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Sample records for investigate intratumoral heterogeneity

  1. Breast cancer intra-tumor heterogeneity

    PubMed Central

    2014-01-01

    In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra-tumor genetic heterogeneity in breast cancers; however, its basis is yet to be fully defined. Two of the most widely evoked concepts to explain the origin of heterogeneity within tumors are the cancer stem cell hypothesis and the clonal evolution model. Although the cancer stem cell model appeared to provide an explanation for the variability among the neoplastic cells within a given cancer, advances in massively parallel sequencing have provided several lines of evidence to suggest that intra-tumor genetic heterogeneity likely plays a fundamental role in the phenotypic heterogeneity observed in cancers. Many challenges remain, however, in the interpretation of the next generation sequencing results obtained so far. Here we review the models that explain tumor heterogeneity, the causes of intra-tumor genetic diversity and their impact on our understanding and management of breast cancer, methods to study intra-tumor heterogeneity and the assessment of intra-tumor genetic heterogeneity in the clinic. PMID:25928070

  2. Deciphering intratumor heterogeneity using cancer genome analysis.

    PubMed

    Ryu, Daeun; Joung, Je-Gun; Kim, Nayoung K D; Kim, Kyu-Tae; Park, Woong-Yang

    2016-06-01

    Intratumor heterogeneity within individual cancer tissues underlies the numerous phenotypes of cancer. Tumor subclones ultimately affect therapeutic outcomes due to their distinct molecular features. Drug-resistant subclones are present at a low frequency in tissues at the time of biopsy, but can also arise as a result of acquired somatic mutations. A number of different approaches have been utilized to understand the nature of intratumor heterogeneity. Clonal analysis using whole exome or genome sequencing data can help monitor subclones in the context of tumor progression. Multiregional biopsies permit the molecular characterization of subclones within tumors. Deep sequencing has also provided researchers with the ability to measure the low allele fraction variant within a small number of cells. Ultimately, single-cell sequencing will enable the identification of every minor population within a tumor microenvironment. In the clinical context, the ability to identify and monitor the subclonal architecture of a tumor is valuable for the development of precise cancer therapeutic methods. PMID:27126234

  3. Towards inverse modeling of intratumor heterogeneity

    NASA Astrophysics Data System (ADS)

    Brutovsky, Branislav; Horvath, Denis

    2015-08-01

    Development of resistance limits efficiency of present anticancer therapies and preventing it remains a big challenge in cancer research. It is accepted, at the intuitive level, that resistance emerges as a consequence of the heterogeneity of cancer cells at the molecular, genetic and cellular levels. Produced by many sources, tumor heterogeneity is extremely complex time dependent statistical characteristics which may be quantified by measures defined in many different ways, most of them coming from statistical mechanics. In this paper, we apply the Markovian framework to relate population heterogeneity to the statistics of the environment. As, from an evolutionary viewpoint, therapy corresponds to a purposeful modi- fication of the cells' fitness landscape, we assume that understanding general relationship between the spatiotemporal statistics of a tumor microenvironment and intratumor heterogeneity will allow to conceive the therapy as an inverse problem and to solve it by optimization techniques. To account for the inherent stochasticity of biological processes at cellular scale, the generalized distancebased concept was applied to express distances between probabilistically described cell states and environmental conditions, respectively.

  4. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

    PubMed Central

    Math, M.; Tarpey, Patrick; Varela, Ignacio; Phillimore, Benjamin; Begum, Sharmin; McDonald, Neil Q.; Butler, Adam; Jones, David; Raine, Keiran; Latimer, Calli; Santos, Claudio R.; Nohadani, Mahrokh; Eklund, Aron C.; Spencer-Dene, Bradley; Clark, Graham; Pickering, Lisa; Stamp, Gordon; Gore, Martin; Szallasi, Zoltan; Downward, Julian; Futreal, P. Andrew

    2016-01-01

    Background Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. Methods To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Results Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Conclusions Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through

  5. Analysis of intratumor heterogeneity unravels lung cancer evolution

    PubMed Central

    de Bruin, Elza C; McGranahan, Nicholas; Swanton, Charles

    2015-01-01

    Lung cancer is a disease with dismal outcome. We recently reported a detailed intratumor heterogeneity analysis in 7 non-small cell lung cancer samples, revealing spatially separated driver events as well as the temporal dynamics of mutational processes and demonstrating an important role for APOBEC-mediated heterogeneity later in disease evolution. PMID:27308463

  6. Analysis of intratumor heterogeneity unravels lung cancer evolution.

    PubMed

    de Bruin, Elza C; McGranahan, Nicholas; Swanton, Charles

    2015-01-01

    Lung cancer is a disease with dismal outcome. We recently reported a detailed intratumor heterogeneity analysis in 7 non-small cell lung cancer samples, revealing spatially separated driver events as well as the temporal dynamics of mutational processes and demonstrating an important role for APOBEC-mediated heterogeneity later in disease evolution. PMID:27308463

  7. Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma

    PubMed Central

    Parker, Nicole R.; Hudson, Amanda L.; Khong, Peter; Parkinson, Jonathon F.; Dwight, Trisha; Ikin, Rowan J.; Zhu, Ying; Cheng, Zhangkai Jason; Vafaee, Fatemeh; Chen, Jason; Wheeler, Helen R.; Howell, Viive M.

    2016-01-01

    Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies. PMID:26940435

  8. Intra-tumor Genetic Heterogeneity in Rectal Cancer

    PubMed Central

    Hardiman, Karin M.; Ulintz, Peter J.; Kuick, Rork; Hovelson, Daniel H.; Gates, Christopher M.; Bhasi, Ashwini; Grant, Ana Rodrigues; Liu, Jianhua; Cani, Andi K.; Greenson, Joel; Tomlins, Scott; Fearon, Eric R.

    2015-01-01

    Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate regions from each of six rectal tumors were dissected and subjected to next-generation whole exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and copy number analysis including measurement of correlation between samples was performed. Somatic mutations profiles in individual cancers were similar to prior studies, with some variants found in previously reported significantly mutated genes and many patient-specific mutations in each tumor. Significant intra-tumor heterogeneity was identified in the spatially disparate regions of individual cancers. All tumors had some heterogeneity but the degree of heterogeneity was quite variable in the samples studied. We found that 67–97% of exonic somatic mutations were shared among all regions of an individual’s tumor. The SciClone computational method identified 2 to 8 shared and unshared subclones in the spatially disparate areas in each tumor. MATH scores ranged from 7 to 41. Allele frequency correlation scores ranged from R2 = 0.69 to 0.96. Measurements of correlation between samples for copy number changes varied from R2 = 0.74 to 0.93. All tumors had some heterogeneity, but the degree was highly variable in the samples studied. The occurrence of significant intra-tumor heterogeneity may allow

  9. Intratumoral Heterogeneity of MicroRNA Expression in Rectal Cancer

    PubMed Central

    Andersen, Rikke Fredslund; Nielsen, Boye Schnack; Sørensen, Flemming Brandt; Appelt, Ane Lindegaard; Jakobsen, Anders; Hansen, Torben Frøstrup

    2016-01-01

    Introduction An increasing number of studies have investigated microRNAs (miRNAs) as potential markers of diagnosis, treatment and prognosis. So far, agreement between studies has been minimal, which may in part be explained by intratumoral heterogeneity of miRNA expression. The aim of the present study was to assess the heterogeneity of a panel of selected miRNAs in rectal cancer, using two different technical approaches. Materials and Methods The expression of the investigated miRNAs was analysed by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization (ISH) in tumour specimens from 27 patients with T3-4 rectal cancer. From each tumour, tissue from three different luminal localisations was examined. Inter- and intra-patient variability was assessed by calculating intraclass correlation coefficients (ICCs). Correlations between RT-qPCR and ISH were evaluated using Spearman’s correlation. Results ICCsingle (one sample from each patient) was higher than 50% for miRNA-21 and miRNA-31. For miRNA-125b, miRNA-145, and miRNA-630, ICCsingle was lower than 50%. The ICCmean (mean of three samples from each patient) was higher than 50% for miRNA-21(RT-qPCR and ISH), miRNA-125b (RT-qPCR and ISH), miRNA-145 (ISH), miRNA-630 (RT-qPCR), and miRNA-31 (RT-qPCR). For miRNA-145 (RT-qPCR) and miRNA-630 (ISH), ICCmean was lower than 50%. Spearman correlation coefficients, comparing results obtained by RT-qPCR and ISH, respectively, ranged from 0.084 to 0.325 for the mean value from each patient, and from -0.085 to 0.515 in the section including the deepest part of the tumour. Conclusion Intratumoral heterogeneity may influence the measurement of miRNA expression and consequently the number of samples needed for representative estimates. Our findings with two different methods suggest that one sample is sufficient for adequate assessment of miRNA-21 and miRNA-31, whereas more samples would improve the assessment of miRNA-125b, miRNA-145, and miRNA-630

  10. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution.

    PubMed

    McGranahan, Nicholas; Swanton, Charles

    2015-01-12

    Precision medicine requires an understanding of cancer genes and mutational processes, as well as an appreciation of the extent to which these are found heterogeneously in cancer cells during tumor evolution. Here, we explore the processes shaping the cancer genome, placing these within the context of tumor evolution and their impact on intratumor heterogeneity and drug development. We review evidence for constraints and contingencies to tumor evolution and highlight the clinical implications of diversity within tumors. We outline the limitations of genome-driven targeted therapies and explore future strategies, including immune and adaptive approaches, to address this therapeutic challenge. PMID:25584892

  11. Correlation of Intra-Tumor 18F-FDG Uptake Heterogeneity Indices with Perfusion CT Derived Parameters in Colorectal Cancer

    PubMed Central

    Tixier, Florent; Groves, Ashley M.; Goh, Vicky; Hatt, Mathieu; Ingrand, Pierre; Le Rest, Catherine Cheze; Visvikis, Dimitris

    2014-01-01

    Application of textural features analysis to 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) images has been used to characterize intra-tumor uptake heterogeneity and has been shown to reflect disease outcome. A current hypothesis is that 18F-FDG uptake heterogeneity may reflect the physiological tracer uptake related to tumor perfusion. The purpose of our study was to investigate the correlations between intra-tumor uptake heterogeneity and vascular parameters derived from dynamic contrast enhanced (DCE) computed tomography (CT) obtained from an integrated 18F-FDG PET/perfusion CT examination. Methods Thirty patients with proven colorectal cancer prospectively underwent integrated 18F-FDG PET/DCE-CT to assess the metabolic-flow phenotype. Both CT blood flow parametric maps and PET images were analyzed. Correlations between PET heterogeneity and perfusion CT were assessed by Spearman's rank correlation analysis. Results Blood flow visualization provided by DCE-CT images was significantly correlated with 18F-FDG PET metabolically active tumor volume as well as with uptake heterogeneity for patients with stage III/IV tumors (|ρ|:0.66 to 0.78; p-value<0.02). Conclusion The positive correlation found with tumor blood flow indicates that intra-tumor heterogeneity of 18F-FDG PET accumulation reflects to some extent tracer distribution and consequently indicates that 18F-FDG PET intra-tumor heterogeneity may be associated with physiological processes such as tumor vascularization. PMID:24926986

  12. Unsupervised Deconvolution of Dynamic Imaging Reveals Intratumor Vascular Heterogeneity and Repopulation Dynamics

    PubMed Central

    Chen, Li; Choyke, Peter L.; Wang, Niya; Clarke, Robert; Bhujwalla, Zaver M.; Hillman, Elizabeth M. C.; Wang, Ge; Wang, Yue

    2014-01-01

    With the existence of biologically distinctive malignant cells originated within the same tumor, intratumor functional heterogeneity is present in many cancers and is often manifested by the intermingled vascular compartments with distinct pharmacokinetics. However, intratumor vascular heterogeneity cannot be resolved directly by most in vivo dynamic imaging. We developed multi-tissue compartment modeling (MTCM), a completely unsupervised method of deconvoluting dynamic imaging series from heterogeneous tumors that can improve vascular characterization in many biological contexts. Applying MTCM to dynamic contrast-enhanced magnetic resonance imaging of breast cancers revealed characteristic intratumor vascular heterogeneity and therapeutic responses that were otherwise undetectable. MTCM is readily applicable to other dynamic imaging modalities for studying intratumor functional and phenotypic heterogeneity, together with a variety of foreseeable applications in the clinic. PMID:25379705

  13. Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma

    PubMed Central

    Marino, Federica Zito; Liguori, Giuseppina; Aquino, Gabriella; La Mantia, Elvira; Bosari, Silvano; Ferrero, Stefano; Rosso, Lorenzo; Gaudioso, Gabriella; De Rosa, Nicla; Scrima, Marianna; Martucci, Nicola; La Rocca, Antonello; Normanno, Nicola; Morabito, Alessandro; Rocco, Gaetano; Botti, Gerardo; Franco, Renato

    2015-01-01

    Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be ‘major’, characterized by a single tumor showing two different histologic types, and ‘minor’, due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes. PMID:26422230

  14. CRISPR-Barcoding for Intratumor Genetic Heterogeneity Modeling and Functional Analysis of Oncogenic Driver Mutations.

    PubMed

    Guernet, Alexis; Mungamuri, Sathish Kumar; Cartier, Dorthe; Sachidanandam, Ravi; Jayaprakash, Anitha; Adriouch, Sahil; Vezain, Myriam; Charbonnier, Françoise; Rohkin, Guy; Coutant, Sophie; Yao, Shen; Ainani, Hassan; Alexandre, David; Tournier, Isabelle; Boyer, Olivier; Aaronson, Stuart A; Anouar, Youssef; Grumolato, Luca

    2016-08-01

    Intratumor genetic heterogeneity underlies the ability of tumors to evolve and adapt to different environmental conditions. Using CRISPR/Cas9 technology and specific DNA barcodes, we devised a strategy to recapitulate and trace the emergence of subpopulations of cancer cells containing a mutation of interest. We used this approach to model different mechanisms of lung cancer cell resistance to EGFR inhibitors and to assess effects of combined drug therapies. By overcoming intrinsic limitations of current approaches, CRISPR-barcoding also enables investigation of most types of genetic modifications, including repair of oncogenic driver mutations. Finally, we used highly complex barcodes inserted at a specific genome location as a means of simultaneously tracing the fates of many thousands of genetically labeled cancer cells. CRISPR-barcoding is a straightforward and highly flexible method that should greatly facilitate the functional investigation of specific mutations, in a context that closely mimics the complexity of cancer. PMID:27453044

  15. Overcoming Intratumor Heterogeneity of Polygenic Cancer Drug Resistance with Improved Biomarker Integration1

    PubMed Central

    Rehemtulla, Alnawaz

    2012-01-01

    Improvements in technology and resources are helping to advance our understanding of cancer-initiating events as well as factors involved with tumor progression, adaptation, and evasion of therapy. Tumors are well known to contain diverse cell populations and intratumor heterogeneity affords neoplasms with a diverse set of biologic characteristics that can be used to evolve and adapt. Intratumor heterogeneity has emerged as a major hindrance to improving cancer patient care. Polygenic cancer drug resistance necessitates reconsidering drug designs to include polypharmacology in pursuit of novel combinatorial agents having multitarget activity to overcome the diverse and compensatory signaling pathways in which cancer cells use to survive and evade therapy. Advances will require integration of different biomarkers such as genomics and imaging to provide for more adequate elucidation of the spatially varying location, type, and extent of diverse intratumor signaling molecules to provide for a rationale-based personalized cancer medicine strategy. PMID:23308059

  16. Intra-tumor heterogeneity: lessons from microbial evolution and clinical implications.

    PubMed

    de Bruin, Elza C; Taylor, Tiffany B; Swanton, Charles

    2013-01-01

    Multiple subclonal populations of tumor cells can coexist within the same tumor. This intra-tumor heterogeneity will have clinical implications and it is therefore important to identify factors that drive or suppress such heterogeneous tumor progression. Evolutionary biology can provide important insights into this process. In particular, experimental evolution studies of microbial populations, which exist as clonal populations that can diversify into multiple subclones, have revealed important evolutionary processes driving heterogeneity within a population. There are transferrable lessons that can be learnt from these studies that will help us to understand the process of intra-tumor heterogeneity in the clinical setting. In this review, we summarize drivers of microbial diversity that have been identified, such as mutation rate and environmental influences, and discuss how knowledge gained from microbial experimental evolution studies may guide us to identify and understand important selective factors that promote intra-tumor heterogeneity. Furthermore, we discuss how these factors could be used to direct and optimize research efforts to improve patient care, focusing on therapeutic resistance. Finally, we emphasize the need for longitudinal studies to address the impact of these potential tumor heterogeneity-promoting factors on drug resistance, metastatic potential and clinical outcome. PMID:24267946

  17. A preliminary investigation into textural features of intratumoral metabolic heterogeneity in (18)F-FDG PET for overall survival prognosis in patients with bulky cervical cancer treated with definitive concurrent chemoradiotherapy.

    PubMed

    Ho, Kung-Chu; Fang, Yu-Hua Dean; Chung, Hsiao-Wen; Yen, Tzu-Chen; Ho, Tsung-Ying; Chou, Hung-Hsueh; Hong, Ji-Hong; Huang, Yi-Ting; Wang, Chun-Chieh; Lai, Chyong-Huey

    2016-01-01

    We examined the role of intratumoral metabolic heterogeneity on (18)F-FDG PET during concurrent chemoradiotherapy (CCRT) in predicting survival outcomes for patients with cervical cancer. This prospective study consisted of 44 patients with bulky (≥ 4 cm) cervical cancer treated with CCRT. All patients underwent serial (18)F-FDG PET studies. Primary cervical tumor standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) were measured in pretreatment and intra-treatment (2 weeks) PET scans. Regional textural features were analyzed using the grey level run length encoding method (GLRLM) and grey-level size zone matrix. Associations between PET parameters and overall survival (OS) were tested by Kaplan-Meier analysis and Cox regression model. In univariate analysis, pretreatment grey-level nonuniformity (GLNU) > 48 by GLRLM textural analysis and intra-treatment decline of run length nonuniformity < 55% and the decline of TLG (∆TLG) < 60% were associated with significantly worse OS. In multivariate analysis, only ∆TLG was significant (P = 0.009). Combining pretreatment with intra-treatment factors, we defined the patients with a initial GLNU > 48 and a ∆TLG ≤ 60% as the high-risk group and the other patients as the low-risk. The 5-year OS rate for the high-risk group was significantly worse than that for the low-risk group (42% vs. 81%, respectively, P = 0.001). The heterogeneity of intratumoral FDG distribution and the early temporal change in TLG may be an important predictor for OS in patients with bulky cervical cancer. This gives the opportunity to adjust individualized regimens early in the treatment course. PMID:27508103

  18. A preliminary investigation into textural features of intratumoral metabolic heterogeneity in 18F-FDG PET for overall survival prognosis in patients with bulky cervical cancer treated with definitive concurrent chemoradiotherapy

    PubMed Central

    Ho, Kung-Chu; Fang, Yu-Hua Dean; Chung, Hsiao-Wen; Yen, Tzu-Chen; Ho, Tsung-Ying; Chou, Hung-Hsueh; Hong, Ji-Hong; Huang, Yi-Ting; Wang, Chun-Chieh; Lai, Chyong-Huey

    2016-01-01

    We examined the role of intratumoral metabolic heterogeneity on 18F-FDG PET during concurrent chemoradiotherapy (CCRT) in predicting survival outcomes for patients with cervical cancer. This prospective study consisted of 44 patients with bulky (≥ 4 cm) cervical cancer treated with CCRT. All patients underwent serial 18F-FDG PET studies. Primary cervical tumor standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) were measured in pretreatment and intra-treatment (2 weeks) PET scans. Regional textural features were analyzed using the grey level run length encoding method (GLRLM) and grey-level size zone matrix. Associations between PET parameters and overall survival (OS) were tested by Kaplan-Meier analysis and Cox regression model. In univariate analysis, pretreatment grey-level nonuniformity (GLNU) > 48 by GLRLM textural analysis and intra-treatment decline of run length nonuniformity < 55% and the decline of TLG (∆TLG) < 60% were associated with significantly worse OS. In multivariate analysis, only ∆TLG was significant (P = 0.009). Combining pretreatment with intra-treatment factors, we defined the patients with a initial GLNU > 48 and a ∆TLG ≤ 60% as the high-risk group and the other patients as the low-risk. The 5-year OS rate for the high-risk group was significantly worse than that for the low-risk group (42% vs. 81%, respectively, P = 0.001). The heterogeneity of intratumoral FDG distribution and the early temporal change in TLG may be an important predictor for OS in patients with bulky cervical cancer. This gives the opportunity to adjust individualized regimens early in the treatment course. PMID:27508103

  19. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity | Office of Cancer Genomics

    Cancer.gov

    Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001).

  20. Intratumor heterogeneity, variability and plasticity: questioning the current concepts in classification and treatment of hepatocellular carcinoma.

    PubMed

    Weiskirchen, Ralf

    2016-04-01

    In the classical view, the formation of a primary tumor is the consequence of a mutational event that first affects a single cell that subsequently passes through a multitude of consecutive hyperplastic and dysplastic stages. At the end of this pathogenetic sequence a cell arises that is potentially able to expanse infinitely having capacity to form a homogenous tumor mass. In contrary to this clonal expansion concept, the majority of primary human tumors display already a startling heterogeneity that can be reflected in different morphological features, physiological activities, and genetic diversity. In the past it was speculated that this cancer cell plasticity within a tumor is the result of an adaptive process that is induced by specific inhibiting therapies. In regard to the formation of hepatocellular carcinoma (HCC) this dogma was once challenged in a recent study that analysed tumor areas that were taken from HCC patients without medical pretreatment. Most of the analyzed samples showed highly significant intratumor heterogeneity. This affected morphological attributes, immunohistochemical stainability of five tumor-associated markers [α-fetoprotein (AFP), EpCAM, CK7, CD44 and glutamine synthetase], and integrity of genes (β-catenin and p53) that are critically involved in the pathogenesis of HCC. Altogether, this study showed that intratumor heterogeneity is a frequent finding in HCC that may contribute to treatment failure and drug resistance in HCC patients. PMID:27115013

  1. Intratumor heterogeneity, variability and plasticity: questioning the current concepts in classification and treatment of hepatocellular carcinoma

    PubMed Central

    2016-01-01

    In the classical view, the formation of a primary tumor is the consequence of a mutational event that first affects a single cell that subsequently passes through a multitude of consecutive hyperplastic and dysplastic stages. At the end of this pathogenetic sequence a cell arises that is potentially able to expanse infinitely having capacity to form a homogenous tumor mass. In contrary to this clonal expansion concept, the majority of primary human tumors display already a startling heterogeneity that can be reflected in different morphological features, physiological activities, and genetic diversity. In the past it was speculated that this cancer cell plasticity within a tumor is the result of an adaptive process that is induced by specific inhibiting therapies. In regard to the formation of hepatocellular carcinoma (HCC) this dogma was once challenged in a recent study that analysed tumor areas that were taken from HCC patients without medical pretreatment. Most of the analyzed samples showed highly significant intratumor heterogeneity. This affected morphological attributes, immunohistochemical stainability of five tumor-associated markers [α-fetoprotein (AFP), EpCAM, CK7, CD44 and glutamine synthetase], and integrity of genes (β-catenin and p53) that are critically involved in the pathogenesis of HCC. Altogether, this study showed that intratumor heterogeneity is a frequent finding in HCC that may contribute to treatment failure and drug resistance in HCC patients. PMID:27115013

  2. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer.

