16,793 research outputs found
Abstract BS3-2: Breast cancer intra-tumor heterogeneity and its clinical implications
No full textAbstract
Breast cancer is a known heterogeneous disease with significant inter-tumor differences being manifested on many levels including histology, response to therapy, and patient survival outcomes. Importantly, even within an individual tumor, significant heterogeneity may exist. This intra-tumor heterogeneity (ITH) poses a challenge to understanding the biology of breast cancer, and an open question is what impact does ITH have on the clinical decision making process?
Over the past ten years, a rich body of genetic, genomic, and proteomic data has been accumulated concerning the ITH of breast cancers. Much of these data is coming from Massively Parallel Sequencing, and it is yielding a wealth of quantitative data concerning DNA- and RNA-based ITH. This variation can be in the form of somatic mutations, DNA copy number changes, and gene expression differences due to epigenetic differences (i.e. cell state changes) and or microenvironmental influences. Notable recent examples of DNA-based ITH include PIK3CA mutation heterogeneity across different metastatic sites within the same patient with some lesions responding to PI3K inhibitors while others did not. Another key example of ITH are ESR1 mutations that arise within the setting of aromatase inhibitor treatment, where it is sometimes seen that within an individual, multiple different mutations in ESR1 can occur and that confer estrogen independence. Lastly, significant epigenetic ITH can also occur, with a prime example being epithelial tumor cell plasticity, which is often manifested as “state changes”. Examples of this include chemotherapy induced changes that may select for epithelial cells with more mesenchymal features (often referred to as EMT), and which is also typically linked to a more treatment resistant state.
Another important concept that is emerging is that it might be better to target the clonal (or trunk) alterations, as opposed to targeting the subclonal variation. The latter, by definition, is not present within all tumor cells, and thus even if that therapy is effective, it will not target all tumor cells. Conversely, if clonal variants (i.e. those present within the founding clone) are targeted, the treatment may be more effective and cause regression and/or complete response. These multiple examples of ITH are biologically important, but the question still remains, what are the clinical implications? These ITH topics will be presented and discussed within the context of how these findings might affect treatment options and decision making.
Citation Format: Perou Perou CM. Breast cancer intra-tumor heterogeneity and its clinical implications [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr BS3-2.</jats:p
PhD
No full textdissertationChediak-Higashi syndrome is an autosomal recessive disorder of humans that has profound effects upon lysosome morphology and function. This fatal disorder results in abnormally large lysosomes that are thought to be caused by misregulated vesicle fusions. This dissertation investigates the molecular mechanism(s) responsible for this disorder using cellular and genetic methodologies in order to better understand how fusion events in the endocytic pathway are regulated. Chediak-Higashi syndrome, the beige mouse, and the Aleutian mink are phenotypically similar disorders that are thought to contain defects in homologous genes. In this dissertation, an in vitro assay for lysosome morphology was developed that allows the mutant and wild type cells to be distinguished. Somatic cell fusions between normal and mutant cells showed that the mutant phenotype was complemented in these heterokaryons. Fusion between any two mutants failed to complement, demonstrating that mice, minks, and humans have defects within homologous genes. It had previously been shown that lysosome function and morphology in macrophages was dependent upon microtubules and microtubule motor proteins. We tested the hypothesis that microtubule motor protein function in beige mouse macrophages was defective by inducing lysosome movements using cytoplasmic acidification or PMA treatment. Beige mouse macrophages were capable of normal lysosome movements, suggesting that microtubule motor protein function was normal. In order to localize the defective gene and determine the molecular mechanism defective in beige, an interspecific backcrossed panel of beige mice was used to map the beige gene to a 3cM interval on mouse chromosome 13. A Yeast Artificial Chromosome (YAC) contig covering the beige region was generated using nidogen as the initial probe. YACs were then introduced into beige mouse fibroblasts using spheroplast fusion and the resulting colonies examined for complementation of the mutant phenotype using our in vitro assay of lysosome morphology. Two partially overlapping YACs were isolated that complemented the beige phenotype. These YACs were further used to identify cDNAs in order to isolate the beige gene. The beige gene will then be used to isolate the human CHS gene by hybridization
Mammographic density and molecular subtypes of breast cancer.
