct/10(8) nucleotides). Also the carriers of the XPD Lys/Lys genotype showed higher levels of DNA adducts than heterozygotes (13.16±9.70 vs. 6.81±5.86 adducts/10(8) nucleotides). Children carrying the XRCC3-241 Met/Met genotype exhibited a higher number of SCE in peripheral blood lymphocytes than carriers of Thr/Met allele (8.15±0.86 vs. 7.62±0.79 SCE/cell). It was also observed that children with the GSTP1 slow conjugator had significantly elevated MN in peripheral blood lymphocytes compared with fast conjugator (4.23±3.49 vs. 6.56±5.00 MN/1000 cells).
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Nutlin-3a, an MDM2 antagonist and p53 activator, helps to preserve the replicative potential of cancer cells treated with a genotoxic dose of resveratrol.
Mol. Biol. Rep.
PUBLISHED: 04-29-2013
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Resveratrol is a natural compound that has been intensely studied due to its role in cancer prevention and potential as an anti-cancer therapy. Its effects include induction of apoptosis and senescence-like growth inhibition. Here, we report that two cancer cell lines (U-2 OS and A549) differ significantly in their molecular responses to resveratrol. Specifically, in U-2 OS cells, the activation of the p53 pathway is attenuated when compared to the activation in A549 cells. This attenuation is accompanied by a point mutation (458: CGA?TGA) in the PPM1D gene and overexpression of the encoded protein, which is a negative regulator of p53. Experimentally induced knockdown of PPM1D in U-2 OS cells resulted in slightly increased activation of the p53 pathway, most clearly visible as stronger phosphorylation of p53 Ser37. When treated with nutlin-3a, a non-genotoxic activator of p53, U-2 OS and A549 cells both responded with substantial activation of the p53 pathway. Nutlin-3a improved the clonogenic survival of both cell lines treated with resveratrol. This improvement was associated with lower activation of DNA-damage signaling (phosphorylation of ATM, CHK2, and histone H2AX) and higher accumulation of cells in the G1 phase of the cell cycle. Thus, the hyperactivation of p53 by nutlin-3a helps to preserve the replicative potential of cells exposed to resveratrol.
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Genetic variation in ALCAM and other chromosomal instability genes in breast cancer survival.
Breast Cancer Res. Treat.
PUBLISHED: 07-24-2011
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Chromosomal instability is a hallmark of many cancers and it has a potential to predict clinical outcome of a cancer patient. We hypothesized that genes whose expression status differs between chromosomal stable and unstable breast tumors represent target genes for the identification of genetic variants predicting breast cancer (BC) risk, disease progression, and survival. We used a published list of 38 genes associated with chromosomal instability as a basis for searching potentially functional and informative tagging single nucleotide polymorphisms (SNPs). As a result, 33 SNPs in 16 genes were genotyped in a population-based series of 783 Swedish BC cases. Two SNPs in the ALCAM gene associated with BC-specific survival. For rs1044243, the HR was 4.35 (95% CI 1.34-14.18), and for rs1157, the HR was 3.42 (95% CI 1.32-8.83) for the homozygous carriers of the minor alleles. For the minor allele carriers of CCL18 SNP rs14304, we observed a significant association with aggressive tumor characteristics: large tumor size (OR 1.53, 95% CI 1.10-2.14), positive lymph node metastasis (OR 1.75, 95% CI 1.02-3.00), and high stage (OR 1.37, 95% CI 1.02-1.85). In a Polish population consisting of 506 familial/early onset BC cases, no association with event-free survival for the ALCAM SNPs nor any association with tumor characteristics for the CCL18 SNP were observed, suggesting either a chance finding in the Swedish population or population-based or etiological differences between sporadic and familial/early onset BC.
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Single nucleotide polymorphisms in the 20q13 amplicon genes in relation to breast cancer risk and clinical outcome.
Breast Cancer Res. Treat.
PUBLISHED: 03-23-2011
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The 20q13 region is frequently amplified/overexpressed in breast tumours. However, the nature of this amplification/overexpression is unknown. Here, we investigated genetic variation in five 20q13 amplicon genes (MYBL2, AURKA, ZNF217, STK4 and PTPN1) and its impact on breast cancer (BC) susceptibility and clinical outcome. As a novel finding, four polymorphisms in STK4 (rs6017452, rs7271519) and AURKA (rs2273535, rs8173) associated with steroid hormone receptor status both in a Swedish population-based cohort of 783 BC cases and in a Polish familial/early onset cohort of 506 BC cases. In the joint analysis, the minor allele carriers of rs6017452 had more often hormone receptor positive tumours (OR 0.57, 95% CI 0.40-0.81), while homozygotes for the minor allele of rs7271519, rs2273535 and rs8173 had more often hormone receptor negative tumours (2.26, 1.30-3.39; 2.39, 1.14-5.01; 2.39, 1.19-4.80, respectively) than homozygotes for the common allele. BC-specific survival analysis of AURKA suggested that the Swedish carriers of the minor allele of rs16979877, rs2273535 and rs8173 might have a worse survival compared with the major homozygotes. The survival probabilities associated with the AURKA genotypes depended on the tumour phenotype. In the Swedish case-control study, associations with BC susceptibility were observed in a dominant model for three MYBL2 promoter polymorphisms (rs619289, P = 0.02; rs826943, P = 0.03 and rs826944, P = 0.02), two AURKA promoter polymorphisms (rs6064389, P = 0.04 and rs16979877, P = 0.02) and one 3UTR polymorphism in ZNF217 (rs1056948, P = 0.01). In conclusion, our data confirmed the impact of the previously identified susceptibility locus and provided preliminary evidence for novel susceptibility variants in BC. We provided evidence for the first time that genetic variants at 20q13 may affect hormone receptor status in breast tumours and influence tumour aggressiveness and survival of the patients. Future studies are needed to confirm the prognostic value of our findings in the clinic.