    PubMed

    Koay, Eugene J; Baio, Flavio E; Ondari, Alexander; Truty, Mark J; Cristini, Vittorio; Thomas, Ryan M; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R; Tamm, Eric P; Qayyum, Aliya; Crane, Christopher H; Javle, Milind; Katz, Matthew H; Gottumukkala, Vijaya N; Rozner, Marc A; Shen, Haifa; Lee, Jeffrey E; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L; Wolff, Robert A; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R; Fleming, Jason B

    2014-01-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  3. How to be good at being bad: centrosome amplification and mitotic propensity drive intratumoral heterogeneity

    PubMed Central

    Rida, Padmashree C. G.; Cantuaria, Guilherme; Reid, Michelle D.; Kucuk, Omer

    2016-01-01

    Cancer is truly an iconic disease—a tour de force whose multiple formidable strengths can be attributed to the bewildering heterogeneity that a tumor can manifest both spatially and temporally. A Darwinian evolutionary process is believed to undergird, at least in part, the generation of this heterogeneity that contributes to poor clinical outcomes. Risk assessment in clinical oncology is currently based on a small number of clinicopathologic factors (like stage, histological grade, receptor status, and serum tumor markers) and offers limited accuracy in predicting disease course as evidenced by the prognostic heterogeneity that persists in risk segments produced by present-day models. We posit that this insufficiency stems from the exclusion of key risk contributors from such models, especially the omission of certain factors implicated in generating intratumoral heterogeneity. The extent of centrosome amplification and the mitotic propensity inherent in a tumor are two such vital factors whose contributions to poor prognosis are presently overlooked in risk prognostication. Supernumerary centrosomes occur widely in tumors and are potent drivers of chromosomal instability that fosters intratumoral heterogeneity. The mitotic propensity of a proliferating population of tumor cells reflects the cell cycling kinetics of that population. Since frequent passage through improperly regulated mitotic divisions accelerates production of diverse genotypes, the mitotic propensity inherent in a tumor serves as a powerful beacon of risk. In this review, we highlight how centrosome amplification and error-prone mitoses contribute to poor clinical outcomes and urge the need to develop these cancer-specific traits as much-needed clinically-facile prognostic biomarkers with immense potential value for individualized cancer treatment in the clinic. PMID:26358854

  4. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    PubMed Central

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya’an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-01-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  5. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    NASA Astrophysics Data System (ADS)

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-12-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  6. Initial assessment of a model relating intratumoral genetic heterogeneity to radiological morphology

    PubMed Central

    Noterdaeme, O; Kelly, M; Friend, P; Soonowalla, Z; Steers, G; Brady, M

    2010-01-01

    Tumour heterogeneity has major implications for tumour development and response to therapy. Tumour heterogeneity results from mutations in the genes responsible for mismatch repair or maintenance of chromosomal stability. Cells with different genetic properties may grow at different rates and exhibit different resistance to therapeutic interventions. To date, there exists no approach to non-invasively assess tumour heterogeneity. Here we present a biologically inspired model of tumour growth, which relates intratumoral genetic heterogeneity to gross morphology visible on radiological images. The model represents the development of a tumour as a set of expanding spheres, each sphere representing a distinct clonal centre, with the sprouting of new spheres corresponding to new clonal centres. Each clonal centre may possess different characteristics relating to genetic composition, growth rate and response to treatment. We present a clinical example for which the model accurately tracks tumour growth and shows the correspondence to genetic variation (as determined by array comparative genomic hybridisation). One clinical implication of our work is that the assessment of heterogeneous tumours using Response Evaluation Criteria In Solid Tumours (RECIST) or volume measurements may not accurately reflect tumour growth, stability or the response to treatment. We believe that this is the first model linking the macro-scale appearance of tumours to their genetic composition. We anticipate that our model will provide a more informative way to assess the response of heterogeneous tumours to treatment, which is of increasing importance with the development of novel targeted anti-cancer treatments. PMID:19690073

  7. DREAMing: a simple and ultrasensitive method for assessing intratumor epigenetic heterogeneity directly from liquid biopsies

    PubMed Central

    Pisanic, Thomas R.; Athamanolap, Pornpat; Poh, Weijie; Chen, Chen; Hulbert, Alicia; Brock, Malcolm V.; Herman, James G.; Wang, Tza-Huei

    2015-01-01

    Many cancers comprise heterogeneous populations of cells at primary and metastatic sites throughout the body. The presence or emergence of distinct subclones with drug-resistant genetic and epigenetic phenotypes within these populations can greatly complicate therapeutic intervention. Liquid biopsies of peripheral blood from cancer patients have been suggested as an ideal means of sampling intratumor genetic and epigenetic heterogeneity for diagnostics, monitoring and therapeutic guidance. However, current molecular diagnostic and sequencing methods are not well suited to the routine assessment of epigenetic heterogeneity in difficult samples such as liquid biopsies that contain intrinsically low fractional concentrations of circulating tumor DNA (ctDNA) and rare epigenetic subclonal populations. Here we report an alternative approach, deemed DREAMing (Discrimination of Rare EpiAlleles by Melt), which uses semi-limiting dilution and precise melt curve analysis to distinguish and enumerate individual copies of epiallelic species at single-CpG-site resolution in fractions as low as 0.005%, providing facile and inexpensive ultrasensitive assessment of locus-specific epigenetic heterogeneity directly from liquid biopsies. The technique is demonstrated here for the evaluation of epigenetic heterogeneity at p14ARF and BRCA1 gene-promoter loci in liquid biopsies obtained from patients in association with non-small cell lung cancer (NSCLC) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), respectively. PMID:26304549

  8. Intra-tumor Heterogeneity in Localized Lung Adenocarcinomas Delineated by Multi-region Sequencing

    PubMed Central

    Zhang, Jianjun; Fujimoto, Junya; Zhang, Jianhua; Wedge, David C.; Song, Xingzhi; Zhang, Jiexin; Seth, Sahil; Chow, Chi-Wan; Cao, Yu; Gumbs, Curtis; Gold, Kathryn A.; Kalhor, Neda; Little, Latasha; Mahadeshwar, Harshad; Moran, Cesar; Protopopov, Alexei; Sun, Huandong; Tang, Jiabin; Wu, Xifeng; Ye, Yuanqing; William, William N.; Lee, Jack J.; Heymach, John V.; Hong, Waun Ki; Swisher, Stephen; Wistuba, Ignacio I.; Futreal, P. Andrew

    2015-01-01

    Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intra-tumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multi-region whole exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20/21 known cancer gene mutations were identified in all regions of individual tumors suggesting single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months post-surgery, 3 patients have relapsed and all 3 patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas. PMID:25301631

  9. Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas

    PubMed Central

    Mroz, Edmund A.; Tward, Aaron M.; Hammon, Rebecca J.; Ren, Yin; Rocco, James W.

    2015-01-01

    Background Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. Methods and Findings Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished

  10. Intratumoral heterogeneity: Clonal cooperation in epithelial-to-mesenchymal transition and metastasis

    PubMed Central

    Neelakantan, Deepika; Drasin, David J; Ford, Heide L

    2015-01-01

    Although phenotypic intratumoral heterogeneity was first described many decades ago, the advent of next-generation sequencing has provided conclusive evidence that in addition to phenotypic diversity, significant genotypic diversity exists within tumors. Tumor heterogeneity likely arises both from clonal expansions, as well as from differentiation hierarchies existent in the tumor, such as that established by cancer stem cells (CSCs) and non-CSCs. These differentiation hierarchies may arise due to genetic mutations, epigenetic alterations, or microenvironmental influences. An additional differentiation hierarchy within epithelial tumors may arise when only a few tumor cells trans-differentiate into mesenchymal-like cells, a process known as epithelial-to-mesenchymal transition (EMT). Again, this process can be influenced by both genetic and non-genetic factors. In this review we discuss the evidence for clonal interaction and cooperation for tumor maintenance and progression, particularly with respect to EMT, and further address the far-reaching effects that tumor heterogeneity may have on cancer therapy. PMID:25482627

  11. Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications.

    PubMed

    Cresswell, George D; Apps, John R; Chagtai, Tasnim; Mifsud, Borbala; Bentley, Christopher C; Maschietto, Mariana; Popov, Sergey D; Weeks, Mark E; Olsen, Øystein E; Sebire, Neil J; Pritchard-Jones, Kathy; Luscombe, Nicholas M; Williams, Richard D; Mifsud, William

    2016-07-01

    The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories in WT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event in WT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution. PMID:27333041

  12. Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival

    PubMed Central

    Desrichard, Alexis; Şenbabaoğlu, Yasin; Hakimi, A. Ari; Makarov, Vladimir; Reis-Filho, Jorge S.; Chan, Timothy A.

    2016-01-01

    As tumors accumulate genetic alterations, an evolutionary process occurs in which genetically distinct subclonal populations of cells co-exist, resulting in intratumor genetic heterogeneity (ITH). The clinical implications of ITH remain poorly defined. Data are limited with respect to whether ITH is an independent determinant of patient survival outcomes, across different cancer types. Here, we report the results of a pan-cancer analysis of over 3300 tumors, showing a varied landscape of ITH across 9 cancer types. While some gene mutations are subclonal, the majority of driver gene mutations are clonal events, present in nearly all cancer cells. Strikingly, high levels of ITH are associated with poorer survival across diverse types of cancer. The adverse impact of high ITH is independent of other clinical, pathologic and molecular factors. High ITH tends to be associated with lower levels of tumor-infiltrating immune cells, but this association is not able to explain the observed survival differences. Together, these data show that ITH is a prognostic marker in multiple cancers. These results illuminate the natural history of cancer evolution, indicating that tumor heterogeneity represents a significant obstacle to cancer control. PMID:26840267

  13. Assessment of intra-tumoral karyotypic heterogeneity by interphase cytogenetics in paraffin wax sections

    PubMed Central

    Southern, S A; Herrington, C S

    1996-01-01

    Aim—To analyse the effect of sectioning on the assessment of karyotypic heterogeneity by interphase cytogenetics in paraffin wax embedded normal squamous epithelium and to apply the principles derived to invasive cervical carcinoma. Methods—Normal male (n = 5) and female (n = 5) squamous epithelia were hybridised with peri-centromeric repeat probes specific for chromosomes X (DXZ1) and 17 (D17Z1) individually and in combination to assess the effect of sectioning on mono-, di-, tri-, and tetrasomic populations. Section thickness, interobserver variation and variation between different areas of the epithelium were evaluated. Invasive squamous carcinomas of the cervix (n = 5) were then hybridised with the DXZ1 probe and intratumoral heterogeneity was assessed by comparison of signal distributions obtained from different areas. Results—The optimum section thickness for the assessment of normal epithelium was 6 μm. Variation in the expected signal number in the range 1-4 did not introduce artefactual heterogeneity at this section thickness. The sensitivity of this approach for the detection of minor subpopulations was calculated to be 13-16%, 17-18% and 10-11% for mono-, tri- and tetrasomic populations, respectively. Karyotypic heterogeneity was detected in two of the five tumours and, in one case where the populations where clustered morphologically, a minor population representing 18% was identified. Conclusions—Interphase cytogenetic analysis of sections from paraffin wax embedded material can be used for the detection of minor subpopulations in tumours. This approach will be of particular value in the assessment of the relation between human papillomavirus infection and tumour karyotype and in the analysis of intraepithelial neoplasia. Images PMID:16696090

  14. Photoacoustic spectroscopic imaging of intra-tumor heterogeneity and molecular identification

    NASA Astrophysics Data System (ADS)

    Stantz, Keith M.; Liu, Bo; Cao, Minsong; Reinecke, Dan; Miller, Kathy; Kruger, Robert

    2006-02-01

    Purpose. To evaluate photoacoustic spectroscopy as a potential imaging modality capable of measuring intra-tumor heterogeneity and spectral features associated with hemoglobin and the molecular probe indocyanine green (ICG). Material and Methods. Immune deficient mice were injected with wildtype and VEGF enhanced MCF-7 breast cancer cells or SKOV3x ovarian cancer cells, which were allowed to grow to a size of 6-12 mm in diameter. Two mice were imaged alive and after euthanasia for (oxy/deoxy)-hemoglobin content. A 0.4 mL volume of 1 μg/mL concentration of ICG was injected into the tail veins of two mice prior to imaging using the photoacoustic computed tomography (PCT) spectrometer (Optosonics, Inc., Indianapolis, IN 46202) scanner. Mouse images were acquired for wavelengths spanning 700-920 nm, after which the major organs were excised, and similarly imaged. A histological study was performed by sectioning the organ and optically imaging the fluorescence distribution. Results. Calibration of PCT-spectroscopy with different samples of oxygenated blood reproduced a hemoglobin dissociation curve consistent with empirical formula with an average error of 5.6%. In vivo PCT determination of SaO II levels within the tumor vascular was measurably tracked, and spatially correlated to the periphery of the tumor. Statistical and systematic errors associated with hypoxia were estimated to be 10 and 13%, respectively. Measured ICG concentrations determined by contrast-differential PCT images in excised organs (tumor, liver) were approximately 0.8 μg/mL, consistent with fluorescent histological results. Also, the difference in the ratio of ICG concentration in the gall bladder-to-vasculature between the mice was consistent with excretion times between the two mice. Conclusion. PCT spectroscopic imaging has shown to be a noninvasive modality capable of imaging intra-tumor heterogeneity of (oxy/deoxy)-hemoglobin and ICG in vivo, with an estimated error in SaO II at 17% and in

  15. Turning the headlights on novel cancer biomarkers: Inspection of mechanics underlying intratumor heterogeneity

    PubMed Central

    McBride, Michelle; Rida, Padmashree C.G.; Aneja, Ritu

    2016-01-01

    Although the existence of intratumoral heterogeneity (ITH) in the expression of common biomarkers has been described by pathologists since the late 1890s, we have only recently begun to fathom the staggering extent and near ubiquity of this phenomenon. From the tumor’s perspective, ITH provides a stabilizing diversity that allows for the evolution of aggressive cancer phenotypes. As the weight of the evidence correlating ITH to poor prognosis burgeons, it has become increasingly important to determine the mechanisms by which a tumor acquires ITH, find clinically-adaptable means to quantify ITH and design strategies to deal with the numerous profound clinical ramifications that ITH forces upon us. Elucidation of the drivers of ITH could enable development of novel biomarkers whose interrogation might permit quantitative evaluation of the ITH inherent in a tumor in order to predict the poor prognosis risk associated with that tumor. This review proposes centrosome amplification (CA), aided and abetted by centrosome clustering mechanisms, as a critical driver of chromosomal instability (CIN) that makes a key contribution to ITH generation. Herein we also evaluate how a tumor’s inherent mitotic propensity, which reflects the cell cycling kinetics within the tumor’s proliferative cells, functions as the indispensable engine underpinning CIN, and determines the rate of CIN. We thus expound how the forces of centrosome amplification and mitotic propensity collaborate to sculpt the genetic landscape of a tumor and spawn extensive subclonal diversity. As such, centrosome amplification and mitotic propensity profiles could serve as clinically facile and powerful prognostic biomarkers that would enable more accurate risk segmentation of patients and design of individualized therapies. PMID:26024970

  16. Understanding Intratumoral Heterogeneity: Lessons from the Analysis of At-Risk Tissue and Premalignant Lesions in the Colon.

    PubMed

    Sievers, Chelsie K; Leystra, Alyssa A; Clipson, Linda; Dove, William F; Halberg, Richard B

    2016-08-01

    Advances in DNA sequencing have created new opportunities to better understand the biology of cancers. Attention is currently focused on precision medicine: does a cancer carry a mutation that is targetable with already available drugs? But, the timing at which multiple, targetable mutations arise during the adenoma to carcinoma sequence remains unresolved. Borras and colleagues identified mutations and allelic imbalance in at-risk mucosa and early polyps in the human colon. Their analyses indicate that mutations in key genes can arise quite early during tumorigenesis and that polyps are often multiclonal with at least two clones. These results are consistent with the "Big Bang" model of tumorigenesis, which postulates that intratumoral heterogeneity is a consequence of a mutational burst in the first few cell divisions following initiation that drives divergence from a single founder with unique but related clones coevolving. Emerging questions center around the ancestry of the tumor and impact of early intratumoral heterogeneity on tumor establishment, growth, progression, and most importantly, response to therapeutic intervention. Additional sequencing studies in which samples, especially at-risk tissue and premalignant neoplasms, are analyzed from animal models and humans will further our understanding of tumorigenesis and lead to more effective strategies for prevention and treatment. Cancer Prev Res; 9(8); 638-41. ©2016 AACRSee related article by Borras, et al., Cancer Prev Res 2016;9(6):417-427. PMID:27199343

  17. Darwinian Dynamics of Intratumoral Heterogeneity: Not Solely Random Mutations but Also Variable Environmental Selection Forces.

    PubMed

    Lloyd, Mark C; Cunningham, Jessica J; Bui, Marilyn M; Gillies, Robert J; Brown, Joel S; Gatenby, Robert A

    2016-06-01

    Spatial heterogeneity in tumors is generally thought to result from branching clonal evolution driven by random mutations that accumulate during tumor development. However, this concept rests on the implicit assumption that cancer cells never evolve to a fitness maximum because they can always acquire mutations that increase proliferative capacity. In this study, we investigated the validity of this assumption. Using evolutionary game theory, we demonstrate that local cancer cell populations will rapidly converge to the fittest phenotype given a stable environment. In such settings, cellular spatial heterogeneity in a tumor will be largely governed by regional variations in environmental conditions, for example, alterations in blood flow. Model simulations specifically predict a common spatial pattern in which cancer cells at the tumor-host interface exhibit invasion-promoting, rapidly proliferating phenotypic properties, whereas cells in the tumor core maximize their population density by promoting supportive tissue infrastructures, for example, to promote angiogenesis. We tested model predictions through detailed quantitative image analysis of phenotypic spatial distribution in histologic sections of 10 patients with stage 2 invasive breast cancers. CAIX, GLUT1, and Ki67 were upregulated in the tumor edge, consistent with an acid-producing invasive, proliferative phenotype. Cells in the tumor core were 20% denser than the edge, exhibiting upregulation of CAXII, HIF-1α, and cleaved caspase-3, consistent with a more static and less proliferative phenotype. Similarly, vascularity was consistently lower in the tumor center compared with the tumor edges. Lymphocytic immune responses to tumor antigens also trended to higher level in the tumor edge, although this effect did not reach statistical significance. Like invasive species in nature, cancer cells at the leading edge of the tumor possess a different phenotype from cells in the tumor core. Our results suggest

  18. Quantitative Computed Tomographic Descriptors Associate Tumor Shape Complexity and Intratumor Heterogeneity with Prognosis in Lung Adenocarcinoma

    PubMed Central

    Grove, Olya; Berglund, Anders E.; Schabath, Matthew B.; Aerts, Hugo J. W. L.; Dekker, Andre; Wang, Hua; Velazquez, Emmanuel Rios; Lambin, Philippe; Gu, Yuhua; Balagurunathan, Yoganand; Eikman, Edward; Gatenby, Robert A.; Eschrich, Steven; Gillies, Robert J.

    2015-01-01

    Two CT features were developed to quantitatively describe lung adenocarcinomas by scoring tumor shape complexity (feature 1: convexity) and intratumor density variation (feature 2: entropy ratio) in routinely obtained diagnostic CT scans. The developed quantitative features were analyzed in two independent cohorts (cohort 1: n = 61; cohort 2: n = 47) of patients diagnosed with primary lung adenocarcinoma, retrospectively curated to include imaging and clinical data. Preoperative chest CTs were segmented semi-automatically. Segmented tumor regions were further subdivided into core and boundary sub-regions, to quantify intensity variations across the tumor. Reproducibility of the features was evaluated in an independent test-retest dataset of 32 patients. The proposed metrics showed high degree of reproducibility in a repeated experiment (concordance, CCC≥0.897; dynamic range, DR≥0.92). Association with overall survival was evaluated by Cox proportional hazard regression, Kaplan-Meier survival curves, and the log-rank test. Both features were associated with overall survival (convexity: p = 0.008; entropy ratio: p = 0.04) in Cohort 1 but not in Cohort 2 (convexity: p = 0.7; entropy ratio: p = 0.8). In both cohorts, these features were found to be descriptive and demonstrated the link between imaging characteristics and patient survival in lung adenocarcinoma. PMID:25739030

  19. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine.

    PubMed

    Hiley, Crispin; de Bruin, Elza C; McGranahan, Nicholas; Swanton, Charles

    2014-01-01

    The presence of multiple subclones within tumors mandates understanding of longitudinal and spatial subclonal dynamics. Resolving the spatial and temporal heterogeneity of subclones with cancer driver events may offer insight into therapy response, tumor evolutionary histories and clinical trial design. PMID:25222836

  20. Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case.

    PubMed

    Saito, Takuya; Kondo, Chihiro; Shitara, Kohei; Ito, Yuichi; Saito, Noriko; Ikehara, Yuzuru; Yatabe, Yasushi; Yamamichi, Keigo; Tanaka, Hideo; Nakanishi, Hayao

    2015-06-01

    Intratumoral heterogeneity of HER2 expression in the metastatic foci of HER2-positive advanced gastric cancer remains unclear. In this study, we compared HER2 expression between primary and metastatic tumors in HER2-positive three autopsied cases and one resected case with multiple organ metastases by immunohistochemistry (IHC) and dual color in situ hybridization (DISH). All four cases judged positive (IHC3+) at the primary tumor tissues showed varying HER2 gene amplification (GA) status. One homogeneously HER2-positive autopsied case (Case 1) and one intratumorally heterogeneous positive resected case (Case 2) with high GA showed a homogeneous positive staining pattern in all the metastatic foci. One heterogeneously HER2-positive autopsied case (Case 3) with low GA showed a partially heterogeneous HER2 staining pattern in all the metastatic foci. In contrast, one heterogeneously HER2-positive autopsied case (Case 4) with equivocal GA showed a completely heterogeneous HER2 staining pattern in the metastatic foci. These results indicate that HER2-positive gastric cancers with low to high GA at the primary tumor show substantially homogeneous HER2 overexpression in the metastatic foci, whereas HER2-positive gastric cancers with equivocal GA expressed HER2 heterogeneously within the metastatic tumor, suggesting that metastatic foci of the latter HER2-positive cases would be potentially resistant to trastuzumab. PMID:25828363

  1. Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

    SciTech Connect

    Hrycushko, Brian A.; Li Shihong; Goins, Beth; Otto, Randal A.; Bao, Ande

    2011-03-15

    Purpose: Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle (liposome)-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. Methods: {sup 99m}Tc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts in nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, {sup 186}Re/{sup 188}Re liposomes. Effective uniform dose (EUD) and tumor control probability (TCP) were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. Results: Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy/MBq (318.2 Gy/mCi) and 5.7 Gy/MBq (209.1 Gy/mCi) could be delivered with this protocol of radiation delivery for {sup 186}Re/{sup 188}Re liposomes, respectively, and 37-92 MBq (1-2.5 mCi)/g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating

  2. Deciphering intra-tumor heterogeneity of lung adenocarcinoma confirms that dominant, branching, and private gene mutations occur within individual tumor nodules.