No full textBACKGROUND: Gene expression profiling has led to a subclassification of breast cancers independent of established clinical parameters, such as the Sorlie-Perou subtypes. Mammographic density (MD) is one of the strongest risk factors for breast cancer, but it is unknown if MD is associated with molecular subtypes of this carcinoma. METHODS: We investigated whether MD was associated with breast cancer subtypes in 110 women with breast cancer, operated in Stockholm, Sweden, during 1994 to 1996. Subtypes were defined using expression data from HGU133A+B chips. The MD of the unaffected breast was measured using the Cumulus software. We used multinomial logistic models to investigate the relationship between MD and Sorlie-Perou subtypes. RESULTS: Although the distribution of molecular subtypes differed in women with high vs low MD, this was statistically non-significant (P=0.249), and further analyses revealed no association between the MD and Sorlie-Perou subtypes as a whole, nor with individual subtypes. CONCLUSION: These findings suggest that although MD is one of the strongest risk factors for breast cancer, it does not seem to be differentially associated with breast cancer molecular subtypes. However, larger studies with more comprehensive covariate information are needed to confirm these results
Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy : results from the BIG 02-98 phase III trial
No full textIntroduction: Pre-clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity. However, dedicated clinical research has not defined a predictive role for TP53 gene mutations. The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02-98 randomized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with or without docetaxel. Methods: The prognostic and predictive values of TP53 were analyzed in tumor samples by gene sequencing within exons 5 to 8. Patients were classified according to p53 protein status predicted from TP53 gene sequence, as wild-type (no TP53 variation or TP53 variations which are predicted not to modify p53 protein sequence) or mutant (p53 nonsynonymous mutations). Mutations were subcategorized according to missense or truncating mutations. Survival analyses were performed using the Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Results: TP53 gene status was determined for 18% (520 of 2887) of the women enrolled in BIG 02-98. TP53 gene variations were found in 17% (90 of 520). Nonsynonymous p53 mutations, found in 16.3% (85 of 520), were associated with older age, ductal morphology, higher grade and hormone-receptor negativity. Of the nonsynonymous mutations, 12.3% (64 of 520) were missense and 3.6% were truncating (19 of 520). Only truncating mutations showed significant independent prognostic value, with an increased recurrence risk compared to patients with non-modified p53 protein (hazard ratio = 3.21, 95% confidence interval = 1.740 to 5.935, P = 0.0002). p53 status had no significant predictive value for response to docetaxel. Conclusions: p53 truncating mutations were uncommon but associated with poor prognosis. No significant predictive role for p53 status was detected
The politics and economics of regulatory impact assessment
No full textThis is the author accepted manuscript. The final version is available from the publisher via the link in this record
Abstract ES7-2: Next Generation Sequencing for the Clinician
No full textAbstract
Gene expression profiling has had a significant impact on breast cancer by providing important biological information regarding mechanisms of carcinogenesis, development, and metastasis. In addition, genomic profiling has also resulted in the development and use of new clinical assays for prognostication and prediction. Most genomic profiling has been accomplished using some type of DNA microarray, which is a robust and validated technology where oligonucleotide probes of predetermined sequence are placed/immobilized on known locations on solid surfaces; next, labeled RNAs coming from tumors, cell lines, or animal model tissues are placed onto the array, allowed to hybridize via base complementarity, and then excess probe washed away and intensity scored for each immobilized starting probe. In this way, thousands to millions of probes can be used to interrogate the transcriptome, and in essence, all mRNA genes/transcripts can be interrogated at once.
Technological advances are rapidly occurring and new sequencing-based approaches are gaining use because they offer the ability to gather much more information than conventional DNA microarrays. These sequencing-based approaches are essentially to take all mRNA (or all microRNAs, or some selected fraction of RNA transcripts), make cDNA and sequence everything, thus providing millions of short sequence reads from a given sample/tumor. These sequence reads are then mapped to predetermined transcript libraries of sequences, and the number of reads that map to a given gene/transcript are added up. Finally, computational analyses are used to derive an expression value for each transcript/gene (i.e. RPKM for example). In this way, the number of reads for a given gene are turned into an expression value that is highly reproducible and likely more quantitative than DNA microarrays or possibly qRT-PCR.
There are also many other advantages of the RNA-sequencing approach to the study of gene expression that include 1) mRNA splicing information is obtained and can be used to define transcripts, 2) sequence variation is also obtained so that mutations and/or germline variants can be detected, 3) the presence of fusion genes/proteins can be detected, and 4) the data appears more quantitative and has a larger dynamic range than conventional DNA microarrays. In addition, a number of alternative library preparation protocols can be used. For example, Ribo-depletion or Cot hybridization kinetics allows the removal of highly abundant rRNA transcripts, thus leaving behind all other RNA transcripts and not limiting the detection to PolyA containing transcripts. Another great advantage of sequencing-based approaches is that no prior knowledge of sequence is needed, thus providing a highly objective and complete means of identifying and quantitating transcripts from any species. However, the only limiting features are the number of reads obtained and the costs for a given experiment. In summary, it is likely that, in the long run, sequencing-based approaches may dominate the discovery focused profiling world; however, smaller gene/transcript sets of known composition may still predominate on the many robust gene expression platforms that exist today.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr ES7-2.</jats:p
Phase Distribution Efficiency of cm-Scale Ultrasonically Powered Receivers
No full textIn the domain of ultrasonically powered biomedical implants, there is an increasing interest in cm-scale ultrasonic receivers (RX). However, when a single-element transducer is used as the RX transducer, an uneven phase distribution across the RX area can significantly reduce the harvestable power. In this paper, we investigate the impact of lateral and angular misalignment on the acoustic field phase distribution across the RX surface. We show that, for a single-element RX transducer, lateral misalignment has minimal effect on the harvestable power, whereas even small angular misalignments can cause a considerable reduction, especially for larger RX sizes. We present a potential solution that consists of subdividing a large RX transducer (e.g. 20 × 20mm2) into smaller elements, which significantly improves power transfer efficiency by taking advantage of the smaller phase variation across the surface of each element. The trade-offs between achieving a minimum acceptable power transfer efficiency and managing the increased complexity in packaging and matching circuitry are also discussed.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Electronic Components, Technology and MaterialsBio-Electronic
Highly efficient laser-driven Compton gamma-ray source
No full textThe recent advancement of high-intensity lasers has made all-optical Compton scattering become a promising way to produce ultrashort brilliant gamma-rays in an ultra-compact system. However, so far achieved Compton gamma-ray sources are limited by low conversion efficiency and spectral intensity. Here we present a highly efficient gamma photon emitter obtained by irradiating a high-intensity laser pulse on a miniature plasma device consisting of a plasma lens and a plasma mirror. This concept exploits strong spatiotemporal laser-shaping process and high-charge electron acceleration process in the plasma lens, as well as an efficient nonlinear Compton scattering process enabled by the plasma mirror. Our full three-dimensional particle-in-cell simulations demonstrate that in this novel scheme, brilliant gamma-rays with very high conversion efficiency (higher than 10(-2)) and spectral intensity (similar to 10(9) photons/0.1%BW) can be achieved by employing currently available petawatt-class lasers with intensity of 10(21) W cm(-2). Such efficient and intense gamma-ray sources would find applications in wide-ranging areas. ©2019 The Author(s)
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