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Genetic variation in genes encoding for polymerase ? subunits associates with breast cancer risk, tumour characteristics and survival.
Breast Cancer Res. Treat.
PUBLISHED: 02-14-2011
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Chromosomal instability is a known hallmark of many cancers. DNA polymerases represent a group of enzymes that are involved in the mechanism of chromosomal instability as they have a central function in DNA metabolism. We hypothesized that genetic variation in the polymerase genes may affect gene expression or protein configuration and by that cancer risk and clinical outcome. We selected four genes encoding for the catalytic subunits of the polymerases ?, ?, ? and ? (POLB, POLD1, POLQ and REV3L, respectively) and two associated proteins (MAD2L2 and REV1) because of their previously reported association with chromosomal instability and/or tumorigenesis. We selected potentially functional and most informative tagging single nucleotide polymorphisms (SNPs) for genotyping in a population-based series of 783 Swedish breast cancer (BC) cases and 1562 controls. SNPs that showed a significant association in the Swedish population were additionally genotyped in a Polish population consisting of 506 familial/early onset BC cases and 568 controls. SNPs in all three polymerase ? subunit genes associated either with BC risk or prognosis. Two SNPs in REV3L and one SNP in MAD2L2 associated with BC risk: rs462779 (multiplicative model: OR 0.79, 95% CI 0.68-0.92), rs3204953 (dominant model: OR 1.28, 95% CI 1.05-1.56) and rs2233004 (recessive model: OR 0.49, 95% CI 0.28-0.86). Homozygous carriers of the minor allele C of the third SNP in REV3L, rs11153292, had significantly worse survival compared to the TT genotype carriers (HR 2.93, 95% CI 1.34-6.44). Minor allele carriers of two REV1 SNPs (rs6761391 and rs3792142) had significantly more often large tumours and tumours with high histological grade and stage. No association was observed for SNPs in POLB, POLQ and POLD1. Altogether, our data suggest a significant role of genetic variation in the polymerase ? subunit genes regarding the development and progression of BC.
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An association between DNA repair gene polymorphisms and survival in patients with resected non-small cell lung cancer.
Mol. Biol. Rep.
PUBLISHED: 12-09-2010
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DNA repair genetic polymorphisms have been studied extensively in relation to lung cancer susceptibility, but much less is known about their role in clinical outcome modulation. In this report, we examined effect of the XPA -4G>A, XPD Asp312Asn, Leu751Gln, hHR23B Ala249Val, XPG Asp1104His, XRCC1 Arg399Gln, XRCC2 -4234G>C and XRCC3 Thr241Met polymorphisms on overall survival in 162 patients with resected non-small cell lung cancer (NSCLC). The XRCC3 Met/Met genotype was significantly associated with increased risk of death among all patients and men in uni- and multivariate analyses. The risk was higher for adenocarcinoma patients possessing the XRCC3 Met/Met or XRCC1 Gln/Gln genotypes, although their frequency was small. The XRCC1 399Gln allele was also associated with poor prognosis in stage II-IIIA and among older individuals. Men homozygous for the XPD 312 Asn/Asn had significantly better survival with the risk of death being at borderline significance in uni- and multivariate models. Younger cases and ever smokers smoking less than median pack-years showed significantly increased risk of death associated with the XPA -4A allele. A presence of one or two XRCC2 -4234C alleles had a protective effect in males and ever smokers with lower cumulative smoking dose, although the CC genotype was rarely observed. When number of combined risk alleles was considered, we found that carriers of >4 adverse alleles were at significantly increased risk of death in uni- and multivariate models. Therefore, our results indicate that selected genetic polymorphisms in DNA repair genes may influence overall survival in resected NSCLC.
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A functional analysis of G23A polymorphism and the alternative splicing in the expression of the XPA gene.
Cell. Mol. Biol. Lett.