    PubMed

    Pelosi, Giuseppe; Pellegrinelli, Alessio; Fabbri, Alessandra; Tamborini, Elena; Perrone, Federica; Settanni, Giulio; Busico, Adele; Picciani, Benedetta; Testi, Maria Adele; Militti, Lucia; Maisonneuve, Patrick; Valeri, Barbara; Sonzogni, Angelica; Proto, Claudia; Garassino, Marina; De Braud, Filippo; Pastorino, Ugo

    2016-06-01

    While pulmonary adenocarcinoma (ADC) is morphologically heterogeneous, little is known about intra-tumor gene mutation heterogeneity (ITH). We therefore subjected 20 ADC nodules, 5 mutated for EGFR and 5 for KRAS, 5 with an ALK translocation, and 5 wild type (WT) for these alterations, to unsupervised next-generation sequencing of tumor regions from diverse architectural patterns. When 2 or more different gene mutations were found in a single tumor, this fulfilled the criteria for ITH. In the 84 studied tumor regions with diverse architecture, 71 gene mutations and 34 WT profiles were found. ITH was observed in 9/15 (60 %) ADC, 3 with an EGFR, 3 with a KRAS, and 3 with an ALK aberration, as reflected in 5, 6, and 9 additional mutations, respectively, detected in these tumors. EGFR mutations were observed in 21/22 and KRAS mutations in 18/22 tumor regions, suggesting that they appear early and have a driver role (dominant or trunk mutations). Branching mutations (in EZH2, PIK3CA, TP53, and EGFR exon 18) occurred in two or more regions, while private mutations (in ABL1, ALK, BRAF, HER2, KDR, LKB1, PTEN, MET, SMAD4, SMARCB1, and SRC) were confined to unique tumor samples of individual lesions, suggesting that they occurred later on during tumor progression. Patients with a tumor showing branching mutations ran a worse clinical course, independent of confounding factors. We conclude that in ADC, ITH exists in a pattern suggesting spatial and temporal hierarchy with dominant, branching, and private mutations. This is consistent with diverse intra-tumor clonal evolution, which has potential implications for patient prognosis or development of secondary therapy resistance. PMID:27056568

  3. Evaluating dynamic contrast-enhanced and photoacoustic CT to assess intra-tumor heterogeneity in xenograft mouse models

    NASA Astrophysics Data System (ADS)

    Stantz, Keith M.; Liu, Bo; Cao, Minsong; Reinecke, Dan; Dzemidzic, Mario; Liang, Yun; Kruger, Robert

    2006-03-01

    Purpose: To evaluate photoacoustic CT spectroscopy (PCT-S) and dynamic contrast-enhanced CT (DCE-CT) ability to measure parameters - oxygen saturation and vascular physiology - associated with the intra-tumor oxygenation status. Material and Methods: Breast (VEGF165 enhance MCF-7) and ovarian (SKOV3x) cancer cells were implanted into the fat pads and flanks of immune deficient mice and allowed to grow to a diameter of 8-15 mm. CT was used to determine physiological parameters by acquiring a sequence of scans over a 10 minute period after an i.v. injection of a radio-opaque contrast agent (Isovue). These time-dependent contrast-enhanced curves were fit to a two-compartmental model determining tumor perfusion, fractional plasma volume, permeability-surface area produce, and fractional interstitial volume on a voxel-by-voxel basis. After which, the tumors were imaged using photoacoustic CT (Optosonics, Inc., Indianapolis, IN 46202). The near infrared spectra (700-910 nm) within the vasculature was fit to linear combination of measured oxy- and deoxy-hemoglobin blood samples to obtain oxygen saturation levels (SaO II). Results: The PCT-S scanner was first calibrated using different samples of oxygenated blood, from which a statistical error ranging from 2.5-6.5% was measured and a plot of the hemoglobin dissociation curve was consistent with empirical formula. In vivo determination of tumor vasculature SaO II levels were measurably tracked, and spatially correlated to the periphery of the tumor. Tumor depend variations in SaO II - 0.32 (ovarian) and 0.60 (breast) - and in vascular physiology - perfusion, 1.03 and 0.063 mL/min/mL, and fractional plasma volume, 0.20 and 0.07 - were observed. Conclusion: Combined, PCT-S and CED-CT has the potential to measure intra-tumor levels of tumor oxygen saturation and vascular physiology, key parameters associated with hypoxia.

  4. Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity.

    PubMed

    Liu, Su-Yang; Joseph, Nancy M; Ravindranathan, Ajay; Stohr, Bradley A; Greenland, Nancy Y; Vohra, Poonam; Hosfield, Elizabeth; Yeh, Iwei; Talevich, Eric; Onodera, Courtney; Van Ziffle, Jessica A; Grenert, James P; Bastian, Boris C; Chen, Yunn-Yi; Krings, Gregor

    2016-09-01

    Malignant phyllodes tumors of the breast are poorly understood rare neoplasms with potential for aggressive behavior. Few efficacious treatment options exist for progressed or metastatic disease. The molecular features of malignant phyllodes tumors are poorly defined, and a deeper understanding of the genetics of these tumors may shed light on pathogenesis and progression and potentially identify novel treatment approaches. We sequenced 510 cancer-related genes in 10 malignant phyllodes tumors, including 5 tumors with liposarcomatous differentiation and 1 with myxoid chondrosarcoma-like differentiation. Intratumoral heterogeneity was assessed by sequencing two separate areas in 7 tumors, including non-heterologous and heterologous components of tumors with heterologous differentiation. Activating hotspot mutations in FGFR1 were identified in 2 tumors. Additional recurrently mutated genes included TERT promoter (6/10), TP53 (4/10), PIK3CA (3/10), MED12 (3/10), SETD2 (2/10) and KMT2D (2/10). Together, genomic aberrations in FGFR/EGFR PI-3 kinase and RAS pathways were identified in 8 (80%) tumors and included mutually exclusive and potentially actionable activating FGFR1, PIK3CA and BRAF V600E mutations, inactivating TSC2 mutation, EGFR amplification and PTEN loss. Seven (70%) malignant phyllodes tumors harbored TERT aberrations (six promoter mutations, one amplification). For comparison, TERT promoter mutations were identified by Sanger sequencing in 33% borderline (n=12) and no (0%, n=8) benign phyllodes tumors (P=0.391 and P=0.013 vs malignant tumors, respectively). Genetic features specific to liposarcoma, including CDK4/MDM2 amplification, were not identified. Copy number analysis revealed intratumoral heterogeneity and evidence for divergent tumor evolution in malignant phyllodes tumors with and without heterologous differentiation. Tumors with liposarcomatous differentiation revealed more chromosomal aberrations in non-heterologous components compared with

  5. Multiple region whole-exome sequencing reveals dramatically evolving intratumor genomic heterogeneity in esophageal squamous cell carcinoma

    PubMed Central

    Cao, W; Wu, W; Yan, M; Tian, F; Ma, C; Zhang, Q; Li, X; Han, P; Liu, Z; Gu, J; Biddle, F G

    2015-01-01

    Cancer is a disease of genome instability and genomic alterations; now, genomic heterogeneity is rapidly emerging as a defining feature of cancer, both within and between tumors. Motivation for our pilot study of tumor heterogeneity in esophageal squamous cell carcinoma (ESCC) is that it is not well studied, but the highest incidences of esophageal cancers are found in China and ESCC is the most common type. We profiled the mutations and changes in copy number that were identified by whole-exome sequencing and array-based comparative genomic hybridization in multiple regions within an ESCC from two patients. The average mutational heterogeneity rate was 90% in all regions of the individual tumors in each patient; most somatic point mutations were nonsynonymous substitutions, small Indels occurred in untranslated regions of genes, and copy number alterations varied among multiple regions of a tumor. Independent Sanger sequencing technology confirmed selected gene mutations with more than 88% concordance. Phylogenetic analysis of the somatic mutation frequency demonstrated that multiple, genomically heterogeneous divergent clones evolve and co-exist within a primary ESCC and metastatic subclones result from the dispersal and adaptation of an initially non-metastatic parental clone. Therefore, a single-region sampling will not reflect the evolving architecture of a genomically heterogeneous landscape of mutations in ESCC tumors and the divergent complexity of this genomic heterogeneity among patients will complicate any promise of a simple genetic or epigenetic diagnostic signature in ESCC. We conclude that any potential for informative biomarker discovery in ESCC and targeted personalized therapies will require a deeper understanding of the functional biology of the ontogeny and phylogeny of the tumor heterogeneity. PMID:26619400

  6. Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity.

    PubMed

    Ricklefs, Franz; Mineo, Marco; Rooj, Arun K; Nakano, Ichiro; Charest, Al; Weissleder, Ralph; Breakefield, Xandra O; Chiocca, E Antonio; Godlewski, Jakub; Bronisz, Agnieszka

    2016-05-15

    A lack of experimental models of tumor heterogeneity limits our knowledge of the complex subpopulation dynamics within the tumor ecosystem. In high-grade gliomas (HGG), distinct hierarchical cell populations arise from different glioma stem-like cell (GSC) subpopulations. Extracellular vesicles (EV) shed by cells may serve as conduits of genetic and signaling communications; however, little is known about how HGG heterogeneity may impact EV content and activity. In this study, we performed a proteomic analysis of EVs isolated from patient-derived GSC of either proneural or mesenchymal subtypes. EV signatures were heterogeneous, but reflected the molecular make-up of the GSC and consistently clustered into the two subtypes. EV-borne protein cargos transferred between proneural and mesenchymal GSC increased protumorigenic behaviors in vitro and in vivo Clinically, analyses of HGG patient data from the The Cancer Genome Atlas database revealed that proneural tumors with mesenchymal EV signatures or mesenchymal tumors with proneural EV signatures were both associated with worse outcomes, suggesting influences by the proportion of tumor cells of varying subtypes in tumors. Collectively, our findings illuminate the heterogeneity among tumor EVs and the complexity of HGG heterogeneity, which these EVs help to maintain. Cancer Res; 76(10); 2876-81. ©2016 AACR. PMID:27013191

  7. An Innovative Fluorescent Semi-quantitative Methylation-specific PCR Method for the Determination of MGMT Promoter Methylation is Reflecting Intra-tumor Heterogeneity.

    PubMed

    Nguyen, Aurelia; Legrain, Michele; Noel, Georges; Coca, Andres; Meyer Ea, Nicolos; Schott, Roland; Lasthaus, Christelle; Chenard, Marie Pierrette; Gaub, Marie Pierre; Lessinger, Jean Marc; Guenot, Dominique; Entz-Werle, Natacha

    2015-01-01

    High grade gliomas (HGG) are usually associated with a very dismal prognosis, which was moderately improving in the last decade with the introduction of the alkylating agent temozolomide in their treatment. The methylation status of MGMT (O6 methylguanine DNA-methyltransferase) promoter is one of the strongest predictive and prognostic factors for the patient chemoresponse. For instance, the molecular method of assessment for MGMT promoter status is not standardized. In this background, we developed a fluorescent capillary gel electrophoresis-based methylation specific-PCR. This technique allowed a semi-quantitative estimate of the relative ratio between methylated and unmethylated alleles. The efficacy and accuracy of the technique was assessed in a retrospective cohort of 178 newly diagnosed adult HGGs, who were homogeneously treated. First, we analyzed the impact on survival of different cut-off points in the MGMT promoter methylation and, to go further, we correlated these different rates to other well-known prognostic molecular factors involved in adult HGGs. This strategy allowed to validate our technique as a very sensitive technique (detection of a low methylation percentage, < 5%), which was feasible in fresh-frozen as well as in FFPE samples and had the propensity to detect intra-tumor heterogeneity. This technique identified a new sub-group of anaplastic oligodendrogliomas or oligoastrocytomas defined by a minor methylation and a worse outcome and, therefore, will help to substratify accurately into more homogeneous subgroups of methylated tumors. PMID:26118907

  8. Intratumor Cellular Heterogeneity and Alterations in ras Oncogene and p53 Tumor Suppressor Gene in Human Prostate Carcinoma

    PubMed Central

    Konishi, Noboru; Hiasa, Yoshio; Matsuda, Hirofumi; Tao, Ming; Tsuzuki, Toshihide; Hayashi, Isao; Kitahori, Yoshiteru; Shiraishi, Taizo; Yatani, Ryuichi; Shimazaki, Jun; Lin, Jung-Chung

    1995-01-01

    To assess the potential role of ras oncogene activation and P53 tumor suppressor gene mutations in the development of human prostate carcinoma, nine cases of histologically heterogeneous prostate tumors obtained from total prostatectomies were probed for these specific events. Each tumor was divided into 5 to 10 areas according to different growth or histological patterns. Targeted DNA sequences coding for ras and p53 were amplified by the polymerase chain reaction, analyzed by single-strand conformational polymorphisms, and confirmed by direct DNA sequencing. Point mutations of the ras gene were found in three of the nine tumors. Two contained K-ras codon 13 and H-ras codon 61 mutations, found in only one and three areas of each lesion, respectively. The third tumor contained two different point mutations in K-ras codons 13 and 61 in different foci of the sample. Loss of heterozygosity at the polymorphic codon 72 in the p53 gene was detected in two of four informative cases (50%) showing fragment cleavage by restriction fragment length polymorphism analysis. Mutations in p53, missense transversions, single base insertions, and two base deletions were also detected in three tumors. The present results reveal mutated ras and p53 occasionally occurring in small foci of the tumor and that genetic mutations in p53, as opposed to those in ras, are more closely associated with invasive growth of heterogeneous prostate carcinoma. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5 PMID:7573356

  9. Molecular evolution and intratumor heterogeneity by topographic compartments in muscle-invasive transitional cell carcinoma of the urinary bladder.

    PubMed

    Diaz-Cano, S J; Blanes, A; Rubio, J; Matilla, A; Wolfe, H J

    2000-03-01

    Superficial transitional cell carcinomas (TCC) of the urinary bladder have been shown to be monoclonal. However, no combined study of clonality and tumor suppressor genes (TSG) is available to date for muscle-invasive TCC. Forty-four muscle-invasive TCC of the urinary bladder selected from women were included in this study. Tumor cells located above and below the muscularis mucosa zone were systematically microdissected and used for DNA extraction. Hha-I digested and undigested samples were used to study the methylation pattern of androgen receptor alleles and undigested samples were used for microsatellite analysis of TSG (TP53, RB1, WT1, and NF1). Both loss of heterozygosity (LOH) and single nucleotide polymorphism (SNP) analyses were performed using optimized denaturing gradient gel electrophoresis. The expression of p53, pRB, and p21WAF1 was assessed by immunohistochemistry. Appropriate controls were run in every case. All except two TCC showed a monoclonal pattern with the same allele inactivated in both compartments. Microsatellite analysis of TSG revealed the same LOH/SNP pattern in both tumor compartments in 30 cases (involving more than 1 TSG locus in 8) and genetic heterogeneity in 14 cases. From the latter group, 9 cases expressed more genetic changes in the deep compartment (involving TP53 gene in all cases, WT1 gene in 2, and NF1 in 1), whereas in 4 cases the superficial compartment showed more genetic changes (three involving NF1 and one involving both RB and TP53). No statistical difference in the immunoexpression was detected, although it tended to be higher in the superficial compartment than in the deep compartment. These concordant data in polymorphic DNA regions indicate that bladder-muscle-invasive TCC are monoclonal proliferations with homogeneous tumor cell selection. Heterogeneous tumor cell selection by topography defined two different genetic compartments: superficial, NF1-defective, and deep, TP53-defective. No differences in the

  10. A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma.

    PubMed

    Lopez, José I; Cortes, Jesús M

    2016-01-01

    Intratumor heterogeneity (ITH) is an inherent process in cancer development which follows for most of the cases a branched pattern of evolution, with different cell clones evolving independently in space and time across different areas of the same tumor. The determination of ITH (in both spatial and temporal domains) is nowadays critical to enhance patient treatment and prognosis. Clear cell renal cell carcinoma (CCRCC) provides a good example of ITH. Sometimes the tumor is too big to be totally analyzed for ITH detection and pathologists decide which parts must be sampled for the analysis. For such a purpose, pathologists follow internationally accepted protocols. In light of the latest findings, however, current sampling protocols seem to be insufficient for detecting ITH with significant reliability. The arrival of new targeted therapies, some of them providing promising alternatives to improve patient survival, pushes the pathologist to obtain a truly representative sampling of tumor diversity in routine practice. How large this sampling must be and how this must be performed are unanswered questions so far.  Here we present a very simple method for tumor sampling that enhances ITH detection without increasing costs. This method follows a divide-and-conquer (DAC) strategy, that is, rather than sampling a small number of large-size tumor-pieces as the routine protocol (RP) advises, we suggest sampling many small-size pieces along the tumor. We performed a computational modeling approach to show that the usefulness of the DAC strategy is twofold: first, we show that DAC outperforms RP with similar laboratory costs, and second, DAC is capable of performing similar to total tumor sampling (TTS) but, very remarkably, at a much lower cost. We thus provide new light to push forward a shift in the paradigm about how pathologists should sample tumors for achieving efficient ITH detection. PMID:27127618

  11. A divide-and-conquer strategy in tumor sampling enhances detection of intratumor heterogeneity in routine pathology: A modeling approach in clear cell renal cell carcinoma

    PubMed Central

    Lopez, José I.; Cortes, Jesús M.

    2016-01-01

    Intratumor heterogeneity (ITH) is an inherent process in cancer development which follows for most of the cases a branched pattern of evolution, with different cell clones evolving independently in space and time across different areas of the same tumor. The determination of ITH (in both spatial and temporal domains) is nowadays critical to enhance patient treatment and prognosis. Clear cell renal cell carcinoma (CCRCC) provides a good example of ITH. Sometimes the tumor is too big to be totally analyzed for ITH detection and pathologists decide which parts must be sampled for the analysis. For such a purpose, pathologists follow internationally accepted protocols. In light of the latest findings, however, current sampling protocols seem to be insufficient for detecting ITH with significant reliability. The arrival of new targeted therapies, some of them providing promising alternatives to improve patient survival, pushes the pathologist to obtain a truly representative sampling of tumor diversity in routine practice. How large this sampling must be and how this must be performed are unanswered questions so far.  Here we present a very simple method for tumor sampling that enhances ITH detection without increasing costs. This method follows a divide-and-conquer (DAC) strategy, that is, rather than sampling a small number of large-size tumor-pieces as the routine protocol (RP) advises, we suggest sampling many small-size pieces along the tumor. We performed a computational modeling approach to show that the usefulness of the DAC strategy is twofold: first, we show that DAC outperforms RP with similar laboratory costs, and second, DAC is capable of performing similar to total tumor sampling (TTS) but, very remarkably, at a much lower cost. We thus provide new light to push forward a shift in the paradigm about how pathologists should sample tumors for achieving efficient ITH detection. PMID:27127618

  12. Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition.

    PubMed

    Soucheray, Margaret; Capelletti, Marzia; Pulido, Inés; Kuang, Yanan; Paweletz, Cloud P; Becker, Jeffrey H; Kikuchi, Eiki; Xu, Chunxiao; Patel, Tarun B; Al-Shahrour, Fatima; Carretero, Julián; Wong, Kwok-Kin; Jänne, Pasi A; Shapiro, Geoffrey I; Shimamura, Takeshi

    2015-10-15

    Non-small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to induce EMT and resistance to EGFR TKI treatment. Furthermore, NSCLC HCC4006 cells with acquired resistance to gefitinib were characterized by a mesenchymal phenotype and displayed a higher prevalence of the EGFR T790M mutated allele. Notably, combined inhibition of EGFR and the TGFβ receptor in HCC4006 cells prevented EMT but was not sufficient to prevent acquired gefitinib resistance because of an increased emergence of the EGFR T790M allele compared with cells treated with gefitinib alone. Conversely, another independent NSCLC cell line, PC9, reproducibly developed EGFR T790M mutations as the primary mechanism underlying EGFR TKI resistance, even though the prevalence of the mutant allele was lower than that in HCC4006 cells. Thus, our findings underscore heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations that give rise to divergent resistance mechanisms in response to treatment and anticipate the complexity of EMT suppression as a therapeutic strategy. PMID:26282169

  13. Targeted Cancer Therapy: Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity (Adv. Healthcare Mater. 11/2016).

    PubMed

    Othman, Basmah A; Greenwood, Christina; Abuelela, Ayman F; Bharath, Anil A; Chen, Shu; Theodorou, Ioannis; Douglas, Trevor; Uchida, Maskai; Ryan, Mary; Merzaban, Jasmeen S; Porter, Alexandra E

    2016-06-01

    On page 1310 J. S. Merzaban, A. E. Porter, and co-workers present fluorescently labeled RGD-targeted ZnO nanoparticles (NPs; green) for the targeted delivery of cytotoxic ZnO to integrin αvβ3 receptors expressed on triple negative breast cancer cells. Correlative light-electron microscopy shows that NPs dissolve into ionic Zn(2+) (blue) upon uptake and cause apoptosis (red) with intra-tumor heterogeneity, thereby providing a possible strategy for targeted breast cancer therapy. Cover design by Ivan Gromicho. PMID:27275627

  14. HER2 intratumoral heterogeneity analyses by concurrent HER2 gene and protein assessment for the prognosis of HER2 negative invasive breast cancer patients.

    PubMed

    Kurozumi, Sasagu; Padilla, Mary; Kurosumi, Masafumi; Matsumoto, Hiroshi; Inoue, Kenichi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari; Ranger-Moore, Jim; Allred, D Craig; Dennis, Eslie; Nitta, Hiroaki

    2016-07-01

    HER2 gene-protein assay (GPA) is a new method for the simultaneous evaluation of HER2 immunohistochemistry (IHC) and HER2 dual in situ hybridization (DISH) on single tissue sections of breast cancer. We investigated the presence of HER2 gene and protein discrepancy and HER2-heterogeneity using HER2-GPA. HER2 status was analyzed for the correlation between the presence of HER2-heterogeneity and patient prognosis. Consecutive 280 invasive breast cancer were examined. Statuses of HER2 protein and gene were evaluated in whole tumor sections of HER2 GPA slides. HER2 protein and gene combination patterns were classified to six phenotypic and genotypic types for each case, as well as at individual cell levels: (A) IHC and DISH positive; (B) IHC positive and DISH negative; (C) IHC equivocal and DISH positive; (D) IHC equivocal and DISH negative; (E) IHC negative and DISH positive; and (F) IHC and DISH negative. The presence of HER2-heterogeneity was determined by the existence of at least two of six types within one tumor. HER2-IHC positive patients had significantly worse survival than IHC negative patients and HER2-DISH positive patients had significantly worse survival than DISH negative patients. HER2 IHC negative and DISH positive patients had significantly worse recurrence-free survival than IHC and DISH negative patients. In the HER2 IHC and DISH negative group, the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Notably, among triple negative breast cancer (TNBC), the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Our study suggests that the presence of HER2-heterogeneity might be a prognostic factor in HER2 negative breast cancer patients, especially in TNBC. PMID:27318853

  15. Investigating Population Heterogeneity With Factor Mixture Models

    ERIC Educational Resources Information Center

    Lubke, Gitta H.; Muthen, Bengt

    2005-01-01

    Sources of population heterogeneity may or may not be observed. If the sources of heterogeneity are observed (e.g., gender), the sample can be split into groups and the data analyzed with methods for multiple groups. If the sources of population heterogeneity are unobserved, the data can be analyzed with latent class models. Factor mixture models…

  16. Multi-site tumor sampling (MSTS) improves the performance of histological detection of intratumor heterogeneity in clear cell renal cell carcinoma (CCRCC)

    PubMed Central

    Guarch, Rosa; Cortés, Jesús M.

