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Sökning: WFRF:(Mengelbier Linda Holmquist)

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1.
  • Chagtai, Tasnim, et al. (författare)
  • Gain of 1q as a prognostic biomarker in Wilms Tumors (WTs) treated with preoperative chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 trial : A SIOP renal tumours biology consortium study
  • 2016
  • Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 34:26, s. 3195-3203
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. Materials and Methods: WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. Results: One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. Conclusion: Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.
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2.
  • Andersson, Natalie, et al. (författare)
  • Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers
  • 2020
  • Ingår i: Cancer Research. - 1538-7445. ; 80:7, s. 1512-1523
  • Tidskriftsartikel (refereegranskat)abstract
    • Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors and 8 rhabdomyosarcomas. Whole genome copy number and whole exome mutational profiling of multiple regions per tumor was performed followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared to clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; p=0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, while in Wilms tumor they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, while others grow worse over time.
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3.
  • Edsjö, Anders, et al. (författare)
  • Neuroblastoma as an experimental model for neuronal differentiation and hypoxia-induced tumor cell dedifferentiation.
  • 2007
  • Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 17:3, s. 248-256
  • Forskningsöversikt (refereegranskat)abstract
    • Neuroblastoma is a childhood tumor derived from precursor or immature cells of the sympathetic nervous system. Neuroblastomas show a tremendous clinical heterogeneity, encompassing truly benign as well as extremely aggressive forms. In vivo as well as in vitro data have shown that the degree of sympathetic neuronal tumor cell differentiation influences patient outcome. Unraveling mechanisms governing neuroblastoma cell differentiation is therefore a central issue in the neuroblastoma research field. In this communication, we discuss some of the in vitro models frequently used to study human neuroblastoma cell differentiation. We also review recent data demonstrating that oxygen shortage, hypoxia, shifts neuroblastoma cells toward an immature, stem cell-like phenotype and discuss the potential clinical impact of hypoxia on neuroblastoma behavior.
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4.
  • Forslund, Ola, et al. (författare)
  • Regarding human cytomegalovirus in neuroblastoma.
  • 2014
  • Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 3:4, s. 1038-1040
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Wolmer-Solberg et al., reported that six human neuroblastoma cell lines and the vast majority of clinical neuroblastoma samples contained HCMV DNA and expressed HCMV proteins. We could not replicate the data and therefore remain skeptical towards the prevalence of HCMV DNA in neuroblastomas.
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5.
  • Gisselsson Nord, David, et al. (författare)
  • Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis.
  • 2010
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 107:47, s. 20489-20493
  • Tidskriftsartikel (refereegranskat)abstract
    • One extra chromosome copy (i.e., trisomy) is the most common type of chromosome aberration in cancer cells. The mechanisms behind the generation of trisomies in tumor cells are largely unknown, although it has been suggested that dysfunction of the spindle assembly checkpoint (SAC) leads to an accumulation of trisomies through failure to correctly segregate sister chromatids in successive cell divisions. By using Wilms tumor as a model for cancers with trisomies, we now show that trisomic cells can form even in the presence of a functional SAC through tripolar cell divisions in which sister chromatid separation proceeds in a regular fashion, but cytokinesis failure nevertheless leads to an asymmetrical segregation of chromosomes into two daughter cells. A model for the generation of trisomies by such asymmetrical cell division accurately predicted several features of clones having extra chromosomes in vivo, including the ratio between trisomies and tetrasomies and the observation that different trisomies found in the same tumor occupy identical proportions of cells and colocalize in tumor tissue. Our findings provide an experimentally validated model explaining how multiple trisomies can occur in tumor cells that still maintain accurate sister chromatid separation at metaphase-anaphase transition and thereby physiologically satisfy the SAC.
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6.
  • Gisselsson Nord, David, et al. (författare)
  • Genetic bottlenecks and the hazardous game of population reduction in cell line based research.
  • 2010
  • Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 316, s. 3379-3386
  • Tidskriftsartikel (refereegranskat)abstract
    • Established tumour cell lines are ubiquitous tools in research, but their representativity is often debated. One possible caveat is that many cell lines are derived from cells with genomic instability, potentially leading to genotype changes in vitro. We applied SNP-array analysis to an established tumour cell line (WiT49). Even though WiT49 exhibited chromosome segregation errors in 30% of cell divisions, only a single chromosome segment exhibited a shift in copy number after 20 population doublings in culture. In contrast, sub-populations derived from single cells expanded for an equal number of population doublings showed on average 5.8 and 8.9 altered segments compared to the original culture and to each other, respectively. Most copy number variants differentiating these single cell clones corresponded to pre-existing variations in the original culture. Furthermore, no sub-clonal variation was detected in any of the populations derived from single cells. This indicates that genetic bottlenecks resulting from population reduction poses a higher threat to genetic representativity than prolonged culture per se, even in cell lines with a high rate of genomic instability. Genetic bottlenecks should therefore be considered a potential caveat in all studies involving sub-cloning, transfection and other conditions leading to a temporary reduction in cell number.