PUBLISHED: 03-25-2010
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The XPA gene has a commonly occurring polymorphism (G23A) associated with cancer risk. This study assessed the functional significance of this polymorphism, which is localised near the translation start codon. Lymphoblastoid cell lines with alternative homozygous genotypes showed no significant differences in their XPA levels. The luciferase reporter assay detected no functional difference between the two sequences. Unexpectedly, we found that the alternatively spliced form of XPA mRNA lacked a part of exon 1. Only the reading frame downstream of codon Met59 was preserved. The alternative mRNA is expressed in various human tissues. The analysis of the 5cDNA ends showed similar transcription start sites for the two forms. The in vitro expression of the alternative XPA labelled with the red fluorescent protein (mRFP) showed a lack of preferential nuclear accumulation of the XPA isoform. The biological role of the alternative XPA mRNA form remains to be elucidated.
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Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1.
Mech. Ageing Dev.
PUBLISHED: 06-14-2009
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Resveratrol decreases cancer risk and improves health of laboratory animals. However, it can also promote genomic instability. Part of the beneficial activity of resveratrol may result from the activation of SIRT1 deacetylase. We examined how resveratrol influenced the growth of human cancer cell lines of different origin: osteosarcoma (U-2 OS) and lung adenocarcinoma (A549) and how it modulated the expression as well as the localization of key proteins, involved in DNA repair and cell cycle regulation. Resveratrol-induced growth arrest was associated with signs of stress-induced senescence. Differential expression of BRCA1, cyclin B1, pRb and p21 in U-2 OS and A549 cells indicates that resveratrol can engage various molecular mechanisms to arrest cell cycle progression. In subset of U-2 OS cells, the upregulated BRCA1 formed foci closely associated with WRN and the telomeric protein (TRF1). Moreover, resveratrol induced telomeric instability in U-2 OS cells and the activation of DNA damage signaling in both cell lines, manifested as the phosphorylation of histone H2AX at serine 139 and of p53 at serines 15 and 37. Our data are consistent with the hypothesis that resveratrol inhibits cell growth and induces senescence by altering DNA metabolism.
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A functional promoter polymorphism in the TERT gene does not affect inherited susceptibility to breast cancer.
Cancer Genet. Cytogenet.
PUBLISHED: 04-22-2009
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Telomere dysfunction is a key mechanism in cancer development. The human telomerase reverse transcriptase (TERT) is the rate-limiting catalytic subunit of the telomerase enzyme, which is necessary for the maintenance of telomere DNA length, chromosomal stability, and cellular immortality. In our attempt to identify functional polymorphisms in the TERT gene and their effect on breast cancer risk, we sequenced the promoter of the gene and identified three single nucleotide polymorphisms (SNPs) with a frequency of at least 10%. One of these SNPs, rs2853669 (-244 T > C), has been shown to affect telomerase activity and telomere length. Recently, this SNP has been suggested to affect familial breast cancer risk. In our case-control study using two large breast cancer sample series, including one with 841 cases with inherited susceptibility to breast cancer, we did not find any association with familial or sporadic breast cancer risk. This well-powered study excludes an effect of the functional -244 T > C SNP and two other correlated SNPs on breast cancer risk.
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Meta- and pooled analysis of GSTP1 polymorphism and lung cancer: a HuGE-GSEC review.
Am. J. Epidemiol.
PUBLISHED: 02-24-2009
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Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.
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Influence of DNA repair gene polymorphisms on prognosis in inoperable non-small cell lung cancer patients treated with radiotherapy and platinum-based chemotherapy.
Int. J. Cancer
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Polymorphisms in DNA repair genes may modulate not only an individual DNA repair capacity, DNA damage levels and cancer risk but also clinical outcome after DNA damage-inducing anticancer therapy. In this study, we analyzed the association between the XPA -4G>A, XPD Asp312Asn, hOGG1 Ser326Cys, XRCC1 Arg399Gln, XRCC2 -4234G>C, XRCC3 -4541A>G and Thr241Met polymorphisms and prognosis in 250 inoperable non-small cell lung cancer (NSCLC) patients treated with radiotherapy and platinum-based chemotherapy. In univariate model, the XPA-4A and XRCC1 399Gln alleles alone and in combination influenced survival only in stage III group. In multivariate analysis, the XPA-4 GA/AA was associated with poor survival (HR 1.55, p = 0.011 overall and HR 1.72, p = 0.008 in stage III). In chemoradiotherapy group, the XPA-4A carriers were at increased risk of death and progression (HR 1.73, p = 0.013 and HR 1.65, p = 0.016, respectively), especially in stage III (p = 0.008). Moreover, individuals with ? 2 XPA/XRCC1 adverse alleles showed a higher risk of death (HR 1.46, p = 0.036 overall; HR 1.85, p = 0.004 in stage III and HR 1.71, p = 0.022 in chemoradiotherapy group) and progression (HR 1.75, p = 0.011 overall and HR 1.93, p = 0.005 in stage III). The XPA-4 GA/AA genotype individually and together with the XRCC1 399Gln was an independent unfavorable prognostic factor in our study. Thus, our findings indicate a prognostic potential of the XPA-4G>A in unresected NSCLC treated with radiotherapy and chemoradiotherapy. The results require validation in an independent population.
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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.