    2016-01-01

    Current standard-of-care tumor sampling protocols for CCRCC (and other cancers) are not efficient at detecting intratumoural heterogeneity (ITH). We have demonstrated in silico that an alternative protocol, multi-site tumor sampling (MSTS) based upon the divide and conquer (DAC) algorithm, can significantly increase the efficiency of ITH detection without extra costs. Now we test this protocol on routine hematoxylin-eosin (HE) sections in a series of 38 CCRCC cases. MSTS was found to outperform traditional sampling when detecting either high grade (p=0.0136) or granular/eosinophilic cells (p=0.0114). We therefore propose that MSTS should be used in routine clinical practice.

  17. A conceptual and methodological framework for investigating etiologic heterogeneity.

    PubMed

    Begg, Colin B; Zabor, Emily C; Bernstein, Jonine L; Bernstein, Leslie; Press, Michael F; Seshan, Venkatraman E

    2013-12-20

    Cancer has traditionally been studied using the disease site of origin as the organizing framework. However, recent advances in molecular genetics have begun to challenge this taxonomy, as detailed molecular profiling of tumors has led to discoveries of subsets of tumors that have profiles that possess distinct clinical and biological characteristics. This is increasingly leading to research that seeks to investigate whether these subtypes of tumors have distinct etiologies. However, research in this field has been opportunistic and anecdotal, typically involving the comparison of distributions of individual risk factors between tumors classified on the basis of candidate tumor characteristics. The purpose of this article is to place this area of investigation within a more general conceptual and analytic framework, with a view to providing more efficient and practical strategies for designing and analyzing epidemiologic studies to investigate etiologic heterogeneity. We propose a formal definition of etiologic heterogeneity and show how classifications of tumor subtypes with larger etiologic heterogeneities inevitably possess greater disease risk predictability overall. We outline analytic strategies for estimating the degree of etiologic heterogeneity among a set of subtypes and for choosing subtypes that optimize the heterogeneity, and we discuss technical challenges that require further methodologic research. We illustrate the ideas by using a pooled case-control study of breast cancer classified by expression patterns of genes known to define distinct tumor subtypes. PMID:23857589

  18. Are geological media homogeneous or heterogeneous for neutron investigations?

    PubMed

    Woźnicka, U; Drozdowicz, K; Gabańska, B; Krynicka, E; Igielski, A

    2003-01-01

    The thermal neutron absorption cross section of a heterogeneous material is lower than that of the corresponding homogeneous one which contains the same components. When rock materials are investigated the sample usually contains grains which create heterogeneity. The heterogeneity effect depends on the mass contribution of highly and low-absorbing centers, on the ratio of their absorption cross sections, and on their sizes. An influence of the granulation of silicon and diabase samples on the absorption cross section measured with Czubek's method has been experimentally investigated. A 20% underestimation of the absorption cross section has been observed for diabase grains of sizes from 6.3 to 12.8 mm. PMID:12485675

  19. Intratumoral Drug Delivery with Nanoparticulate Carriers

    PubMed Central

    Holback, Hillary

    2011-01-01

    Stiff extracellular matrix, elevated interstitial fluid pressure, and the affinity for the tumor cells in the peripheral region of a solid tumor mass have long been recognized as significant barriers to diffusion of small-molecular-weight drugs and antibodies. However, their impacts on nanoparticle-based drug delivery have begun to receive due attention only recently. This article reviews biological features of many solid tumors that influence transport of drugs and nanoparticles and properties of nanoparticles relevant to their intratumoral transport, studied in various tumor models. We also discuss several experimental approaches employed to date for enhancement of intratumoral nanoparticle penetration. The impact of nanoparticle distribution on the effectiveness of chemotherapy remains to be investigated and should be considered in the design of new nanoparticulate drug carriers. PMID:21213021

  20. Intratumoral diversity of telomere length in individual neuroblastoma tumors.

    PubMed

    Pezzolo, Annalisa; Pistorio, Angela; Gambini, Claudio; Haupt, Riccardo; Ferraro, Manuela; Erminio, Giovanni; De Bernardi, Bruno; Garaventa, Alberto; Pistoia, Vito

    2015-04-10

    The purpose of the work was to investigate telomere length (TL) and mechanisms involved in TL maintenance in individual neuroblastoma (NB) tumors. Primary NB tumors from 102 patients, ninety Italian and twelve Spanish, diagnosed from 2000 to 2008 were studied. TL was investigated by quantitative fluorescence in situ hybridization (IQ-FISH) that allows to analyze individual cells in paraffin-embedded tissues. Fluorescence intensity of chromosome 2 centromere was used as internal control to normalize TL values to ploidy. Human telomerase reverse transcriptase (hTERT) expression was detected by immunofluorescence in 99/102 NB specimens.The main findings are the following: 1) two intratumoral subpopulations of cancer cells displaying telomeres of different length were identified in 32/102 tumors belonging to all stages. 2) hTERT expression was detected in 99/102 tumors, of which 31 displayed high expression and 68 low expression. Alternative lengthening of telomeres (ALT)-mechanism was present in 60/102 tumors, 20 of which showed high hTERT expression. Neither ALT-mechanism nor hTERT expression correlated with heterogeneous TL. 3) High hTERT expression and ALT positivity were associated with significantly reduced Overall Survival. 4) High hTERT expression predicted relapse irrespective of patient age. Intratumoral diversity in TL represents a novel feature in NB.In conclusion, diversity of TL in individual NB tumors was strongly associated with disease progression and death, suggesting that these findings are of translational relevance. The combination of high hTERT expression and ALT positivity may represent a novel biomarker of poor prognosis that deserves further investigation. PMID:25595889

  1. Investigating the effects of target heterogeneity on the cratering process.

    NASA Astrophysics Data System (ADS)

    Barnouin, O. S.

    2012-12-01

    Pre-existing target structures are known to influence the dynamics and morphologies of many terrestrial and planetary impact craters. Good examples include the Chesapeake and Ries craters, which both possess an inverted sombrero structure as a result of a weaker sedimentary surface layer overlying a stronger crystalline basement. But beyond such horizontal layering, closer analyses of the subsurface geology present in these and other planetary craters indicate that vertical heterogeneity in the strength and geochemistry of a target are also often present. These may influence the formation and subsequent modification of terrestrial craters. Evidence indicates that at Meteor crater, for example, pre-existing vertical jointing of the target gives this crater its square appearance, either by confining and re-directing the shock and subsequent rarefraction waves, or by allowing preferential weathering zones of weakness along the joints. In this study, we present a series of laboratory investigations and 2- and 3-dimensional numerical calculations of crater formation in a conceptually simple but physically complex target: a box of randomly distributed quartz spheres of identical size. These investigations provide constraints on how all types of target heterogeneity influence the cratering process. In both the laboratory and numerical studies, we measure the rate of crater growth, the transient crater shape, and in some instances the velocity of individual ejecta. These investigations vary the ratio of the impact shock thickness to target grain size by altering the impact velocity, projectile size, and target grain size. The laboratory data were collected at the NASA Ames vertical gun range, the NASA Johnson Space Center vertical gun range, and the University of Tokyo vertical gun range using non-intrusive diagonistic techniques. The numerical investigations were performed using the CTH hydrocode that solves the equations of motion, while conserving mass, energy, and

  2. Investigating heterogeneous protein annotations toward cross-corpora utilization

    PubMed Central

    2009-01-01

    Background The number of corpora, collections of structured texts, has been increasing, as a result of the growing interest in the application of natural language processing methods to biological texts. Many named entity recognition (NER) systems have been developed based on these corpora. However, in the biomedical community, there is yet no general consensus regarding named entity annotation; thus, the resources are largely incompatible, and it is difficult to compare the performance of systems developed on resources that were divergently annotated. On the other hand, from a practical application perspective, it is desirable to utilize as many existing annotated resources as possible, because annotation is costly. Thus, it becomes a task of interest to integrate the heterogeneous annotations in these resources. Results We explore the potential sources of incompatibility among gene and protein annotations that were made for three common corpora: GENIA, GENETAG and AIMed. To show the inconsistency in the corpora annotations, we first tackle the incompatibility problem caused by corpus integration, and we quantitatively measure the effect of this incompatibility on protein mention recognition. We find that the F-score performance declines tremendously when training with integrated data, instead of training with pure data; in some cases, the performance drops nearly 12%. This degradation may be caused by the newly added heterogeneous annotations, and cannot be fixed without an understanding of the heterogeneities that exist among the corpora. Motivated by the result of this preliminary experiment, we further qualitatively analyze a number of possible sources for these differences, and investigate the factors that would explain the inconsistencies, by performing a series of well-designed experiments. Our analyses indicate that incompatibilities in the gene/protein annotations exist mainly in the following four areas: the boundary annotation conventions, the scope of

  3. Final Technical Report - Investigation into the Relationship between Heterogeneity and Heavy-Tailed Solute Transport

    SciTech Connect

    Weissmann, Gary S

    2013-12-06

    The objective of this project was to characterize the influence that naturally complex geologic media has on anomalous dispersion and to determine if the nature of dispersion can be estimated from the underlying heterogeneous media. The UNM portion of this project was to provide detailed representations of aquifer heterogeneity through producing highly-resolved models of outcrop analogs to aquifer materials. This project combined outcrop-scale heterogeneity characterization (conducted at the University of New Mexico), laboratory experiments (conducted at Sandia National Laboratory), and numerical simulations (conducted at Sandia National Laboratory and Colorado School of Mines). The study was designed to test whether established dispersion theory accurately predicts the behavior of solute transport through heterogeneous media and to investigate the relationship between heterogeneity and the parameters that populate these models. The dispersion theory tested by this work was based upon the fractional advection-dispersion equation (fADE) model. Unlike most dispersion studies that develop a solute transport model by fitting the solute transport breakthrough curve, this project explored the nature of the heterogeneous media to better understand the connection between the model parameters and the aquifer heterogeneity. We also evaluated methods for simulating the heterogeneity to see whether these approaches (e.g., geostatistical) could reasonably replicate realistic heterogeneity. The UNM portion of this study focused on capturing realistic geologic heterogeneity of aquifer analogs using advanced outcrop mapping methods.

  4. Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity.

    PubMed

    Othman, Basmah A; Greenwood, Christina; Abuelela, Ayman F; Bharath, Anil A; Chen, Shu; Theodorou, Ioannis; Douglas, Trevor; Uchida, Maskai; Ryan, Mary; Merzaban, Jasmeen S; Porter, Alexandra E

    2016-06-01

    ZnO nanoparticles (NPs) are reported to show a high degree of cancer cell selectivity with potential use in cancer imaging and therapy. Questions remain about the mode by which the ZnO NPs cause cell death, whether they exert an intra- or extracellular effect, and the resistance among different cancer cell types to ZnO NP exposure. The present study quantifies the variability between the cellular toxicity, dynamics of cellular uptake, and dissolution of bare and RGD (Arg-Gly-Asp)-targeted ZnO NPs by MDA-MB-231 cells. Compared to bare ZnO NPs, RGD-targeting of the ZnO NPs to integrin αvβ3 receptors expressed on MDA-MB-231 cells appears to increase the toxicity of the ZnO NPs to breast cancer cells at lower doses. Confocal microscopy of live MDA-MB-231 cells confirms uptake of both classes of ZnO NPs with a commensurate rise in intracellular Zn(2+) concentration prior to cell death. The response of the cells within the population to intracellular Zn(2+) is highly heterogeneous. In addition, the results emphasize the utility of dynamic and quantitative imaging in understanding cell uptake and processing of targeted therapeutic ZnO NPs at the cellular level by heterogeneous cancer cell populations, which can be crucial for the development of optimized treatment strategies. PMID:27111660

  5. Quantifying Metabolic Heterogeneity in Head and Neck Tumors in Real Time: 2-DG Uptake Is Highest in Hypoxic Tumor Regions

    PubMed Central

    Nakajima, Erica C.; Laymon, Charles; Oborski, Matthew; Hou, Weizhou; Wang, Lin; Grandis, Jennifer R.; Ferris, Robert L.; Mountz, James M.; Van Houten, Bennett

    2014-01-01

    Purpose Intratumoral metabolic heterogeneity may increase the likelihood of treatment failure due to the presence of a subset of resistant tumor cells. Using a head and neck squamous cell carcinoma (HNSCC) xenograft model and a real-time fluorescence imaging approach, we tested the hypothesis that tumors are metabolically heterogeneous, and that tumor hypoxia alters patterns of glucose uptake within the tumor. Experimental Design Cal33 cells were grown as xenograft tumors (n = 16) in nude mice after identification of this cell line's metabolic response to hypoxia. Tumor uptake of fluorescent markers identifying hypoxia, glucose import, or vascularity was imaged simultaneously using fluorescent molecular tomography. The variability of intratumoral 2-deoxyglucose (IR800-2-DG) concentration was used to assess tumor metabolic heterogeneity, which was further investigated using immunohistochemistry for expression of key metabolic enzymes. HNSCC tumors in patients were assessed for intratumoral variability of 18F-fluorodeoxyglucose (18F-FDG) uptake in clinical PET scans. Results IR800-2-DG uptake in hypoxic regions of Cal33 tumors was 2.04 times higher compared to the whole tumor (p = 0.0001). IR800-2-DG uptake in tumors containing hypoxic regions was more heterogeneous as compared to tumors lacking a hypoxic signal. Immunohistochemistry staining for HIF-1α, carbonic anhydrase 9, and ATP synthase subunit 5β confirmed xenograft metabolic heterogeneity. We detected heterogeneous 18F-FDG uptake within patient HNSCC tumors, and the degree of heterogeneity varied amongst tumors. Conclusion Hypoxia is associated with increased intratumoral metabolic heterogeneity. 18F-FDG PET scans may be used to stratify patients according to the metabolic heterogeneity within their tumors, which could be an indicator of prognosis. PMID:25127378

  6. Hierarchical spike clustering analysis for investigation of interneuron heterogeneity.

    PubMed

    Boehlen, Anne; Heinemann, Uwe; Henneberger, Christian

    2016-04-21

    Action potentials represent the output of a neuron. Especially interneurons display a variety of discharge patterns ranging from regular action potential firing to prominent spike clustering or stuttering. The mechanisms underlying this heterogeneity remain incompletely understood. We established hierarchical cluster analysis of spike trains as a measure of spike clustering. A clustering index was calculated from action potential trains recorded in the whole-cell patch clamp configuration from hippocampal (CA1, stratum radiatum) and entorhinal (medial entorhinal cortex, layer 2) interneurons in acute slices and simulated data. Prominent, region-dependent, but also variable spike clustering was detected using this measure. Further analysis revealed a strong positive correlation between spike clustering and membrane potentials oscillations but an inverse correlation with neuronal resonance. Furthermore, clustering was more pronounced when the balance between fast-activating K(+) currents, assessed by the spike repolarisation time, and hyperpolarization-activated currents, gauged by the size of the sag potential, was shifted in favour of fast K(+) currents. Simulations of spike clustering confirmed that variable ratios of fast K(+) and hyperpolarization-activated currents could underlie different degrees of spike clustering and could thus be crucial for temporally structuring interneuron spike output. PMID:26987719

  7. Investigation of stochastic radiation transport methods in random heterogeneous mixtures

    NASA Astrophysics Data System (ADS)

    Reinert, Dustin Ray

    Among the most formidable challenges facing our world is the need for safe, clean, affordable energy sources. Growing concerns over global warming induced climate change and the rising costs of fossil fuels threaten conventional means of electricity production and are driving the current nuclear renaissance. One concept at the forefront of international development efforts is the High Temperature Gas-Cooled Reactor (HTGR). With numerous passive safety features and a meltdown-proof design capable of attaining high thermodynamic efficiencies for electricity generation as well as high temperatures useful for the burgeoning hydrogen economy, the HTGR is an extremely promising technology. Unfortunately, the fundamental understanding of neutron behavior within HTGR fuels lags far behind that of more conventional water-cooled reactors. HTGRs utilize a unique heterogeneous fuel element design consisting of thousands of tiny fissile fuel kernels randomly mixed with a non-fissile graphite matrix. Monte Carlo neutron transport simulations of the HTGR fuel element geometry in its full complexity are infeasible and this has motivated the development of more approximate computational techniques. A series of MATLAB codes was written to perform Monte Carlo simulations within HTGR fuel pebbles to establish a comprehensive understanding of the parameters under which the accuracy of the approximate techniques diminishes. This research identified the accuracy of the chord length sampling method to be a function of the matrix scattering optical thickness, the kernel optical thickness, and the kernel packing density. Two new Monte Carlo methods designed to focus the computational effort upon the parameter conditions shown to contribute most strongly to the overall computational error were implemented and evaluated. An extended memory chord length sampling routine that recalls a neutron's prior material traversals was demonstrated to be effective in fixed source calculations containing

  8. Consensus-based recommendations for investigating clinical heterogeneity in systematic reviews

    PubMed Central

    2013-01-01

    Background Critics of systematic reviews have argued that these studies often fail to inform clinical decision making because their results are far too general, that the data are sparse, such that findings cannot be applied to individual patients or for other decision making. While there is some consensus on methods for investigating statistical and methodological heterogeneity, little attention has been paid to clinical aspects of heterogeneity. Clinical heterogeneity, true effect heterogeneity, can be defined as variability among studies in the participants, the types or timing of outcome measurements, and the intervention characteristics. The objective of this project was to develop recommendations for investigating clinical heterogeneity in systematic reviews. Methods We used a modified Delphi technique with three phases: (1) pre-meeting item generation; (2) face-to-face consensus meeting in the form of a modified Delphi process; and (3) post-meeting feedback. We identified and invited potential participants with expertise in systematic review methodology, systematic review reporting, or statistical aspects of meta-analyses, or those who published papers on clinical heterogeneity. Results Between April and June of 2011, we conducted phone calls with participants. In June 2011 we held the face-to-face focus group meeting in Ann Arbor, Michigan. First, we agreed upon a definition of clinical heterogeneity: Variations in the treatment effect that are due to differences in clinically related characteristics. Next, we discussed and generated recommendations in the following 12 categories related to investigating clinical heterogeneity: the systematic review team, planning investigations, rationale for choice of variables, types of clinical variables, the role of statistical heterogeneity, the use of plotting and visual aids, dealing with outlier studies, the number of investigations or variables, the role of the best evidence synthesis, types of statistical methods

  9. Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose.

    PubMed

    Nakamura, Hiroyuki; Abu Lila, Amr S; Nishio, Miho; Tanaka, Masao; Ando, Hidenori; Kiwada, Hiroshi; Ishida, Tatsuhiro

    2015-12-28

    Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems. PMID:26548975

  10. Association between intratumoral lymphatic microvessel density (LMVD) and clinicopathologic features in endometrial cancer: a retrospective cohort study

    PubMed Central

    2010-01-01

    Background Lymph node metastasis in endometrial cancer significantly decreases survival rate. Few data on the influence of intratumoral lymphatic microvessel density (LMVD) on survival in endometrial cancer are available. Our aim was to assess the intratumoral LMVD of endometrial carcinomas and to investigate its association with classical pathological factors, lymph node metastasis and survival. Methods Fifty-seven patients with endometrial carcinoma diagnosed between 2000 and 2008 underwent complete surgical staging and evaluation of intratumoral LMVD and other histologic variables. Lymphatic microvessels were identified by immunohistochemical staining using monoclonal antibody against human podoplanin (clone D2-40) and evaluated by counting the number of immunostained lymphatic vessels in 10 hot spot areas at 400× magnification. The LMVD was expressed by the mean number of vessels in these 10 hot spot microscopic fields. We next investigated the association of LMVD with the clinicopathologic findings and prognosis. Results The mean number of lymphatic vessels counted in all cases ranged between 0 and 4.7. The median value of mean LMVD was 0.5, and defined the cut-off for low and high LMVD. We identified low intratumoral LMVD in 27 (47.4%) patients and high LMVD in 30 (52.6%) patients. High intratumoral LMVD was associated with lesser miometrial and adnaexal infiltration, lesser cervical and peritoneal involvement, and fewer fatal cases. Although there was lower lymph node involvement among cases with high LMVD, the difference did not reach significance. No association was seen between LMVD and FIGO staging, histological type, or vascular invasion. On the other hand, low intratumoral LMVD was associated with poor outcome. Seventy-five percent of deaths occurred in patients with low intratumoral LMVD. Conclusion Our results show association of high intratumoral LMVD with features related to more localized disease and better outcome. We discuss the role of

  11. Increased efficacy of photodynamic therapy of R3230AC mammary adenocarcinoma by intratumoral injection of Photofrin II.

    PubMed Central

    Gibson, S. L.; van der Meid, K. R.; Murant, R. S.; Hilf, R.

    1990-01-01

    Photodynamic therapy consists of the systemic administration of a derivative of haematoporphyrin (Photofrin II) followed 24-72 h later by exposure of malignant lesions to photoradiation. We investigated the efficacy of this treatment after direct intratumoral injection of Photofrin II. This direct treatment regimen resulted in higher rates of inhibition of mitochondrial cytochrome c oxidase (5.13% J-1 cm-2 x 10(-1) and succinate dehydrogenase (3.14% J-1 cm-2 x 10(-1] in vitro at 2 h after intratumoral injection compared to rates of inhibition obtained after intraperitoneal drug administration: 0.51 and 0.42% J-1 cm-2 x 10(-1), respectively. A significant delay in tumour growth in vivo was observed in animals that received intratumoral injections 2 h before photoradiation compared to animals injected intraperitoneally at either 2 or 24 h before photoradiation. The treatment protocols were compared with control groups, consisting of Photofrin II administration intratumorally or intraperitoneally without photoradiation, or photoradiation in the absence of Photofrin II. These data indicate that the intratumoral injection regimen with Photofrin II enhanced the efficacy of photodynamic therapy. The greater delay in tumour growth observed after intratumoral administration of Photofrin II suggests a mechanism favouring direct cell damage. PMID:2139578

  12. An Experimental Investigation of Foam Flow in Homogeneous and Heterogeneous Porous Media, SUPRI TR-112

    SciTech Connect

    Apaydin, Osman G.; Bertin, Henri; Castanier, Louis M.; Kovscek, Anthony R.