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7.
  • Helczynska, Karolina, et al. (författare)
  • Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.
  • 2008
  • Ingår i: Cancer Research. - 1538-7445. ; 68:22, s. 9212-9220
  • Tidskriftsartikel (refereegranskat)abstract
    • Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.
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8.
  • Holmquist Mengelbier, Linda, et al. (författare)
  • Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster.
  • 2010
  • Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 177:5, s. 2609-2621
  • Tidskriftsartikel (refereegranskat)abstract
    • Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self-renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor.
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9.
  • Holmquist Mengelbier, Linda, et al. (författare)
  • Effect of hypoxia on the tumor phenotype: the neuroblastoma and breast cancer models
  • 2006
  • Ingår i: Advances in experimental medicine and biology. - 0065-2598. ; 587, s. 179-193
  • Konferensbidrag (refereegranskat)abstract
    • The tumor oxygenation status associates with aggressive behavior. Oxygen shortage, hypoxia, is a major driving force behind tumor vascularization, and hypoxia enhances mutational rate, metastatic spread, and resistance to radiation and chemotherapy. We recently discovered that hypoxia promotes dedifferentiation of neuroblastoma and breast carcinoma cells and development of stem cell-like features. In both these tumor forms there is a correlation between low differentiation stage and poor outcome, and we conclude that the dedifferentiating effect of lowered oxygen adds to the aggressive phenotype induced by hypoxia. With neuroblastoma and breast carcinoma as human tumor model systems, we have addressed questions related to hypoxia-induced molecular mechanisms governing malignant behavior of tumor cells, with emphasis on differentiation and growth control. By global gene expression analyses we are currently screening for gene products exclusively expressed or modified in hypoxic cells with the aim to use them as targets for treatment.
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10.
  • Holmquist Mengelbier, Linda (författare)
  • Hypoxia-induced phenotypic modulation of human neuroblastoma cells
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Neuroblastoma is a childhood tumour derived from cells of the sympathetic nervous system, which are arrested at low differentiation stages. Low differentiation stage and high tumour stage correlate to poor outcome. In earlier studies we have found that hypoxia induces dedifferentiation of neuroblastoma cells, which implies that hypoxia evokes a more aggressive phenotype. Here we employ microarray analysis to investigate the hypoxic effects, in neuroblastoma cells, on the expression of a larger set of genes. Genes involved in survival and treatment resistance were upregulated, which support the concept of an aggressive hypoxic phenotype. The microarray results further strengthened the concept of hypoxia-induced dedifferentiation of neuroblastoma cells. Hypoxia-treated neuroblastoma cells were reoxygenated to determine the persistence of the hypoxic phenotype. Based on neuronal- and neural crest marker gene expression analysis, we conclude that the hypoxic phenotype persisted for at least 24 h upon reoxygenation. Hence, there was no selection for dedifferentiated cells; instead the hypoxic phenotype appears adaptable and dynamically reversible. Major transcription factors that act in response to hypoxia are the hypoxia-inducible factors HIF-1a and HIF-2a. Intriguingly, HIF-2a, but not HIF-1a, was detected adjacent to blood vessels in neuroblastoma specimen, indicating a role for HIF-2a at more physiological oxygen levels. Analysis of HIF-protein levels in neuroblastoma cells exposed to hypoxia (1% O2) or 5% O2 (mimicking a more physiological oxygen level) revealed that HIF-1a is primarily and only transiently induced at 1% O2. HIF-2a, on the other hand, is induced at both 1 and 5% O2 and its protein levels increase over time. In a microarray analysis we extracted a set of genes with regulation patterns similar to that of the HIF-protein patterns seen in neuroblastoma cells grown at either 1 or 5% O2. We propose that the differences in HIF target gene utilization are dependent on time and oxygen conditions, rather than on target gene specificity. According to that concept, we propose that HIF-1a primarily drives gene transcription at acute hypoxia, while HIF-2a is active at prolonged hypoxia and at 5% O2, conclusions supported by HIF-1a and HIF-2a siRNA analyses and expression of the HIF-driven genes VEGF and DEC1/BHLB2. Evaluation of a clinical neuroblastoma material showed correlation between HIF-2a immunostaining and poor patient outcome. Our results further implicate HIF-2a as a possible individual prognostic marker for neuroblastoma patients. Tumour growth of neuroblastoma cells knocked down for HIF-2a in nude mice was slower than neuroblastoma cells transfected with a scramble siRNA sequence. These observations support a role for HIF-2a in neuroblastoma progression. Immunostaining of neuroblastoma specimen revealed co-localization of VEGF and HIF-2a, suggesting a putative mechanism for neuroblastoma tumour growth due to HIF-2a-induced VEGF expression. Our results implicate an oncogenic role for HIF-2a in neuroblastoma aggressiveness, which might be exploited in the treatment of aggressive neuroblastomas.
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