Convergent science physical oncology最新文献

{"title":"Delayed Onset of Symptoms Through Feedback Interference in Chronic Cancers.","authors":"Seth Haney,&nbsp;Tannishtha Reya,&nbsp;Maxim Bazhenov","doi":"10.1088/2057-1739/2/4/045002","DOIUrl":"https://doi.org/10.1088/2057-1739/2/4/045002","url":null,"abstract":"<p><p>In many cancers, such as Chronic Myelogenous Leukemia (CML), pancreatic, and colorectal cancer, long delays exist between the initiation of the disease and the onset of debilitating symptoms. The early stages of these diseases present manageable symptoms and, in the case of CML, highly effective treatment options. Progression to the more aggressive stages of the diseases limits effective treatment and significantly exacerbates patient prognosis. The mechanisms causing delay and disease progression are largely unknown. The later stages of these diseases are characterized by excessive build up of primitive cell types, indicating a disruption in the normal cell differentiation process that is commonly regulated through feedback from differentiated types. In this study, we propose a mechanism where mutated primitive cells produce a feedback interference signal that desensitizes them to a normal homeostatic feedback. Using a mathematical model, we show that this mechanism can account for the long delay period between occurrence of genetic changes and symptomatic onset characterized by fast growth of cancerous cell population. Finally, we explore novel concepts for potential treatment of chronic cancers.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/2/4/045002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36084089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stochasticity and determinism in cancer creation and progression.","authors":"Paul C Davies,&nbsp;David B Agus","doi":"10.1088/2057-1739/1/2/026003","DOIUrl":"https://doi.org/10.1088/2057-1739/1/2/026003","url":null,"abstract":"Cancer is the most intensively studied biological phenomenon, yet it remains poorly understood. Mortality and morbidity rates for many major cancer types have scarcely changed in decades. We posit that this lack of progress stems from a flawed conceptual model for the nature of cancer. A novel NCI physical science and cancer initiative encouraged us to re-consider the conceptual foundations of the current cancer paradigm, and we present an outline of an alternative view here. We focus on the deep evolutionary roots of cancer, and hypothesize that at least some hallmarks of the cancer phenotype express ancient ancestral pathways that are highly-conserved. The inappropriate expression of these pathways may be triggered by, but are not created by, mutational changes.","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/1/2/026003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35581200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering low-dimensional, miR-based signatures of acute myeloid and lymphoblastic leukemias with a machine-learning-driven network approach.","authors":"Julián Candia,&nbsp;Srujana Cherukuri,&nbsp;Yin Guo,&nbsp;Kshama A Doshi,&nbsp;Jayanth R Banavar,&nbsp;Curt I Civin,&nbsp;Wolfgang Losert","doi":"10.1088/2057-1739/1/2/025002","DOIUrl":"https://doi.org/10.1088/2057-1739/1/2/025002","url":null,"abstract":"<p><p>Complex phenotypic differences among different acute leukemias cannot be fully captured by analyzing the expression levels of one single molecule, such as a miR, at a time, but requires systematic analysis of large sets of miRs. While a popular approach for analysis of such datasets is principal component analysis (PCA), this method is not designed to optimally discriminate different phenotypes. Moreover, PCA and other low-dimensional representation methods yield linear or non-linear combinations of all measured miRs. Global human miR expression was measured in AML, B-ALL, and TALL cell lines and patient RNA samples. By systematically applying support vector machines to all measured miRs taken in dyad and triad groups, we built miR networks using cell line data and validated our findings with primary patient samples. All the coordinately transcribed members of the miR-23a cluster (which includes also miR-24 and miR-27a), known to function as tumor suppressors of acute leukemias, appeared in the AML, B-ALL and T-ALL centric networks. Subsequent qRT-PCR analysis showed that the most connected miR in the B-ALL-centric network, miR-708, is highly and specifically expressed in B-ALLs, suggesting that miR-708 might serve as a biomarker for B-ALL. This approach is systematic, quantitative, scalable, and unbiased. Rather than a single signature, our approach yields a network of signatures reflecting the redundant nature of biological signaling pathways. The network representation allows for visual analysis of all signatures by an expert and for future integration of additional information. Furthermore, each signature involves only small sets of miRs, such as dyads and triads, which are well suited for in depth validation through laboratory experiments. In particular, loss-and gain-of-function assays designed to drive changes in leukemia cell survival, proliferation and differentiation will benefit from the identification of multi-miR signatures that characterize leukemia subtypes and their normal counterpart cells of origin.