    1999-08-09

    Foam is used to reduce the high mobility of gas-drive fluids and improve the contact between oil and these injected fluids. We require a better understanding of the effect of surfactant concentration on foam flow in porous media. Besides this, the literature on foam flow and transport in heterogeneous systems is sparse although the field situation is primarily heterogeneous and multidimensional. In this study, foam flow experiments were conducted first in homogeneous sand packs to investigate the effect of surfactant concentration on foam flow and then a heterogeneous experimental setup was prepared to observe heterogeneity and multidimensional flow effects on foam propagation. The homogeneous core experiments were conducted in a cylindrical aluminum core holder that was packed with a uniform Ottawa sand. Sand permeability is about 7.0 Darcy. The experiments were interpreted in terms of evolution of in-situ water saturation as a function of time by the usage of CT scanner, cumulative water, and pressure drop across the core. At very low surfactant concentration, no significant benefit was observed. But when stable foam generation started sweep efficiency (water recovery), breakthrough time, and pressure drop increased as surfactant concentration increased.

  13. Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery.

    PubMed

    Campa, Michael J; Moody, M Anthony; Zhang, Ruijun; Liao, Hua-Xin; Gottlin, Elizabeth B; Patz, Edward F

    2016-02-01

    Intratumoral B lymphocytes are an integral part of the lung tumor microenvironment. Interrogation of the antibodies they express may improve our understanding of the host response to cancer and could be useful in elucidating novel molecular targets. We used two strategies to explore the repertoire of intratumoral B cell antibodies. First, we cloned VH and VL genes from single intratumoral B lymphocytes isolated from one lung tumor, expressed the genes as recombinant mAbs, and used the mAbs to identify the cognate tumor antigens. The Igs derived from intratumoral B cells demonstrated class switching, with a mean VH mutation frequency of 4%. Although there was no evidence for clonal expansion, these data are consistent with antigen-driven somatic hypermutation. Individual recombinant antibodies were polyreactive, although one clone demonstrated preferential immunoreactivity with tropomyosin 4 (TPM4). We found that higher levels of TPM4 antibodies were more common in cancer patients, but measurement of TPM4 antibody levels was not a sensitive test for detecting cancer. Second, in an effort to focus our recombinant antibody expression efforts on those B cells that displayed evidence of clonal expansion driven by antigen stimulation, we performed deep sequencing of the Ig genes of B cells collected from seven different tumors. Deep sequencing demonstrated somatic hypermutation but no dominant clones. These strategies may be useful for the study of B cell antibody expression, although identification of a dominant clone and unique therapeutic targets may require extensive investigation. PMID:26739486

  14. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses

    PubMed Central

    Rusk, Anthony W.; Tung, David; Miller, Maria; Roix, Jeffrey; Khanna, Kristen V.; Murthy, Ravi; Benjamin, Robert S.; Helgason, Thorunn; Szvalb, Ariel D.; Bird, Justin E.; Roy-Chowdhuri, Sinchita; Zhang, Halle H.; Qiao, Yuan; Karim, Baktiar; McDaniel, Jennifer; Elpiner, Amanda; Sahora, Alexandra; Lachowicz, Joshua; Phillips, Brenda; Turner, Avenelle; Klein, Mary K.; Post, Gerald; Diaz, Luis A.; Riggins, Gregory J.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Bettegowda, Chetan; Huso, David L.; Varterasian, Mary

    2015-01-01

    Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted. PMID:25122639

  15. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses.

    PubMed

    Roberts, Nicholas J; Zhang, Linping; Janku, Filip; Collins, Amanda; Bai, Ren-Yuan; Staedtke, Verena; Rusk, Anthony W; Tung, David; Miller, Maria; Roix, Jeffrey; Khanna, Kristen V; Murthy, Ravi; Benjamin, Robert S; Helgason, Thorunn; Szvalb, Ariel D; Bird, Justin E; Roy-Chowdhuri, Sinchita; Zhang, Halle H; Qiao, Yuan; Karim, Baktiar; McDaniel, Jennifer; Elpiner, Amanda; Sahora, Alexandra; Lachowicz, Joshua; Phillips, Brenda; Turner, Avenelle; Klein, Mary K; Post, Gerald; Diaz, Luis A; Riggins, Gregory J; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Bettegowda, Chetan; Huso, David L; Varterasian, Mary; Saha, Saurabh; Zhou, Shibin

    2014-08-13

    Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted. PMID:25122639

  16. Determinants of In-Group and Out-Group Perceptions of Heterogeneity: An Investigation of Sino-American Stereotypes.

    ERIC Educational Resources Information Center

    Lee, Yueh-Ting; Ottati, Victor

    1993-01-01

    Investigates familiarity as a determinant of perceptions of group heterogeneity, the objective level of heterogeneity characteristic of the target group, and the tendency for perceivers to see social groups consistently with 182 Chinese and 182 American college students and some teachers. Cultural differences in judgments are explored. (SLD)

  17. Numerical and Experimental Investigation of Soil Heterogeneity around Landmines in Natural Soil

    NASA Astrophysics Data System (ADS)

    Wallen, B.; Smits, K. M.; Howington, S. E.

    2015-12-01

    The environment in which landmines are placed is oftentimes highly heterogeneous. These heterogeneities such as differences in soil type, packing and moisture, combined with changes in surface and climate conditions can oftentimes mask the presence of the mine. Understanding the impact of heterogeneity on heat and mass transfer behavior in the vicinity of landmines is paramount to properly identifying landmine locations for demining operations. This study investigates the impact of soil heterogeneity on soil moisture and temperature distributions around buried objects with the goal of increasing our ability to model and predict the environmental conditions that are most dynamic to mine detection performance. A ten-day field experiment was conducted in which two anti-personnel landmines at different depths and a limestone block of comparable size were buried. The site was instrumented with a series of sensors, monitoring atmospheric, surface and subsurface conditions to include measurements of soil moisture, soil and air temperature, relative humidity, vapor concentration, and meteorological conditions such as wind speed and net radiation. Infrared thermal imaging was used to provide continuous profiles of surface temperature conditions. The soil was well characterized in the laboratory to provide good understanding of field conditions for numerical modeling efforts. Experimental results demonstrate the strongest thermal contrast between shallow landmine emplacement and the surrounding soil occurring as the sun approaches its zenith and two hours after sunset until the sun directly impacts the soil above the landmine. A finite-element model of fluid flow and heat transport through porous media is compared against experimental observations, capturing the diurnal variation. A validated model, like this one, offers the opportunity to improve landmine detection probabilities and reduce false alarms caused by environmental variability.

  18. Targeting intratumoral androgens: statins and beyond.

    PubMed

    Schweizer, Michael T; Yu, Evan Y

    2016-09-01

    While initially effective, androgen deprivation therapy (ADT) is not curative, and nearly all men with advanced prostate cancer will eventually progress to the more resistant, and ultimately lethal form of the disease, so called castration-resistant prostate cancer (CRPC). The maintenance of androgens within the prostate cancer microenvironment likely represents one of the key mechanisms by which this transition from hormone-sensitive to CRPC occurs. This can be accomplished either through intratumoral androgen biosynthesis or the active transport of androgens and androgenic precursors into the tumor microenvironment. More recently, preclinical and clinical data supported therapeutic strategies that seek to target these two mechanisms, either through the use of drugs that impair androgen biosynthesis (e.g. inhibiting the steroidogenic enzymes CYP17 and AKR1C3 with abiraterone and indomethacin, respectively) or drugs that inhibit the SLCO transporters responsible for importing androgens (e.g. statins). PMID:27583031

  19. Trochlear Nerve Schwannoma With Repeated Intratumoral Hemorrhage.

    PubMed

    Liu, Pengfei; Bao, Yuhai; Zhang, Wenchuan

    2016-09-01

    Trochlear nerve schwannoma is extremely rare, with only 35 pathologically confirmed patients being reported in the literature. Here, the authors report a patient of trochlear nerve schwannoma in the prepontine cistern manifesting as facial pain and double vision and presenting the image characteristics of repeated intratumoral hemorrhage, which has never been reported in the literature. Total tumor along with a portion of the trochlear nerve was removed by using a retrosigmoid approach. Facial pain disappeared after operation, and the diplopia remained. Follow-up studies have shown no tumor recurrence for 2 years and the simultaneous alleviation of diplopia. Information regarding the clinical presentation, radiological features and surgical outcomes of trochlear nerve schwannoma are discussed and reviewed in the paper. PMID:27607129

  20. An Investigation of Homogeneous and Heterogeneous Sonochemistry for Destruction of Hazardous Waste

    SciTech Connect

    Hua, Inez

    1999-06-01

    The primary objective of this research project is to acquire a deeper fundamental knowledge of acoustic cavitation and cavitation chemistry, and in doing so, to ascertain how ultrasonic irradiation can be more effectively applied to environmental problems. The primary objective will be accomplished by examining numerous aspects of sonochemical systems and acoustic cavitation. During the course of the project, the research group will investigate sonochemical kinetics and reactive intermediates, the behavior of heterogeneous (solid/liquid) systems, and the significance of physical variables during sonolysis. An additional component of the project includes utilizing various techniques to image cavitation bubble cloud development.

  1. Influence investigation of a void region on modeling light propagation in a heterogeneous medium.

    PubMed

    Yang, Defu; Chen, Xueli; Ren, Shenghan; Qu, Xiaochao; Tian, Jie; Liang, Jimin

    2013-01-20

    A void region exists in some biological tissues, and previous studies have shown that inaccurate images would be obtained if it were not processed. A hybrid radiosity-diffusion method (HRDM) that couples the radiosity theory and the diffusion equation has been proposed to deal with the void problem and has been well demonstrated in two-dimensional and three-dimensional (3D) simple models. However, the extent of the impact of the void region on the accuracy of modeling light propagation has not been investigated. In this paper, we first implemented and verified the HRDM in 3D models, including both the regular geometries and a digital mouse model, and then investigated the influences of the void region on modeling light propagation in a heterogeneous medium. Our investigation results show that the influence of the region can be neglected when the size of the void is less than a certain range, and other cases must be taken into account. PMID:23338186

  2. Computational investigation of stoichiometric effects, binding site heterogeneities, and selectivities of molecularly imprinted polymers.

    PubMed

    Terracina, Jacob J; Bergkvist, Magnus; Sharfstein, Susan T

    2016-06-01

    A series of quantum mechanical (QM) computational optimizations of molecularly imprinted polymer (MIP) systems were used to determine optimal monomer-to-target ratios. Imidazole- and xanthine-derived target molecules were studied. The investigation included both small-scale models (3-7 molecules) and larger-scale models (15-35 molecules). The optimal ratios differed between the small and larger scales. For the larger models containing multiple targets, binding-site surface area analysis was used to quantify the heterogeneity of these sites. The more fully surrounded sites had greater binding energies. No discretization of binding modes was seen, furthering arguments for continuous affinity distribution models. Molecular mechanical (MM) docking was then used to measure the selectivities of the QM-optimized binding sites. Selectivity was also shown to improve as binding sites become more fully encased by the monomers. For internal sites, docking consistently showed selectivity favoring the molecules that had been imprinted via QM geometry optimizations. The computationally imprinted sites were shown to exhibit size-, shape-, and polarity-based selectivity. Here we present a novel approach to investigate the selectivity and heterogeneity of imprinted polymer binding sites, by applying the rapid orientation screening of MM docking to the highly accurate QM-optimized geometries. Modeling schemes were designed such that no computing clusters or other specialized modeling equipment would be required. Improving the in silico analysis of MIP system properties will ultimately allow for the production of more sensitive and selective polymers. PMID:27207254

  3. Heterogeneously catalyzed hydrolysis of chlorine nitrate: Fourier-transform ion cyclotron resonance investigations of stratospheric chemistry

    NASA Astrophysics Data System (ADS)

    Schindler, Thomas; Berg, Christian; Niedner-Schatteburg, Gereon; Bondybey, Vladimir E.

    1996-03-01

    High resolution Fourier-transform ion cyclotron resonance (FT-ICR) mass spectroscopy is used to investigate reactions of large ionic water clusters H+(H2O)n and X-(H2O)n (n=1-100, X=O or OH). Reactions of the clusters with chlorine nitrate, important ``reservoir compound'' involved in the stratospheric ozone chemistry, are investigated to evaluate the importance of heterogeneously catalyzed reactions for ozone depletion. It is found that reactions of both cationic and anionic clusters result in effective hydrolysis of chlorine nitrate and return of the more active hypochlorous acid, HOCl into the gas phase. The chemistry of clusters is discussed, and its validity and relevance as a model for ``real life'' processes in the so-called polar stratospheric clouds (PSC's) is assessed.

  4. Intratumoral Hemorrhage in a Patient With Cerebellar Hemangioblastoma

    PubMed Central

    Wang, Zhen; Hu, Jun; Xu, Liang; Malaguit, Jay; Chen, Sheng

    2015-01-01

    Abstract Spontaneous hemorrhage is rarely associated with hemangioblastomas. Intratumoral hemorrhage occurring in cerebellar hemangioblastomas is more rare. A 25-year-old man was admitted to our hospital with headache. We found a round cystic lesion with solid part in the right cerebellum. The lesion was resected. The final pathological diagnosis was hemangioblastomas. The radiological features of this case were similar to normal hemangioblastomas, whereas our histological examination showed the occurrence of the intratumoral hemorrhage. If the hemangioblastoma ruptures in our case, the outcome of the patient will be worse. It is difficult to identify the intratumoral hemorrhage of hemangioblastomas and quite dangerous if it is diagnosed late. Diagnosing an intratumoral hemorrhage of hemangioblastomas still needs a further discussion. Genetic screening may help us make an early diagnosis. Furthermore, the mechanism about intratumoral hemorrhage of hemangioblastomas remains unknown. The mutation of D6Mit135 gene on chromosome 6 may be responsible for the vascular dilation and hemorrhage induction in the hemangioblastomas. Tumor size, upregulation of vascular endothelial growth factor, spinalradicular location, and solid type are also factors relating to the hemorrhage of hemangioblastomas. The purpose of reporting our case is 2-fold: to remind clinicians to consider the possibility of internal hemorrhaging while diagnosing this disease, and provide a starting point to discuss mechanisms regarding the intratumoral hemorrhage of hemangioblastomas. PMID:25634201

  5. Effect of intratumoral administration on biodistribution of 64Cu-labeled nanoshells

    PubMed Central

    Xie, Huan; Goins, Beth; Bao, Ande; Wang, Zheng Jim; Phillips, William T

    2012-01-01

    Background Gold nanoshells are excellent agents for photothermal ablation cancer therapy and are currently under clinical trial for solid tumors. Previous studies showed that passive delivery of gold nanoshells through intravenous administration resulted in limited tumor accumulation, which represents a major challenge for this therapy. In this report, the impact of direct intratumoral administration on the pharmacokinetics and biodistribution of the nanoshells was systematically investigated. Methods The gold nanoshells were labeled with the radionuclide, copper-64 (64Cu). Intratumoral infusion of 64Cu-nanoshells and two controls, ie, 64Cu-DOTA (1,4,7,10-tetraazaciclododecane- 1,4,7,10-tetraacetic acid) and 64Cu-DOTA-PEG (polyethylene glycol), as well as intravenous injection of 64Cu-nanoshells were performed in nude rats, each with a head and neck squamous cell carcinoma xenograft. The pharmacokinetics was determined by radioactive counting of serial blood samples collected from the rats at different time points post-injection. Using positron emission tomography/computed tomography imaging, the in vivo distribution of 64Cu-nanoshells and the controls was monitored at various time points after injection. Organ biodistribution in the rats at 46 hours was analyzed by radioactive counting and compared between the different groups. Results The resulting pharmacokinetic curves indicated a similar trend between the intratumorally injected agents, but a significant difference with the intravenously injected 64Cu-nanoshells. Positron emission tomography images and organ biodistribution results on rats after intratumoral administration showed higher retention of 64Cu-nanoshells in tumors and less concentration in other healthy organs, with a significant difference from the controls. It was also found that, compared with intravenous injection, tumor concentrations of 64Cu-nanoshells improved substantially and were stable at 44 hours post-injection. Conclusion There was a

  6. Laboratory Investigations of Heterogeneous Chemistry Important to Ozone Depletion in the Stratosphere

    NASA Astrophysics Data System (ADS)

    Zhang, Renyi

    Results of laboratory investigations of heterogeneous chemistry important to ozone depletion in the stratosphere are presented. Thermodynamic properties (such as melting points, enthalpies of fusion, etc.) for acids which are present in the stratosphere (HCl, HNO_3 , and H_2SO_4 ) are studied using laboratory-assembled apparatus of electrical conductivity and differential thermal analysis and using a commercial differential scanning calorimeter (DSC). Vapor pressures and infrared spectra of liquid and supercooled solutions, and of liquid-solid and solid -solid coexistence mixtures for the HCl/H_2 O and H_2SO_4 /H_2O binary systems are investigated. Equilibrium constants and standard enthalpies of formation for the pure crystalline hydrates of those acids as well as their corresponding liquid compositions are determined from the vapor pressure and calorimetric data. A theoretical approach, which allows determination of vapor pressures for two adjacent hydrates in thermodynamic equilibrium and for the coexistence systems involving a hydrate and ice in a binary system, is presented in terms of chemical equilibrium principles and compared with the experimental data for thermodynamic consistence. Vapor pressures of HNO_3 and HCl over H_2SO_4 /HNO_3/H_2 O and H_2SO_4 /HCl/H_2O solutions as well as over H_2SO_4/HNO _3/HCl/H_2O solutions are also measured in order to predict incorporation of stratospheric acids into the background sulfate aerosols. From the data, the Henry's law solubility constants for those systems are determined and the equilibrium compositions of aqueous stratospheric aerosols are predicted as a function of ambient temperature and mixing ratios of H_2 O and HNO_3. The results indicate that at the low temperatures characteristic of the stratosphere at high latitudes in the winter and spring, the HNO_3 content reaches levels of the order of 10% wt in the background sulfate aerosols. The results also reveal that the amount of dissolved HCl in the

  7. Acidolysis of a lignin model: investigation of heterogeneous catalysis using Montmorillonite clay.

    PubMed

    Bouxin, Florent; Baumberger, Stéphanie; Pollet, Brigitte; Haudrechy, Arnaud; Renault, Jean-Hugues; Dole, Patrice

    2010-01-01

    The use of heterogeneous conditions involving Montmorillonite K10 clay was investigated as a mild alternative to homogeneous acidolysis of a lignin model. Guaiacyl Dehydrogenation Oligomers (DHOs) synthesized by horseradish peroxidase were selected as starting material. Hydrolysis products were analyzed by gel permeation chromatography and by HPLC/mass spectrometry. Several experimental parameters were studied such as catalyst and substrate concentration, as well as reaction solvent composition in order to minimize high molar mass product formation generated by recombination mechanisms. In both catalytic modes, the best hydrolysis conditions were similar in terms of solvent composition with dioxane/water (90/10, v/v) and catalyst H(+) concentration of about 0.01 mol/L. Although the homogeneous catalysis generated only 28% of low molecular weight (LMW) products (monomers and dimers), clay catalysis generated 35%. In light of the qualitative analysis, both catalytic methods gave the same products, thus supporting similar hydrolysis mechanisms. PMID:19747820

  8. Investigation of flow and solute transport at the field scale through heterogeneous deformable porous media

    NASA Astrophysics Data System (ADS)

    Chang, Ching-Min; Yeh, Hund-Der

    2016-09-01

    This work describes an investigation of the spatial statistical structure of specific discharge field and solute transport process of a nonreactive solute at the field scale through a heterogeneous deformable porous medium. The flow field is driven by a vertical gradient in the excess pore water pressure induced by a step increase in load applied on the upper part of a finite-thickness aquifer. The non-stationary spectral representation is adopted to characterize the spatial covariance of the specific discharge field necessary for the development of the solute particle trajectory statistics using the Lagrangian formalism. We show that the statistics of the specific discharge and particle trajectory derived herein are non-stationary and functions of the coefficient of soil compressibility, μ. The effect of μ on the relative variation of specific discharge and the solute particle trajectory statistics are analyzed upon evaluating our expressions.

  9. Investigation of photon beam models in heterogeneous media of modern radiotherapy.

    PubMed

    Ding, W; Johnston, P N; Wong, T P Y; Bubb, I F

    2004-06-01

    This study investigates the performance of photon beam models in dose calculations involving heterogeneous media in modern radiotherapy. Three dose calculation algorithms implemented in the CMS FOCUS treatment planning system have been assessed and validated using ionization chambers, thermoluminescent dosimeters (TLDs) and film. The algorithms include the multigrid superposition (MGS) algorithm, fast Fourier Transform Convolution (FFTC) algorithm and Clarkson algorithm. Heterogeneous phantoms used in the study consist of air cavities, lung analogue and an anthropomorphic phantom. Depth dose distributions along the central beam axis for 6 MV and 10 MV photon beams with field sizes of 5 cm x 5 cm and 10 cm x 10 cm were measured in the air cavity phantoms and lung analogue phantom. Point dose measurements were performed in the anthropomorphic phantom. Calculated results with three dose calculation algorithms were compared with measured results. In the air cavity phantoms, the maximum dose differences between the algorithms and the measurements were found at the distal surface of the air cavity with a 10 MV photon beam and a 5 cm x 5 cm field size. The differences were 3.8%. 24.9% and 27.7% for the MGS. FFTC and Clarkson algorithms. respectively. Experimental measurements of secondary electron build-up range beyond the air cavity showed an increase with decreasing field size, increasing energy and increasing air cavity thickness. The maximum dose differences in the lung analogue with 5 cm x 5 cm field size were found to be 0.3%. 4.9% and 6.9% for the MGS. FFTC and Clarkson algorithms with a 6 MV photon beam and 0.4%. 6.3% and 9.1% with a 10 MV photon beam, respectively. In the anthropomorphic phantom, the dose differences between calculations using the MGS algorithm and measurements with TLD rods were less than +/-4.5% for 6 MV and 10 MV photon beams with 10 cm x 10 cm field size and 6 MV photon beam with 5 cm x 5 cm field size, and within +/-7.5% for 10 MV with 5 cm

  10. Numerical investigations of triggering mechanisms of shallow landslides due to heterogeneous spatio-temporal hydrological patterns.

    NASA Astrophysics Data System (ADS)

    Schwarz, Massimiliano; Cohen, Denis

    2016-04-01

    regional scale rely on the infinite slope assumption for stability calculations and on continuous hydrological properties of the soil. The objective of the present study is to investigate the influence of non-continuos hydrological features (such as ephemeral springs) on the triggering mechanisms of shallow landslides using a discrete element model (SOSlope) in which the stress-strain behavior of soil is explicitly considered. The application of a stress-strain calculation allows for the simulation of local versus global loading due to hydrological processes. In particular, this study investigates the effects of different types of hydrological loading on the force redistribution on a slope associated with local displacements and following failures of soil masses. Strength and stiffness of soil are considered heterogeneous and are calculated based on the assumption of root distributions within a forested hillslope.

  11. Ultrastructural Heterogeneity of Carbonaceous Material in Ancient Cherts: Investigating Biosignature Origin and Preservation.

    PubMed

    Qu, Yuangao; Engdahl, Anders; Zhu, Shixing; Vajda, Vivi; McLoughlin, Nicola

    2015-10-01

    Opaline silica deposits on Mars may be good target sites where organic biosignatures could be preserved. Potential analogues on Earth are provided by ancient cherts containing carbonaceous material (CM) permineralized by silica. In this study, we investigated the ultrastructure and chemical characteristics of CM in the Rhynie chert (c. 410 Ma, UK), Bitter Springs Formation (c. 820 Ma, Australia), and Wumishan Formation (c. 1485 Ma, China). Raman spectroscopy indicates that the CM has experienced advanced diagenesis or low-grade metamorphism at peak metamorphic temperatures of 150-350°C. Raman mapping and micro-Fourier transform infrared (micro-FTIR) spectroscopy were used to document subcellular-scale variation in the CM of fossilized plants, fungi, prokaryotes, and carbonaceous stromatolites. In the Rhynie chert, ultrastructural variation in the CM was found within individual fossils, while in coccoidal and filamentous microfossils of the Bitter Springs and formless CM of the Wumishan stromatolites ultrastructural variation was found between, not within, different microfossils. This heterogeneity cannot be explained by secondary geological processes but supports diverse carbonaceous precursors that experienced differential graphitization. Micro-FTIR analysis found that CM with lower structural order contains more straight carbon chains (has a lower R3/2 branching index) and that the structural order of eukaryotic CM is more heterogeneous than prokaryotic CM. This study demonstrates how Raman spectroscopy combined with micro-FTIR can be used to investigate the origin and preservation of silica-permineralized organics. This approach has good capability for furthering our understanding of CM preserved in Precambrian cherts, and potential biosignatures in siliceous deposits on Mars. PMID:26496525

  12. Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia.

    PubMed

    Landau, Dan A; Clement, Kendell; Ziller, Michael J; Boyle, Patrick; Fan, Jean; Gu, Hongcang; Stevenson, Kristen; Sougnez, Carrie; Wang, Lili; Li, Shuqiang; Kotliar, Dylan; Zhang, Wandi; Ghandi, Mahmoud; Garraway, Levi; Fernandes, Stacey M; Livak, Kenneth J; Gabriel, Stacey; Gnirke, Andreas; Lander, Eric S; Brown, Jennifer R; Neuberg, Donna; Kharchenko, Peter V; Hacohen, Nir; Getz, Gad; Meissner, Alexander; Wu, Catherine J

    2014-12-01

    Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories. PMID:25490447

  13. Investigating the Effect of Hydraulic Data and Heterogeneity on Stochastic Inversion of a Physically Based Groundwater Model

    NASA Astrophysics Data System (ADS)

    Wang, D.; Zhang, Y.

    2014-12-01

    This research explores the interactions between data quantity, data quality and heterogeneity resolution on stochastic inversion of a physically based model. To further investigate aquifer heterogeneity, simulations are used to examine the impact of geostatistical models on inversion quality, as well as the spatial sensitivity to heterogeneity using local and global methods. The model domain is a two-dimensional steady-state confined aquifer with lateral flows through two hydrofacies with alternating patterns.To examine general effects, the control variable method was adopted to reveal the impact of three factors on estimated hydraulic conductivity (K) and hydraulic head boundary conditions (BCs): (1) data availability, (2) data error, and (3) characterization of heterogeneity. Results show that fewer data increase model sensitivity to measurement error and heterogeneity. Extremely large data errors can cause severe model deterioration, regardless of sufficient data availability or high resolution representation of heterogeneity. Smaller data errors can alleviate the bias caused by the limited observations. For heterogeneity resolution, once general patterns of geological structures are captured, its influence is minimal compared to the other factors.Next, two geostatistical models (spherical and exponential variograms), were used to explore the representation of heterogeneity under the same nugget effects. The results show that stochastic inversion based on the exponential variogram improves both the precision and accuracy of the inverse model, as compared to the spherical variogram. This difference is particularly important for determining accurate BCs through stochastic inversion.Last, sensitivity analysis was conducted to further investigate the effect of varying the K of each hydrofacies on model inversion. Results from the partial local method show that the inversion is more sensitive to perturbations of K in regions with high heterogeneity. Using the

  14. Characterization of Soil Heterogeneity Across Scales in an Intensively Investigated Soil Volume

    NASA Astrophysics Data System (ADS)

    Patterson, Matthew; Gimenez, Daniel; Nemes, Attila; Dathe, Annette; French, Helen; Bloem, Esther; Koestel, John; Jarvis, Nick

    2016-04-01

    Heterogeneous water flow in undisturbed soils is a natural occurrence that is complex to model due to potential changes in hydraulic properties in soils over changes in space. The use of geophysical methods, such as Electrical Resistivity Tomography (ERT), can provide a minimally-invasive approximation of the spatial heterogeneity of the soil. This spatial distribution can then be combined with measured hydraulic properties to inform a model. An experiment was conducted on an Intensively Investigated Soil Volume (IISV), with dimensions of 2m x 1m x 0.8m, located in an agricultural field that is part of the Gryteland catchment in Ås, Norway. The location of the IISV was determined through surface ERT runs at two sequential resolutions. The first run was used to find an area of higher apparent electrical resistivity in a 23.5 x 11.5 m area with 0.5 m spacing. The second run measured apparent electrical resistivity in a 4.7 x 1 m area with 0.1 m spacing, from which the final IISV volume was derived. Distinct features found in the higher resolution run of the IISV, including a recent tire track from a harvester, were used as a spatial reference point for the installation of 20 pairs of TDR probes and tensiometers. The instruments measured water content, temperature and pressure potential at 10 minute intervals and ran continuously for a period of two weeks. After completion of the data collection the IISV was intensively sampled, with 30 samples taken for bulk density, 62 for hydraulic property measurements, and 20 to be used for both CT scanning and hydraulic property measurements. The measurement of hydraulic properties is ongoing and retention will be measured in the 0 - 100 cm range on a sand table, and from 100 - approx. 900 cm with an automated evaporation method. The formation of spatial clusters to represent the soil heterogeneity as relatively homogeneous units based on mesoscale properties like apparent electrical resistivity, bulk density, texture, in

  15. Investigating cultural heterogeneity in San Pedro de Atacama, northern Chile, through biogeochemistry and bioarchaeology.

    PubMed

    Knudson, Kelly J; Torres-Rouff, Christina

    2009-04-01

    Individuals living in the San Pedro de Atacama oases and the neighboring upper Loa River Valley of northern Chile experienced the collapse of an influential foreign polity, environmental decline, and the appearance of a culturally distinct group during the Late Intermediate Period (ca. AD 1,100-1,400). We investigate cultural heterogeneity at the Loa site of Caspana through analyses of strontium and oxygen isotopes, cranial modification styles, and mortuary behavior, integrating biological aspects of identity, particularly geographic origins, with cultural aspects of identity manifested in body modification and mortuary behavior. We test the hypothesis that the Caspana population (n = 66) represents a migrant group, as supported by archeological and ethnographic evidence, rather than a culturally distinct local group. For Caspana archeological human tooth enamel, mean (87)Sr/(86)Sr = 0.70771 +/- 0.00038 (1sigma, n = 30) and mean delta(18)O(c(V-PDB)) = -3.9 +/- 0.6 per thousand (1sigma, n = 16); these isotopic data suggest that only one individual lived outside the region. Material culture suggests that the individuals buried at Caspana shared some cultural affinity with the San Pedro oases while maintaining distinct cultural traditions. Finally, cranial modification data show high frequencies of head shaping [92.4% (n = 61/65)] and an overwhelming preference for annular modification [75.4% (n = 46/61)], contrasting sharply with practices in the San Pedro area. Based on multiple lines of evidence, we argue that, rather than representing a group of altiplano migrants, the Caspana population existed in the region for some time. However, cranial modification styles and mortuary behavior that are markedly distinct from patterns in surrounding areas raise the possibility of cultural heterogeneity and cultural fissioning. PMID:19051258

  16. Using Local Born and Local Rytov Fourier Modeling and Migration Methods for Investigation of Heterogeneous Structures

    SciTech Connect

    Fehler, M.C.; Huang, L.-J.

    1998-12-10

    During the past few years, there has been interest in developing migration and forward modeling approaches that are both fast and reliable particularly in regions that have rapid spatial variations in structure. The authors have been investigating a suite of modeling and migration methods that are implemented in the wavenumber-space domains and operate on data in the frequency domain. The best known example of these methods is the split-step Fourier method (SSF). Two of the methods that the authors have developed are the extended local Born Fourier (ELBF) approach and the extended local Rytov Fourier (ELRF) approach. Both methods are based on solutions of the scalar (constant density) wave equation, are computationally fast and can reliably model effects of both deterministic and random structures. The authors have investigated their reliability for migrating both 2D synthetic data and real 2D field data. The authors have found that the methods give images that are better than those that can be obtained using other methods like the SSF and Kirchhoff migration approaches. More recently, the authors have developed an approach for solving the acoustic (variable density) wave equation and have begun to investigate its applicability for modeling one-way wave propagation. The methods will be introduced and their ability to model seismic wave propagation and migrate seismic data will be investigated. The authors will also investigate their capability to model forward wave propagation through random media and to image zones of small scale heterogeneity such as those associated with zones of high permeability.

  17. Chemical Structure and Concentration of Intratumor Catabolites Determine Efficacy of Antibody Drug Conjugates

    PubMed Central

    Yu, Shang-Fan; Ma, Yong; Xu, Keyang; Dragovich, Peter S.; Pillow, Thomas H.; Liu, Luna; Del Rosario, Geoffrey; He, Jintang; Pei, Zhonghua; Sadowsky, Jack D.; Erickson, Hans K.; Hop, Cornelis E. C. A.; Khojasteh, S. Cyrus

    2016-01-01

    Despite recent technological advances in quantifying antibody drug conjugate (ADC) species, such as total antibody, conjugated antibody, conjugated drug, and payload drug in circulation, the correlation of their exposures with the efficacy of ADC outcomes in vivo remains challenging. Here, the chemical structures and concentrations of intratumor catabolites were investigated to better understand the drivers of ADC in vivo efficacy. Anti-CD22 disulfide-linked pyrrolobenzodiazepine (PBD-dimer) conjugates containing methyl- and cyclobutyl-substituted disulfide linkers exhibited strong efficacy in a WSU-DLCL2 xenograft mouse model, whereas an ADC derived from a cyclopropyl linker was inactive. Total ADC antibody concentrations and drug-to-antibody ratios (DAR) in circulation were similar between the cyclobutyl-containing ADC and the cyclopropyl-containing ADC; however, the former afforded the release of the PBD-dimer payload in the tumor, but the latter only generated a nonimmolating thiol-containing catabolite that did not bind to DNA. These results suggest that intratumor catabolite analysis rather than systemic pharmacokinetic analysis may be used to better explain and predict ADC in vivo efficacy. These are good examples to demonstrate that the chemical nature and concentration of intratumor catabolites depend on the linker type used for drug conjugation, and the potency of the released drug moiety ultimately determines the ADC in vivo efficacy. PMID:27417182

  18. The role of intratumoral lymphovascular density in distinguishing primary from secondary mucinous ovarian tumors

    PubMed Central

    de Lacerda Almeida, Bernardo Gomes; Bacchi, Carlos E; Carvalho, Jesus P; Ferreira, Cristiane R; Carvalho, Filomena M

    2014-01-01

    OBJECTIVE: Ovarian mucinous metastases commonly present as the first sign of the disease and are capable of simulating primary tumors. Our aim was to investigate the role of intratumoral lymphatic vascular density together with other surgical-pathological features in distinguishing primary from secondary mucinous ovarian tumors. METHODS: A total of 124 cases of mucinous tumors in the ovary (63 primary and 61 metastatic) were compared according to their clinicopathological features and immunohistochemical profiles. The intratumoral lymphatic vascular density was quantified by counting the number of vessels stained by the D2-40 antibody. RESULTS: Metastases occurred in older patients and were associated with a higher proportion of tumors smaller than 10.0 cm; bilaterality; extensive necrosis; extraovarian extension; increased expression of cytokeratin 20, CDX2, CA19.9 and MUC2; and decreased expression of cytokeratin 7, CA125 and MUC5AC. The lymphatic vascular density was increased among primary tumors. However, after multivariate analysis, the best predictors of a secondary tumor were a size of 10.0 cm or less, bilaterality and cytokeratin 7 negativity. Lack of MUC2 expression was an important factor excluding metastasis. CONCLUSIONS: The higher intratumoral lymphatic vascular density in primary tumors when compared with secondary lesions suggests differences in the microenvironment. However, considering the differential diagnosis, the best discriminator of a secondary tumor is the combination of tumor size, laterality and the pattern of expression of cytokeratin 7 and MUC2. PMID:25518016

  19. Improved Intratumoral Oxygenation Through Vascular Normalization Increases Glioma Sensitivity to Ionizing Radiation

    SciTech Connect

    McGee, Mackenzie C.; Hamner, J. Blair; Williams, Regan F.; Rosati, Shannon F.; Sims, Thomas L.; Ng, Catherine Y.; Gaber, M. Waleed; Calabrese, Christopher; Wu Jianrong; Nathwani, Amit C.; Merchant, Thomas E.; Davidoff, Andrew M.

    2010-04-15

    Purpose: Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation. Methods and Materials: Orthotopic U87 xenografts were treated with either continuous interferon-beta (IFN-beta) or bevacizumab, alone, or combined with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; the tumor vasculature using immunohistochemical staining, and tumor oxygenation using hypoxyprobe staining. Results: Both IFN-beta and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-beta caused a doubling in the percentage of area of perivascular cell staining, and bevacizumab caused a rapid decrease in the percentage of area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab, the effect was transient, being lost by 5 days. Administration of IFN-beta or bevacizumab before RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-beta or bevacizumab or 5 days after bevacizumab. Conclusion: Bevacizumab and continuous delivery of IFN-beta each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the antitumor activity of ionizing radiation. Additional investigation into the use and timing of these and other agents that modify the vascular phenotype, combined with RT, is warranted to optimize cytotoxic activity.

  20. Single Cell Proteolytic Assays to Investigate Cancer Clonal Heterogeneity and Cell Dynamics Using an Efficient Cell Loading Scheme

    NASA Astrophysics Data System (ADS)

    Chen, Yu-Chih; Cheng, Yu-Heng; Ingram, Patrick; Yoon, Euisik

    2016-06-01

    Proteolytic degradation of the extracellular matrix (ECM) is critical in cancer invasion, and recent work suggests that heterogeneous cancer populations cooperate in this process. Despite the importance of cell heterogeneity, conventional proteolytic assays measure average activity, requiring thousands of cells and providing limited information about heterogeneity and dynamics. Here, we developed a microfluidic platform that provides high-efficiency cell loading and simple valveless isolation, so the proteolytic activity of a small sample (10–100 cells) can be easily characterized. Combined with a single cell derived (clonal) sphere formation platform, we have successfully demonstrated the importance of microenvironmental cues for proteolytic activity and also investigated the difference between clones. Furthermore, the platform allows monitoring single cells at multiple time points, unveiling different cancer cell line dynamics in proteolytic activity. The presented tool facilitates single cell proteolytic analysis using small samples, and our findings illuminate the heterogeneous and dynamic nature of proteolytic activity.

  1. Single Cell Proteolytic Assays to Investigate Cancer Clonal Heterogeneity and Cell Dynamics Using an Efficient Cell Loading Scheme

    PubMed Central

    Chen, Yu-Chih; Cheng, Yu-Heng; Ingram, Patrick; Yoon, Euisik

    2016-01-01

    Proteolytic degradation of the extracellular matrix (ECM) is critical in cancer invasion, and recent work suggests that heterogeneous cancer populations cooperate in this process. Despite the importance of cell heterogeneity, conventional proteolytic assays measure average activity, requiring thousands of cells and providing limited information about heterogeneity and dynamics. Here, we developed a microfluidic platform that provides high-efficiency cell loading and simple valveless isolation, so the proteolytic activity of a small sample (10–100 cells) can be easily characterized. Combined with a single cell derived (clonal) sphere formation platform, we have successfully demonstrated the importance of microenvironmental cues for proteolytic activity and also investigated the difference between clones. Furthermore, the platform allows monitoring single cells at multiple time points, unveiling different cancer cell line dynamics in proteolytic activity. The presented tool facilitates single cell proteolytic analysis using small samples, and our findings illuminate the heterogeneous and dynamic nature of proteolytic activity. PMID:27283981

  2. An investigation of homogeneous and heterogeneous sonochemistry for destruction of hazardous waste. 1998 annual progress report

    SciTech Connect

    Hua, I.

    1998-06-01

    'The primary objective of this research project is to acquire a deeper fundamental knowledge of acoustic cavitation and cavitation chemistry, and in doing so, to ascertain how ultrasonic irradiation can be more effectively applied to environmental problems. The primary objective will be accomplished by examining numerous aspects of sonochemical systems and acoustic cavitation. During the course of the project, the research group will investigate the significance of physical variables during sonolysis, sonochemical kinetics and reactive intermediates, and the behavior of heterogeneous (solid/liquid) systems. An additional component of the project includes utilizing various techniques to image cavitation bubble cloud development. This report summarizes results after 2 years of a 3 year investigation. Four on-going projects will be described. The first project is the destruction of polychlorinated biphenyls at multiple ultrasonic frequencies. The second project is a comprehensive study of how ultrasonic frequency influences sonochemical reaction rates; in particular, hydrogen peroxide formation. Finally, the sonochemical destruction of the pesticides dichlorvos (at 500 kHz) and carbofuran (parallel-plate reactor) has been examined.'

  3. Effects of Spatially Heterogeneous Porosity on Matrix-Diffusion as Investigated by X ray Absorption Imaging

    SciTech Connect

    Boney, C.; Christian-Frear, T.; Meigs, L.C.; Tidwell, V.C.

    1998-10-20

    Laboratory experiments were performed to investigate the effects of spatial variation in porosity on matrix-diffusion processes. Four centimeter-scale slabs of Culebra dolomite taken from the Waste Isolation Pilot Plant site were used in the tests. Experiments involved the simple diffusion of iodine into a single edge of each rock slab while X ray absorption imaging was used to measure the resulting two-dmensional solute concentration field as a function of time. X ray imaging was also used to quantify the two-dimensional porosity field of each rock slab. Image analysis provided a unique opportunity to both visuake and quantifj the effects of the spatially variable porosi~ on matrixdMusion. Four key results were obtained. First, significant variation in rates of diffusion were realized over the relatively small length (centimeter) and time scales (months) investigated. Second, clear evidence of diffusion preferentially following zones of relatively higher porosity was noted. Third, rate of difhion was found to vary as tracer diffused into the rock slabs encountering changing porosity conditions. Fourth, strong correlation between porosi~ and the calculated diffusion coefficients was found. In fact, the nature of the correlation can be related to the geometry, position, and orientation of the heterogeneous porosity features populating each rock slab.

  4. Investigation of coupled heat and mass transfer in heterogeneous porous media using numerical simulations

    NASA Astrophysics Data System (ADS)

    Illangasekare, T. H.; Frippiat, C. C.; Zyvoloski, G. A.

    2007-12-01

    A significant body of knowledge exists on separates processes of thermal and mass transport in granular and fractured subsurface formations. However, the need to simulate these processes in a fully coupled way has become necessary to deal with problems associated with long-term-storage of nuclear waste, and the development of new technologies for subsurface remediation. Another emerging area for research is associated with the development of technologies for in situ extraction of underground resources. Numerical models that couple thermal and mass transport processes will play a crucial role in understanding the fundamental processes associated with these new technologies, as well as in making predictions on how complex subsurface systems are expected to behave. It is our hypothesis that heat transport will have a significant impact on distributions of solute concentration, through temperature-dependent dissolution and precipitation, and temperature-dependent rate-limited diffusive transfer of solutes in fractured or highly heterogeneous media. A number of issues related to the validity of existing numerical tools that capture these processes, and their application to field systems through up-scaling need to be investigated. With this overall goal in mind, in this preliminary study, we explore the effect of the variability of subsurface properties on heat and mass transport using simulations conducted using an existing multiphase model. The finite-element code FEHM (Finite-Element Heat and Mass transport code) used in this study was developed at Los Alamos National Laboratory. This code allows for the coupled simulation of flow, heat and mass transport, accounting for density effects and dissolution and/or precipitation reactions. Our analysis is based on two- and three-dimensional simulations using synthetic data sets. Heterogeneous facies distributions are generated according to Markov Chain transition probability models. A distributed source of constant

  5. Investigation on Interference Coordination Employing Almost Blank Subframes in Heterogeneous Networks for LTE-Advanced Downlink

    NASA Astrophysics Data System (ADS)

    Miki, Nobuhiko; Saito, Yuya; Shirakabe, Masashige; Morimoto, Akihito; Abe, Tetsushi

    This paper investigates the application of inter-cell interference coordination (ICIC) in heterogeneous networks for the LTE-Advanced downlink where picocells are overlaid onto macrocells. In LTE-Advanced, in order to perform ICIC, almost blank subframes (ABSs) are employed, where only the cell-specific reference signal (CRS) is transmitted to protect the subframes in the picocells from severe interference from the macrocells. Furthermore, multicast/broadcast over single-frequency network (MBSFN) subframes are employed to reduce the interference of the CRS on the data channel, although the control channel still suffers from interference from the CRS. When the cell range expansion (CRE), which offload the UEs from macrocells to picocells, is used to improve the system performance, the influence from the CRS increases. In order to assess the influence, the required CRE bias to improve the data channel is investigated based on a system-level simulation under various conditions such as the number of picocells, the protected subframe ratio, and the user distribution. The simulation results show that the cell-edge user throughput is improved with the CRE bias of more than 8dB, employing ABSs. Furthermore, simulation results show that one dominant source of interference is observed for the sets of user equipment (UEs) connected to the picocells via CRE with such a bias value. Based on observation, the influence that the CRS has on the control channel, i.e., physical control format indicator channel (PCFICH), and physical downlink control channel (PDCCH) is investigated based on a link-level simulation combined with a system-level simulation. The simulation results show that protecting the PCFICH is very important compared to protecting the PDCCH, since the block error rate (BLER) performance of the PCFICH becomes worse than the required BLER of 10-3 to support various conditions, although the BLER performance of the PDCCH can exceed the required BLER of 10-2 by spanning

  6. Numerical investigations on mapping permeability heterogeneity in coal seam gas reservoirs using seismo-electric methods

    NASA Astrophysics Data System (ADS)

    Gross, L.; Shaw, S.

    2016-04-01

    Mapping the horizontal distribution of permeability is a key problem for the coal seam gas industry. Poststack seismic data with anisotropy attributes provide estimates for fracture density and orientation which are then interpreted in terms of permeability. This approach delivers an indirect measure of permeability and can fail if other sources of anisotropy (for instance stress) come into play. Seismo-electric methods, based on recording the electric signal from pore fluid movements stimulated through a seismic wave, measure permeability directly. In this paper we use numerical simulations to demonstrate that the seismo-electric method is potentially suitable to map the horizontal distribution of permeability changes across coal seams. We propose the use of an amplitude to offset (AVO) analysis of the electrical signal in combination with poststack seismic data collected during the exploration phase. Recording of electrical signals from a simple seismic source can be closer to production planning and operations. The numerical model is based on a sonic wave propagation model under the low frequency, saturated media assumption and uses a coupled high order spectral element and low order finite element solver. We investigate the impact of seam thickness, coal seam layering, layering in the overburden and horizontal heterogeneity of permeability.