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/1/2/025002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34620757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosomal defects track tumor subpopulations and change in progression in oligodendroglioma.","authors":"David W. Nauen, Andrew Guajardo, Lisa M Haley, Kerry Powell, P. Burger, C. Gocke","doi":"10.1088/2057-1739/1/1/015001","DOIUrl":"https://doi.org/10.1088/2057-1739/1/1/015001","url":null,"abstract":"To assess karyotypic changes and tumor subpopulations in progression of oligodendroglioma (ODG) we analyzed histologically diagnosed 1p/19q codeleted cases using single nucleotide polymorphism (SNP) microarray data. We separated cases according to grade, which was assigned blind to karyotype information beyond 1p/19q status. The 51 WHO grade II (O2) and 18 WHO grade III (O3) specimens showed frequent chromosomal locations and patterns of change including loss of heterozygosity (LOH), often copy-neutral, on 9p and LOH on 4p and 4q together. Analysis of co-occurrence indicated that most defects were independent but also suggested increased likelihood of defects on 11q, 13q, and 14q in the presence of defects on 18, 4, and 9, respectively. We used the relative degree of change in B-allele frequency as an indicator of an abnormality's extent, and we present simulated data to clarify how information on subpopulations was thus inferred. Among 9p defects, 89.3% involved the whole tumor, whereas only 47.6% of 4q defects did so. We modeled extent through the tumor as due to a karyotypic change's likelihood of occurring and the fitness it confers on its subpopulation, and used group data to estimate these values. To assess progression directly, we evaluated specimens from six patients who underwent multiple resections since 1996. Four of these patients had received no chemotherapy or radiation, permitting assessment of the natural history of the tumor karyotype in situ. Defects present throughout a tumor at first resection remained so, whereas among subpopulations, some expanded, some remained constant, and some disappeared. The rate of expansion among subpopulations that did so was not uniform, and estimates of fitness predicted subpopulation composition at recurrence. These results extend prior studies of increased karyotypic abnormality in progression of oligodendroglioma and reveal the complex dynamics of subpopulations in the tumor over time.","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/1/1/015001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60652892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive value of <i>ex vivo</i> biodynamic imaging in determining response to chemotherapy in dogs with spontaneous non-Hodgkin's lymphomas: a preliminary study.","authors":"M R Custead,&nbsp;R An,&nbsp;J J Turek,&nbsp;G E Moore,&nbsp;D D Nolte,&nbsp;M O Childress","doi":"10.1088/2057-1739/1/1/015003","DOIUrl":"https://doi.org/10.1088/2057-1739/1/1/015003","url":null,"abstract":"<p><p>Biodynamic imaging (BDI) is a novel phenotypic cancer profiling technology which optically characterizes changes in subcellular motion within living tumor tissue samples in response to <i>ex vivo</i> treatment with cancer chemotherapy drugs. The purpose of this preliminary study was to assess the ability of <i>ex vivo</i> BDI to predict <i>in vivo</i> clinical response to chemotherapy in ten dogs with naturally-occurring non-Hodgkin's lymphomas. Pre-treatment tumor biopsy samples were obtained from all dogs and treated <i>ex vivo</i> with doxorubicin (10 <i>μ</i>M). BDI measured six dynamic biomarkers of subcellular motion from all biopsy samples at baseline and at regular intervals for 9 h following drug application. All dogs subsequently received doxorubicin to treat their lymphomas. Best overall response to and progression-free survival time following chemotherapy were recorded for all dogs. Receiver operating characteristic (ROC) curves were used to determine accuracy and identify possible cut-off values for the BDI-measured biomarkers which could accurately predict those dogs' cancers that would and would not respond to doxorubicin chemotherapy. One biomarker (designated 'MEM') showed 100% discriminative capability for predicting clinical response to doxorubicin (area under the ROC curve = 1.00, 95% CI 0.692-1.000), while other biomarkers also showed promising predictive capability. These preliminary findings suggest that <i>ex vivo</i> BDI can accurately predict treatment outcome following doxorubicin chemotherapy in a spontaneous animal cancer model, and is worthy of further investigation as a technology for personalized cancer medicine.</p>","PeriodicalId":91466,"journal":{"name":"Convergent science physical oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1088/2057-1739/1/1/015003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34453254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}