  7. Genomic Investigation into Strain Heterogeneity and Pathogenic Potential of the Emerging Gastrointestinal Pathogen Campylobacter ureolyticus

    PubMed Central

    Bullman, Susan; Lucid, Alan; Corcoran, Daniel; Sleator, Roy D.; Lucey, Brigid

    2013-01-01

    The recent detection and isolation of C. ureolyticus from patients with diarrhoeal illness and inflammatory bowel diseases warrants further investigation into its role as an emerging pathogen of the human gastrointestinal tract. Regarding the pathogenic mechanisms employed by this species we provide the first whole genome analysis of two C. ureolyticus isolates including the type strain. Comparative analysis, subtractive hybridisation and gene ontology searches against other Campylobacter species identifies the high degree of heterogenicity between C. ureolyticus isolates, in addition to the identification of 106 putative virulence associated factors, 52 of which are predicted to be secreted. Such factors encompass each of the known virulence tactics of pathogenic Campylobacter spp. including adhesion and colonisation (CadF, PEB1, IcmF and FlpA), invasion (ciaB and 16 virB-virD4 genes) and toxin production (S-layer RTX and ZOT). Herein, we provide the first virulence catalogue for C. ureolyticus, the components of which theoretically provide this emerging species with sufficient arsenal to establish pathology. PMID:24023611

  8. Advanced information management tools for investigation and case management support in a networked heterogeneous computing environment

    NASA Astrophysics Data System (ADS)

    Clifton, T. E., III; Lehrer, Nancy; Klopfenstein, Mark; Hoshstrasser, Belinda; Campbell, Rachel

    1997-02-01

    The right information, at the right time and place, is key to successful law enforcement. The information exists; the challenge is in getting the information to the law enforcement professionals in a usable form, when they need it. Over the last year, the authors have applied advanced information management technologies towards addressing this challenge, in concert with a complementary research effort in secure wireless network technology by SRI International. The goal of the combined efforts is to provide law enforcement professionals the ability to access a wide range of heterogeneous and legacy data sources (structured, as well as free text); process information into digital multimedia case folders; and create World Wide Web-based multimedia products, accessible by selected field investigators via Fortezza-enhanced secure web browsers over encrypted wireless communications. We discuss the results of our knowledge acquisition activities at federal, regional, and local law enforcement organizations; our technical solution; results of the one year development and demonstration effort; and plans for future research.

  9. An investigation of interference coordination in heterogeneous network for LTE-Advanced systems

    NASA Astrophysics Data System (ADS)

    Hasan, M. K.; Ismail, A. F.; H, Aisha-Hassan A.; Abdullah, Khaizuran; Ramli, H. A. M.

    2013-12-01

    The novel "femtocell" in Heterogeneous Network (HetNet) for LTE-Advanced (LTE-A) set-up will allow Malaysian wireless telecommunication operators (Maxis, Celcom, Digi, U-Mobile, P1, YTL and etc2.) to extend connectivity coverage where access would otherwise be limited or unavailable, particularly indoors of large building complexes. A femtocell is a small-sized cellular base station that encompasses all the functionality of a typical station. It therefore allows a simpler and self-contained deployment including private residences. For the Malaysian service providers, the main attractions of femtocell usage are the improvements to both coverage and capacity. The operators can provide a better service to end-users in turn reduce much of the agitations and complaints. There will be opportunity for new services at reduced cost. In addition, the operator not only benefits from the improved capacity and coverage but also can reduce both capital expenditure and operating expense i.e. alternative to brand new base station or macrocell installation. Interference is a key issue associated with femtocell development. There are a large number of issues associated with interference all of which need to be investigated, identified, quantified and solved. This is to ensure that the deployment of any femtocells will take place successfully. Among the most critical challenges in femtocell deployment is the interference between femtocell-to-macrocell and femtocell-to-femtocell in HetNets. In this paper, all proposed methods and algorithms will be investigated in the OFDMA femtocell system considering HetNet scenarios for LTE-A.

  10. In Vivo Confocal Fluorescence Imaging of the Intratumor Distribution of the Photosensitizer Mono-l-Aspartylchlorin-e61

    PubMed Central

    Mitra, Soumya; Foster, Thomas H

    2008-01-01

    We present an in vivo fluorescence microscopic evaluation of intratumor distribution of the photosensitizer mono-l-aspartylchlorin-e6 (NPe6) in an intradermal mouse EMT6 tumor model. Although the identification of favorable photophysical and pharmacological properties has led to the development of new photosensitizers in photodynamic therapy, their intratumor distribution kinetics have remained relatively understudied. In this study, we used confocal fluorescence microscopy to follow the transport of NPe6 in vivo after systemic administration through the tail vein. Labeling of vasculature using fluorophore-conjugated anti-CD31 antibodies allows visualization of the uptake of NPe6 in tumor and normal vessels and its partitioning kinetics into the adjacent parenchyma for 3 hours after injection. During the initial 60 minutes after injection, the drug is predominantly confined to the vasculature. Subsequently, it significantly redistributes throughout the extravascular regions with no discernable difference in its extravasation rate between tumor and normal tissues. Further, we investigate the sensitizer's altered intratumor distribution in response to photodynamic therapy irradiation and observe that treatment-induced changes in vessel permeability caused enhanced accumulation of NPe6 in the extravascular space. Our findings are of immediate clinical relevance and demonstrate the importance of an in vivo imaging approach to examine the dynamic process of intratumor drug distribution. PMID:18472960

  11. Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies

    PubMed Central

    Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Darwiche, Kaid; Vogl, Thomas; Goldberg, Eugene P; Huang, Haidong; Simoff, Michael; Li, Qiang; Browning, Robert; Turner, Francis J; Le Pivert, Patrick; Spyratos, Dionysios; Zarogoulidis, Konstantinos; Celikoglu, Seyhan I; Celikoglu, Firuz; Brachmann, Johannes

    2013-01-01

    Strategies to enhance the already established doublet chemotherapy regimen for lung cancer have been investigated for more than 20 years. Initially, the concept was to administer chemotherapy drugs locally to the tumor site for efficient diffusion through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR) negative stage IIIa–IV International Union Against Cancer 7 (UICC-7), and with Eastern Cooperative Oncology Group (ECOG) 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%–1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin–based systemic chemotherapy in (higher) standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of

  12. Investigating Velocity Spectra at the Hugoniot State of Shock Loaded Heterogeneous Materials

    NASA Astrophysics Data System (ADS)

    Lajeunesse, Jeff; Borg, John; Stewart, Sarah; Thadhani, Naresh

    2015-06-01

    Hugoniot states achieved in heterogeneous materials have shown oscillations in particle velocity about an averaged state for both experimental and simulated data. These oscillations arise from the scattering of the transmitted shock wave due to the presence of internal interfaces within heterogeneous materials. The goal of this work is to determine if the spectra of oscillatory behavior can be associated to characteristic length scales of the corresponding un-shocked heterogeneous material. Similarities between different types of shock-loaded materials are compared such as sand, concrete, aluminum foam, and layered composites. I would like to acknowledge the AFOSR under grant: FA9550-12-1-0128, ``Dynamic High-Pressure Behavior of Hierarchical Heterogenous Geological Granular Materials'' and the D.o.D. Supercomputing Resource Center.

  13. Chemical structure and heterogeneity differences of two lignins from loblolly pine as investigated by advanced solid-state NMR spectroscopy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Advanced solid-state NMR was employed to investigate differences in chemical structure and heterogeneity between milled wood lignin (MWL) and residual enzyme lignin (REL). Wiley and conventional milled woods were also studied. The advanced NMR techniques included 13C quantitative direct polarization...

  14. Lysimeter Soil Retriever (LSR) - A tool for investigation on heterogeneity of the migration and structural changes

    NASA Astrophysics Data System (ADS)

    Reth, S.; Gierig, M.; Winkler, J. B.; Mueller, C. W.; Nitsche, C.; Seyfarth, M.

    2009-04-01

    Generally research fields of lysimeter studies scheduled as long term experiments. In the course of the studies, the lysimeters act more or less as a "black box". Usually the soil material is identified and analysed at the beginning of the experiments. But there is also a strong need to analyze the soil without disturbance of the soil structure after the experiments in order to obtain information about spatial and structural changes within the soil profile. The new technique of the Lysimeter Soil Retriever for the first time enables studies on the heterogeneous migration of percolating water, and changes of soil structure as well as soil organic matter (SOM) and biomass distribution, as well as the distribution of mycorrhiza and microbes in different depths on intact soil profiles. The main target by using the LSR is the preparation of an intact soil monolith from the field lysimeter and the immediate dissection into slices to enable a direct sampling of its soil environment at several depths. Distribution and composition of SOM, pF-values, soil porosity, as well as degradation of PAH were only a few parameters, which are determined at the different soil depths. In this presentation we give some examples for the different application of the LSR and the advantage for the experiments: - The soil of 8 lysimeters, planted with young beeches was retrieved after several years of fumigation with doubled atmospheric ozone concentrations and application of fungi. Due to the accurate sectioning of the soil monoliths a very dense and intensive soil sampling was possible. As the whole soil space of 8 lysimeters could be sampled, precise spatial information were obtained about the rapid formation of SOM depth gradients within the experiment duration. - After the investigation on the mobilization of polycyclic aromatic hydrocarbons (PAH) by the seepage water, the lysimeter soil was retrieved. Investigations on the microbiological degradation of the PAH were possible in the whole

  15. Cell sorting in cancer research--diminishing degree of cell heterogeneity.

    PubMed

    Barteneva, Natasha S; Ketman, Kenneth; Fasler-Kan, Elizaveta; Potashnikova, Daria; Vorobjev, Ivan A

    2013-08-01

    Increasing evidence of intratumor heterogeneity and its augmentation due to selective pressure of microenvironment and recent achievements in cancer therapeutics lead to the need to investigate and track the tumor subclonal structure. Cell sorting of heterogeneous subpopulations of tumor and tumor-associated cells has been a long established strategy in cancer research. Advancement in lasers, computer technology and optics has led to a new generation of flow cytometers and cell sorters capable of high-speed processing of single cell suspensions. Over the last several years cell sorting was used in combination with molecular biological methods, imaging and proteomics to characterize primary and metastatic cancer cell populations, minimal residual disease and single tumor cells. It was the principal method for identification and characterization of cancer stem cells. Analysis of single cancer cells may improve early detection of tumors, monitoring of circulating tumor cells, evaluation of intratumor heterogeneity and chemotherapeutic treatments. The aim of this review is to provide an overview of major cell sorting applications and approaches with new prospective developments such as microfluidics and microchip technologies. PMID:23481260

  16. Lidar Investigation of Infiltration Water Heterogeneity in the Tamala Limestone, SW WA

    NASA Astrophysics Data System (ADS)

    Mahmud, K.; Mariethoz, G.; Treble, P. C.; Baker, A.

    2014-12-01

    To better manage groundwater resources in carbonate areas and improve our understanding of speleothem archives, it is important to understand and predict unsaturated zone hydrology in karst. The high level of complexity and spatial heterogeneity of such systems is challenging and requires knowledge of the typical geometry of karstic features. We present an exhaustive characterization of Golgotha Cave, SW Western Australia, based on an extensive LIDAR measurement campaign. The cave is developed in Quaternary age aeolianite (dune limestone) and contains speleothem records. We collect 30 representative 3D scan images from this site using FARO Focus3D, a high-speed 3D laser scanner, to visualize, study and extract 2D and 3D information from various points of view and at different scales. In addition to LIDAR data, 32 automatic drip loggers are installed at this site to measure the distribution and volume of water flow. We perform mathematical morphological analyses on the cave ceiling, to determine statistical information regarding the stalactites widths, lengths and spatial distribution. We determine a relationship between stalactites diameter and length. We perform tests for randomness to investigate the relationship between stalactite distribution and ceiling features such as fractures and apply this to identify different types of possible flow patterns such as fracture flow, solution pipe flow, primary matrix flow etc. We also relate stalactites density variation with topography of the cave ceiling which shows hydraulic gradient deviations. Finally we use Image Quilting, one of the recently developed multiple-point geostatistics methods, with the training images derived from LIDAR data to create a larger cave system to represent not only the caves that are visible, but the entire system which is inaccessible. As a result, an integral geological model is generated which may allow other scientists, geologist, to work on two different levels, integrating different

  17. Investigations of the impact of wettability heterogeneity on trapping and relative permeability using pore-scale simulations

    NASA Astrophysics Data System (ADS)

    Jiang, F.

    2015-12-01

    Wettability is one of the most important factors influencing the multi-phase fluid flow behavior in porous media. However, the role of wettability at pore-scale still remains poorly understood. In this study, we carried out a series of pore-scale simulations of multiphase displacement process to investigate the impact of wettability heterogeneity on trapping, sweep efficiency and relative permeability using lattice Boltzmann method. We first artificially generated mixed-wet bead pack models with varying degree of wettability by introducing spatial heterogeneity. Based on these models, we then calculated the relative permeability curves and performed the drainage and imbibition simulations to obtain the residual non-wetting phase distributions. The results indicate that strong wettability heterogeneity results in a decrease of non-wetting phase permeability due to the pinned interfaces at wettability discontinuities. The wetting phase permeability as well as the sweep efficiency are largely influenced by the degree of wettability rather than the wettability heterogeneity. The non-wetting phase is observed to be less trapped with strong heterogeneity conditions.

  18. Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection.

    PubMed

    Chen, Kang-jie; Zhou, Lin; Xie, Hai-yang; Ahmed, Taki-eldin; Feng, Xiao-wen; Zheng, Shu-sen

    2012-09-01

    Tumor-infiltrating lymphocytes (TILs) represent the host immune response to cancer. CD8(+) cytotoxic T cells (CTLs) have a central role in the elimination of tumors, while regulatory T cells (Tregs) can suppress the immune reaction. The aim of this study was to investigate the prognostic value of TILs, especially Tregs and CTLs, in hepatocellular carcinoma (HCC) patients after resection. CD3(+), CD4(+), CD8(+), and FoxP3(+) TILs were assessed by immunohistochemistry in tumor tissue from 141 randomly selected HCC patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Kaplan-Meier and Cox regression analysis using the median values as cutoff. The density of intratumoral Tregs (P = 0.040) and peritumoral CTLs (P = 0.004) were an independent factor for overall survival (OS), but not for disease-free survival (DFS). The density of CD3(+) and CD4(+) TILs, and the prevalence of Tregs and CTLs were associated with neither OS nor DFS. The presence of low intratumoral Tregs with high intratumoral CTLs was a negative independent prognostic factor for OS (P = 0.001), while that of low intratumoral Tregs and low peritumoral CTLs independently correlated with improved DFS (P = 0.008). Moreover, the combined analysis of Tregs and CTLs displayed better prognostic performances than any of them alone. Additionally, higher density of intratumoral Tregs correlated with both the presence of liver cirrhosis (P = 0.025) and increased tumor size (P = 0.050). Tregs within tumor environment are promising prognostic parameters for HCC patients, and their combination with CTLs can predict prognosis more effectively. PMID:21678026

  19. Investigation of detonation velocity in heterogeneous explosive system using the reactive Burgers' analog

    NASA Astrophysics Data System (ADS)

    Di Labbio, G.; Kiyanda, C. B.; Mi, X.; Higgins, A. J.; Nikiforakis, N.; Ng, H. D.

    2016-06-01

    In this study, the applicability of the Chapman-Jouguet (CJ) criterion is tested numerically for heterogeneous explosive media using a simple detonation analog. The analog system consists of a reactive Burgers' equation coupled with an Arrhenius type reaction wave, and the heterogeneity of the explosive media is mimicked using a discrete energy source approach. The governing equation is solved using a second order, finite-volume approach and the average propagation velocity of the discrete detonation is determined by tracking the leading shock front. Consistent with previous studies, the averaged velocity of the leading shock front from the unsteady numerical simulations is also found to be in good agreement with the velocity of a CJ detonation in a uniform medium wherein the energy source is spatially homogenized. These simulations have thus implications for whether the CJ criterion is valid to predict the detonation velocity in heterogeneous explosive media.

  20. Impact of peritumoral and intratumoral budding in esophageal adenocarcinomas.

    PubMed

    Thies, Svenja; Guldener, Lars; Slotta-Huspenina, Julia; Zlobec, Inti; Koelzer, Viktor H; Lugli, Alessandro; Kröll, Dino; Seiler, Christian A; Feith, Marcus; Langer, Rupert

    2016-06-01

    Tumor budding has prognostic significance in many carcinomas and is defined as the presence of detached isolated single cells or small cell clusters up to 5 cells at the invasion front (peritumoral budding [PTB]) or within the tumor (intratumoral budding [ITB]). For esophageal adenocarcinomas (EACs), there are currently only few data about the impact of this morphological feature. We investigated tumor budding in a large collective of 200 primarily resected EACs. Pancytokeratin staining was demonstrated to be superior to hematoxylin and eosin staining for the detection of buds with substantial to excellent interobserver agreement and used for subsequent analysis. PTB and ITB were scored across 10 high-power fields (HPFs). The median count of tumor buds was 130/10 HPFs for PTB (range, 2-593) and 80/10 HPFs for ITB (range, 1-656). PTB and ITB correlated significantly with each other (r = 0.9; P < .001). High PTB and ITB rates were seen in more advanced tumor categories (P < .001 each); tumors with lymph node metastases (P < .001/P = .002); and lymphatic, vascular, and perineural invasion and higher tumor grading (P < .001 each). Survival analysis showed an association with worse survival for high-grade ITB (P = .029) but not PTB (P = .385). However, in multivariate analysis, lymph node and resection status, but not ITB, were independent prognostic parameters. In conclusion, PTB and ITB can be observed in EAC to various degrees. High-grade budding is associated with aggressive tumor phenotype. Assessment of tumor budding, especially ITB, may provide additional prognostic information about tumor behavior and may be useful in specific cases for risk stratification of EAC patients. PMID:26980046

  1. Intratumoral Immunocytokine Treatment Results in Enhanced Antitumor Effects

    PubMed Central

    Johnson, Erik E.; Lum, Hillary D.; Rakhmilevich, Alexander L.; Schmidt, Brian E.; Furlong, Meghan; Buhtoiarov, Ilia N.; Hank, Jacquelyn A.; Raubitschek, Andrew; Colcher, David; Reisfeld, Ralph A.; Gillies, Stephen D.; Sondel, Paul M.

    2008-01-01

    Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors, and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled 111In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy. PMID:18438664

  2. Spatial Dependence and Heterogeneity in Bayesian Factor Analysis: A Cross-National Investigation of Schwartz Values

    ERIC Educational Resources Information Center

    Stakhovych, Stanislav; Bijmolt, Tammo H. A.; Wedel, Michel

    2012-01-01

    In this article, we present a Bayesian spatial factor analysis model. We extend previous work on confirmatory factor analysis by including geographically distributed latent variables and accounting for heterogeneity and spatial autocorrelation. The simulation study shows excellent recovery of the model parameters and demonstrates the consequences…

  3. Investigating Phenotypic Heterogeneity in Children with Autism Spectrum Disorder: A Factor Mixture Modeling Approach

    ERIC Educational Resources Information Center

    Georgiades, Stelios; Szatmari, Peter; Boyle, Michael; Hanna, Steven; Duku, Eric; Zwaigenbaum, Lonnie; Bryson, Susan; Fombonne, Eric; Volden, Joanne; Mirenda, Pat; Smith, Isabel; Roberts, Wendy; Vaillancourt, Tracy; Waddell, Charlotte; Bennett, Teresa; Thompson, Ann

    2013-01-01

    Background: Autism spectrum disorder (ASD) is characterized by notable phenotypic heterogeneity, which is often viewed as an obstacle to the study of its etiology, diagnosis, treatment, and prognosis. On the basis of empirical evidence, instead of three binary categories, the upcoming edition of the DSM 5 will use two dimensions--social…

  4. The development and testing of a 2D laboratory seismic modelling system for heterogeneous structure investigations

    NASA Astrophysics Data System (ADS)

    Mo, Yike; Greenhalgh, Stewart A.; Robertsson, Johan O. A.; Karaman, Hakki

    2015-05-01

    Lateral velocity variations and low velocity near-surface layers can produce strong scattered and guided waves which interfere with reflections and lead to severe imaging problems in seismic exploration. In order to investigate these specific problems by laboratory seismic modelling, a simple 2D ultrasonic model facility has been recently assembled within the Wave Propagation Lab at ETH Zurich. The simulated geological structures are constructed from 2 mm thick metal and plastic sheets, cut and bonded together. The experiments entail the use of a piezoelectric source driven by a pulse amplifier at ultrasonic frequencies to generate Lamb waves in the plate, which are detected by piezoelectric receivers and recorded digitally on a National Instruments recording system, under LabVIEW software control. The 2D models employed were constructed in-house in full recognition of the similitude relations. The first heterogeneous model features a flat uniform low velocity near-surface layer and deeper dipping and flat interfaces separating different materials. The second model is comparable but also incorporates two rectangular shaped inserts, one of low velocity, the other of high velocity. The third model is identical to the second other than it has an irregular low velocity surface layer of variable thickness. Reflection as well as transmission experiments (crosshole & vertical seismic profiling) were performed on each model. The two dominant Lamb waves recorded are the fundamental symmetric mode (non-dispersive) and the fundamental antisymmetric (flexural) dispersive mode, the latter normally being absent when the source transducer is located on a model edge but dominant when it is on the flat planar surface of the plate. Experimental group and phase velocity dispersion curves were determined and plotted for both modes in a uniform aluminium plate. For the reflection seismic data, various processing techniques were applied, as far as pre-stack Kirchhoff migration. The

  5. Molecular- and nm-scale Investigation of the Structure and Compositional Heterogeneity of Naturally Occurring Ferrihydrite

    NASA Astrophysics Data System (ADS)

    Cismasu, C.; Michel, F. M.; Stebbins, J. F.; Tcaciuc, A. P.; Brown, G. E.

    2008-12-01

    Ferrihydrite is a hydrated Fe(III) nano-oxide that forms in vast quantities in contaminated acid mine drainage environments. As a result of its high surface area, ferrihydrite is an important environmental sorbent, and plays an essential role in the geochemical cycling of pollutant metal(loid)s in these settings. Despite its environmental relevance, this nanomineral remains one of the least understood environmental solids in terms of its structure (bulk and surface), compositional variations, and the factors affecting its reactivity. Under natural aqueous conditions, ferrihydrite often precipitates in the presence of several inorganic compounds such as aluminum, silica, arsenic, etc., or in the presence of organic matter. These impurities can affect the molecular-level structure of naturally occurring ferrihydrite, thus modifying fundamental properties that are directly correlated with solid-phase stability and surface reactivity. Currently there exists a significant gap in our understanding of the structure of synthetic vs. natural ferrihydrites, due to the inherent difficulties associated to the investigation of these poorly crystalline nanophases. In this study, we combined synchrotron- and laboratory-based techniques to characterize naturally occurring ferrihydrite from an acid mine drainage system situated at the New Idria mercury mine in California. We used high-energy X-ray total scattering and pair distribution function analysis to elucidate quantitative structural details of these samples. We have additionally used scanning transmission X-ray microscopy high resolution imaging (30 nm) to evaluate the spatial relationship of major elements Si, Al, and C within ferrihydrite. Al, Si and C K-edge near- edge X-ray absorption fine structure spectroscopy and 27Al nuclear magnetic resonance spectroscopy were used to obtain short-range structural information. By combining these techniques we attain the highest level of resolution permitted by current analytical

  6. Monte Carlo Investigation on the Effect of Heterogeneities on Strut Adjusted Volume Implant (SAVI) Dosimetry

    NASA Astrophysics Data System (ADS)

    Koontz, Craig

    Breast cancer is the most prevalent cancer for women with more than 225,000 new cases diagnosed in the United States in 2012 (ACS, 2012). With the high prevalence, comes an increased emphasis on researching new techniques to treat this disease. Accelerated partial breast irradiation (APBI) has been used as an alternative to whole breast irradiation (WBI) in order to treat occult disease after lumpectomy. Similar recurrence rates have been found using ABPI after lumpectomy as with mastectomy alone, but with the added benefit of improved cosmetic and psychological results. Intracavitary brachytherapy devices have been used to deliver the APBI prescription. However, inability to produce asymmetric dose distributions in order to avoid overdosing skin and chest wall has been an issue with these devices. Multi-lumen devices were introduced to overcome this problem. Of these, the Strut-Adjusted Volume Implant (SAVI) has demonstrated the greatest ability to produce an asymmetric dose distribution, which would have greater ability to avoid skin and chest wall dose, and thus allow more women to receive this type of treatment. However, SAVI treatments come with inherent heterogeneities including variable backscatter due to the proximity to the tissue-air and tissue-lung interfaces and variable contents within the cavity created by the SAVI. The dose calculation protocol based on TG-43 does not account for heterogeneities and thus will not produce accurate dosimetry; however Acuros, a model-based dose calculation algorithm manufactured by Varian Medical Systems, claims to accurately account for heterogeneities. Monte Carlo simulation can calculate the dosimetry with high accuracy. In this thesis, a model of the SAVI will be created for Monte Carlo, specifically using MCNP code, in order to explore the affects of heterogeneities on the dose distribution. This data will be compared to TG-43 and Acuros calculated dosimetry to explore their accuracy.

  7. Histologic Assessment of Intratumoral Lymphoplasmacytic Infiltration Is Useful in Predicting Prognosis of Patients with Hepatocellular Carcinoma

    PubMed Central

    Hayashi, Akimasa; Shibahara, Junji; Misumi, Kento; Arita, Junichi; Sakamoto, Yoshihiro; Hasegawa, Kiyoshi; Kokudo, Norihiro; Fukayama, Masashi

    2016-01-01

    In the present study, we investigated the clinicopathologic significance of intratumoral lymphoplasmacytic infiltration in a large cohort of patients with solitary hepatocellular carcinoma (HCC). Based on examination of hematoxylin and eosin-stained sections, significant infiltration was defined as dense lymphoplasmacytic infiltration, either multifocal or diffuse, in 2 or more fields under low-power magnification. Of 544 cases, 216 (39.7%) were positive for significant infiltration (HCC-LI group), while 328 (60.3%) were negative (HCC-NLI group). There were no significant between-group differences in patient age, sex, or background etiology. The lower incidence of Child-Pugh stage B (P = 0.001) and lower level of indocyanine green retention rate at 15 minutes (P < 0.001) in the HCC-LI group indicated better liver function in this group. Histologically, tumors were significantly smaller in size in the HCC-LI group than in the HCC-NLI group (P < 0.001). In addition, prominent neutrophilic infiltration, interstitial fibrosis and tumor steatosis were significantly more frequent (P < 0.001) in the HCC-LI group, while tumor necrosis was significantly less frequent (P = 0.008). Kaplan-Meier analyses revealed that overall and recurrence-free survival were significantly better in the HCC-LI group (P < 0.001). Multivariate Cox regression analysis showed that intratumoral lymphoplasmacytic infiltration was independently prognostic of both overall and recurrence-free survival (P < 0.001), with absence of infiltration showing high Cox-hazard ratios for poor prognosis. In conclusion, intratumoral lymphoplasmacytic infiltration, as determined by assessment of hematoxylin and eosin-stained slides, was significantly associated with the clinical and pathologic features of HCC and has profound prognostic importance. PMID:27195977

  8. Use of posterior predictive checks as an inferential tool for investigating individual heterogeneity in animal population vital rates

    PubMed Central

    Chambert, Thierry; Rotella, Jay J; Higgs, Megan D

    2014-01-01

    The investigation of individual heterogeneity in vital rates has recently received growing attention among population ecologists. Individual heterogeneity in wild animal populations has been accounted for and quantified by including individually varying effects in models for mark–recapture data, but the real need for underlying individual effects to account for observed levels of individual variation has recently been questioned by the work of Tuljapurkar et al. (Ecology Letters, 12, 93, 2009) on dynamic heterogeneity. Model-selection approaches based on information criteria or Bayes factors have been used to address this question. Here, we suggest that, in addition to model-selection, model-checking methods can provide additional important insights to tackle this issue, as they allow one to evaluate a model's misfit in terms of ecologically meaningful measures. Specifically, we propose the use of posterior predictive checks to explicitly assess discrepancies between a model and the data, and we explain how to incorporate model checking into the inferential process used to assess the practical implications of ignoring individual heterogeneity. Posterior predictive checking is a straightforward and flexible approach for performing model checks in a Bayesian framework that is based on comparisons of observed data to model-generated replications of the data, where parameter uncertainty is incorporated through use of the posterior distribution. If discrepancy measures are chosen carefully and are relevant to the scientific context, posterior predictive checks can provide important information allowing for more efficient model refinement. We illustrate this approach using analyses of vital rates with long-term mark–recapture data for Weddell seals and emphasize its utility for identifying shortfalls or successes of a model at representing a biological process or pattern of interest. We show how posterior predictive checks can be used to strengthen inferences in

  9. Investigating the heterogeneous freezing behavior of supercooled droplets containing different amounts of SNOMAX

    NASA Astrophysics Data System (ADS)

    Niedermeier, D.; Budke, C.; Koop, T.; Hartmann, S.; Augustin, S.; Stratmann, F.; Wex, H.

    2013-12-01

    Heterogeneous ice nucleation, a fundamental process for ice formation in the atmosphere, has been observed to occur in clouds at temperatures higher than -20 °C (Kanitz et al., 2011). However, laboratory studies showed that mineral dust particles, which are the most abundant atmospheric ice nuclei (IN), are ice active at lower temperature (Murray et al., 2012). Biological particles such as bacteria nucleate ice at higher temperatures similar to those observed in the atmosphere. But their atmospheric relevance is controversially discussed (Hartmann et al., 2013; Hoose et al., 2010). In order to achieve a better understanding, fundamental processes underlying ice nucleation on bacteria should be investigated. Within the Ice Nuclei research UnIT (INUIT), the ice nucleating ability of SNOMAX, which contains non-viable Pseudomonas syringae bacteria as well as their fragments, was quantified using different measurement devices featuring different measurement techniques. Here, results determined with the Bielefeld Ice Nucleation ARraY (BINARY, Budke et al., 2013) and the Leipzig Aerosol Cloud Interaction Simulator (LACIS, Hartmann et al., 2011) are presented exemplarily. Within these devices, droplets with different amounts of SNOMAX were exposed to supercooling temperatures until they froze (BINARY: cooling rate: 1K/min; LACIS: residence time of supercooled droplets at a certain temperature: ~0.2s). Frozen fractions were determined in a temperature range of ca. -4 to -20 °C. These fractions increase steeply and, in part, level off at values lower than 100% (i.e., they reach a plateau value indicating the number of SNOMAX IN per droplet) depending on the SNOMAX concentration. With increasing amount of SNOMAX per droplet, the frozen fraction curve is shifted to higher temperature and the plateau value increases, reaching 100% for the highest SNOMAX concentrations. It has been suggested that ice nucleation active (INA) macromolecules, i.e. protein complexes in the case of

  10. Small scale laboratory design investigation of leakage of gaseous CO2 through heterogeneous subsurface system

    NASA Astrophysics Data System (ADS)

    Basirat, F.; Sharma, P.; Niemi, A.; Fagerlund, F.

    2012-04-01

    The technology for geological sequestration of carbon dioxide has been developed to reduce the CO2 emissions into the atmosphere from the use of fossil fuels in power generation and other industries. One of the main concerns associated with the geological storage is the possible leakage of CO2 into the shallow aquifers, for which effective detection methods are needed. The processes related to the spreading and trapping of CO2 in the reservoir formation and in supercritical conditions have received major attention and form the basis of understanding of CO2 trapping processes. Some of the CO2 may, however, also leak to the upper layers of the rock and all the way to land surface through faults and imperfections in the seal. A proper understanding and capability to detect such leaks is essential for a safe performance of any storage operation. This, in turn, involves a proper understanding of the processes related to the transport of gaseous CO2 in the near-surface conditions, a topic that has received considerably less attention. The objective of this study is to analyze the transport and migration of gaseous CO2 in heterogeneous porous media, in controlled laboratory conditions. CO2 may reach the unsaturated zone by different leak mechanisms which may subsequently affect how and where it can be detected by leakage monitoring program. These mechanisms include exsolution from CO2 supersaturated water and continuous bubbling or gas flow along a leakage path. Below the water table, gaseous CO2 can also be trapped under capillary barriers. However, as more CO2 is supplied by leakage from below the water table, the pressure may at some point exceed the entry pressure of the barrier leading to a leak event. Similarly, fluctuations in the water table may also produce leak events of temporarily trapped CO2. In the unsaturated zone, the CO2 is heavier than air and may accumulate below ground surface and move laterally. The presence of heterogeneity influences both the

  11. Relaxation Nuclear Magnetic Resonance Imaging Investigation of Heterogeneous Aging in a Hydroxy-Terminated Polybutadiene-Based Elastomer

    SciTech Connect

    Alam, Todd M.; Cherry, Brian R.; Minard, Kevin R.; Celina, Mat C.

    2005-12-27

    Relaxation nuclear magnetic resonance imaging (R-NMRI) was employed to investigate the effects of thermo-oxidative aging in a hydroxy-terminated polybutadiene (HTPB) based elastomer. A series of three-dimensional (3D) Hahn-echo weighted single point images (SPI) of the elastomer were utilized to generate a 3D parameter map of the aged material. NMR spin-spin relaxation times (T2) were measured for each voxel producing a 3D NMR parameter (T2) map of the aged polymer. These T2 maps reveal a dramatic reduction of local polymer mobility near the aging surface with the degree of T2 heterogeneity varying as a function of aging. Using correlations between NMR T2 and material modulus, the impact of this heterogeneous thermo-oxidative aging on the material properties is discussed.

  12. Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges.

    PubMed

    Lu, Li-Chun; Hsu, Chih-Hung; Hsu, Chiun; Cheng, Ann-Lii

    2016-04-01

    Tumor heterogeneity in hepatocellular carcinoma (HCC), such as that found in second primary tumors after curative treatment, synchronous multifocal tumors of different clonality, or intratumor heterogeneity, poses severe challenges for the development and administration of systemic molecular targeted therapies. Various methodologies, including historical DNA ploidy analysis, integrated hepatitis B virus DNA analysis, DNA fingerprinting, and next-generation sequencing technologies, are used to explore tumor heterogeneity in HCC. It is estimated that 30%-60% of recurrent or metastatic tumors harbor clones different from the primary tumor, 22%-79% of synchronous tumors vary clonally, and 12%-66% of single tumors contain intratumor heterogeneity. Substantial intertumor and intratumor heterogeneity renders biomarker identification, which is critical for the development and administration of molecular targeted therapy, challenging when applied to a single tumor biopsy specimen. The use of circulating tumor cells or circulating tumor DNA to evaluate overall tumor heterogeneity may help resolve this problem. This article reviews previous studies of tumor heterogeneity and discusses the implications and future opportunities regarding tumor heterogeneity in HCC. PMID:27386431

  13. Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges

    PubMed Central

    Lu, Li-Chun; Hsu, Chih-Hung; Hsu, Chiun; Cheng, Ann-Lii

    2016-01-01

    Tumor heterogeneity in hepatocellular carcinoma (HCC), such as that found in second primary tumors after curative treatment, synchronous multifocal tumors of different clonality, or intratumor heterogeneity, poses severe challenges for the development and administration of systemic molecular targeted therapies. Various methodologies, including historical DNA ploidy analysis, integrated hepatitis B virus DNA analysis, DNA fingerprinting, and next-generation sequencing technologies, are used to explore tumor heterogeneity in HCC. It is estimated that 30%-60% of recurrent or metastatic tumors harbor clones different from the primary tumor, 22%-79% of synchronous tumors vary clonally, and 12%-66% of single tumors contain intratumor heterogeneity. Substantial intertumor and intratumor heterogeneity renders biomarker identification, which is critical for the development and administration of molecular targeted therapy, challenging when applied to a single tumor biopsy specimen. The use of circulating tumor cells or circulating tumor DNA to evaluate overall tumor heterogeneity may help resolve this problem. This article reviews previous studies of tumor heterogeneity and discusses the implications and future opportunities regarding tumor heterogeneity in HCC.

  14. Intratumoral oxygen gradients mediate sarcoma cell invasion.

    PubMed

    Lewis, Daniel M; Park, Kyung Min; Tang, Vitor; Xu, Yu; Pak, Koreana; Eisinger-Mathason, T S Karin; Simon, M Celeste; Gerecht, Sharon

    2016-08-16

    Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O2 depletion. Here, we report the impact of hypoxic O2 gradients on sarcoma cell invasion and migration. O2 gradient measurements showed that large sarcoma mouse tumors (>300 mm(3)) contain a severely hypoxic core [≤0.1% partial pressure of O2 (pO2)] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO2). To analyze tumor invasion, we used O2-controllable hydrogels to recreate the physiopathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O2 gradient accurately, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O2 acts as a 3D physicotactic agent during sarcoma tumor invasion and propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets. PMID:27486245

  15. Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

    PubMed Central

    Springer, Charles S; Li, Xin; Tudorica, Luminita A; Oh, Karen Y; Roy, Nicole; Chui, Stephen Y-C; Naik, Arpana M; Holtorf, Megan L; Afzal, Aneela; Rooney, William D; Huang, Wei

    2014-01-01

    Shutter-speed pharmacokinetic analysis of dynamic-contrast-enhanced (DCE)-MRI data allows evaluation of equilibrium inter-compartmental water interchange kinetics. The process measured here – transcytolemmal water exchange – is characterized by the mean intracellular water molecule lifetime (τi). The τi biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE-MRI. We present population-averaged in vivo human breast whole tumor τi changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while Ktrans (measuring mostly contrast agent (CA) extravasation) and kep (CA intravasation rate constant) decrease, τi increases. However, high-resolution, (1 mm)2, parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms τi value means a trans-membrane water cycling flux of 1013 H2O molecules s−1/cell for a 12 µm diameter cell. Analyses of intratumor variations (and therapy-induced changes) of τi in combination with concomitant changes of ve (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, PW, not of cell size. These can be interpreted in light of literature results showing that τi changes are dominated by a PW(active) component that reciprocally reflects the membrane driving P-type ATPase ion pump turnover. For mammalian cells, this is the Na+,K+-ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy. PMID:24798066

  16. Heterogeneity of blood flow in tibial cortical bone: An experimental investigation using microspheres

    SciTech Connect

    Willans, S.M.; McCarthy, I.D. )

    1991-03-01

    The distribution of tibial blood flow was measured by injecting approximately (600-1000) x 10(3) 15 mu microspheres, labelled with either tin-113 (113Sn) or cobalt-57 (57Co) into femoral arteries of five mature greyhounds. The diaphyseal cortex, stripped of periosteum and devoid of marrow, was sawn into 40 pieces (10 transverse sections x 4 anatomical quarters/section). Relative deposition densities of the 113Sn microspheres in 40 pieces of cortex were found. These values, together with their associated masses, proved, from a statistical point of view, that flow rate heterogeneity was substantial in the diaphysis. In particular, for the diaphyseal cortex, distribution of relative deposition densities (flow rates) in six bones was found to be positively-skewed with a relative dispersion ((SD/mean) x 100) of approximately 40%.

  17. Experimental investigation of supercritical CO2 trapping mechanisms at the Intermediate Laboratory Scale in well-defined heterogeneous porous media

    DOE PAGESBeta

    Trevisan, Luca; Pini, Ronny; Cihan, Abdullah; Birkholzer, Jens T.; Zhou, Quanlin; Illangasekare, Tissa H.

    2014-12-31

    The heterogeneous nature of typical sedimentary formations can play a major role in the propagation of the CO2 plume, eventually dampening the accumulation of mobile phase underneath the caprock. From core flooding experiments, it is also known that contrasts in capillary threshold pressure due to different pore size can affect the flow paths of the invading and displaced fluids and consequently influence the build- up of non-wetting phase (NWP) at interfaces between geological facies. The full characterization of the geologic variability at all relevant scales and the ability to make observations on the spatial and temporal distribution of the migrationmore » and trapping of supercritical CO2 is not feasible from a practical perspective. To provide insight into the impact of well-defined heterogeneous systems on the flow dynamics and trapping efficiency of supercritical CO2 under drainage and imbibition conditions, we present an experimental investigation at the meter scale conducted in synthetic sand reservoirs packed in a quasi-two-dimensional flow-cell. Two immiscible displacement experiments have been performed to observe the preferential entrapment of NWP in simple heterogeneous porous media. The experiments consisted of an injection, a fluid redistribution, and a forced imbibition stages conducted in an uncorrelated permeability field and a homogeneous base case scenario. We adopted x-ray attenuation analysis as a non-destructive technique that allows a precise measurement of phase saturations throughout the entire flow domain. By comparing a homogeneous and a heterogeneous scenario we have identified some important effects that can be attributed to capillary barriers, such as dampened plume advancement, higher non-wetting phase saturations, larger contact area between the injected and displaced phases, and a larger range of non-wetting phase saturations.« less

  18. Intratumor photosensitizer injection for photodynamic therapy: Pre-clinical experience with methylene blue, Pc 4, and Photofrin

    NASA Astrophysics Data System (ADS)

    Baran, Timothy M.; Foster, Thomas H.

    2016-03-01

    Intravenous administration of some photosensitizers, including the FDA-approved Photofrin, results in significant systemic photosensitivity and a 2-3-day drug-light interval. Direct intratumor injection of photosensitizer could potentially eliminate these negative aspects of photodynamic therapy (PDT), while requiring a lower photosensitizer dose to achieve comparable drug concentration in the target tissue. We performed PDT using intratumor injection of 3 photosensitizers, methylene blue (MB), Pc 4, and Photofrin, in mouse tumor models. After a 0-15 minute drug-light interval, illumination was delivered by appropriate diode lasers. For animals receiving MB or Pc 4, surface illumination was delivered using a microlens-terminated fiber. For animals receiving Photofrin, interstitial illumination was delivered by a 1 cm diffuser. In animals receiving MB or Pc 4, tumor dimensions were measured daily post-PDT, with a cure being defined as no palpable tumor 90 days post-treatment. For Photofrin, animals were sacrificed 24 hours post-PDT and tumors were excised, with samples HE stained to assess PDT-induced necrosis. 55% of tumors were cured with MB-PDT, and significant tumor growth delay (p=0.002) was observed for Pc 4. For Photofrin PDT, the mean necrosis radius was 3.4+/-0.8 mm, compared to 2.9+/-1.3 mm for systemic administration, which was not a significant difference (p=0.58). Intratumoral injection of the photosensitizers methylene blue, Pc 4, and Photofrin is feasible, and results in appreciable tumor response. Further investigation is necessary to optimize treatment protocols and assess the systemic photosensitivity induced by intratumor injection.

  19. WE-E-17A-05: Complementary Prognostic Value of CT and 18F-FDG PET Non-Small Cell Lung Cancer Tumor Heterogeneity Features Quantified Through Texture Analysis

    SciTech Connect

    Desseroit, M; Cheze Le Rest, C; Tixier, F; Majdoub, M; Visvikis, D; Hatt, M; Guillevin, R; Perdrisot, R

    2014-06-15

    Purpose: Previous studies have shown that CT or 18F-FDG PET intratumor heterogeneity features computed using texture analysis may have prognostic value in Non-Small Cell Lung Cancer (NSCLC), but have been mostly investigated separately. The purpose of this study was to evaluate the potential added value with respect to prognosis regarding the combination of non-enhanced CT and 18F-FDG PET heterogeneity textural features on primary NSCLC tumors. Methods: One hundred patients with non-metastatic NSCLC (stage I–III), treated with surgery and/or (chemo)radiotherapy, that underwent staging 18F-FDG PET/CT images, were retrospectively included. Morphological tumor volumes were semi-automatically delineated on non-enhanced CT using 3D SlicerTM. Metabolically active tumor volumes (MATV) were automatically delineated on PET using the Fuzzy Locally Adaptive Bayesian (FLAB) method. Intratumoral tissue density and FDG uptake heterogeneities were quantified using texture parameters calculated from co-occurrence, difference, and run-length matrices. In addition to these textural features, first order histogram-derived metrics were computed on the whole morphological CT tumor volume, as well as on sub-volumes corresponding to fine, medium or coarse textures determined through various levels of LoG-filtering. Association with survival regarding all extracted features was assessed using Cox regression for both univariate and multivariate analysis. Results: Several PET and CT heterogeneity features were prognostic factors of overall survival in the univariate analysis. CT histogram-derived kurtosis and uniformity, as well as Low Grey-level High Run Emphasis (LGHRE), and PET local entropy were independent prognostic factors. Combined with stage and MATV, they led to a powerful prognostic model (p<0.0001), with median survival of 49 vs. 12.6 months and a hazard ratio of 3.5. Conclusion: Intratumoral heterogeneity quantified through textural features extracted from both CT and FDG PET

  20. Experimental Investigation of Dissolution-Driven Convection in Heterogeneous Porous Medium

    NASA Astrophysics Data System (ADS)

    Ni, Rui; Salibindla, Ashwanth K. R.; Masuk, Ashik Ullah Mohammad; Shen, Jikang

    2015-11-01

    Subsurface carbon sequestration in saline aquifers has emerged as one promising method to mitigate anthropogenic emission of CO2 because of the potential storage capacity of the accessible formations. Being injected into the porous formation underground, the buoyant CO2 will start to migrate upward and may eventually leak back to the surface through faults in the overlying caprock. This leaking process may be hindered or even completely stopped due to the dissolution of CO2 into the brine. For those locations, where the supercritical CO2 is above the brine, the dissolution between the two fluids leads to a mixture with higher density than both CO2 and brine; and thus the resultant solution on the interface is unstable, drawing the CO2 -rich mixture downward and rendering the sequestration significantly more stable. Previous laboratory experiments on dissolution-driven convection were mostly limited to a simplified case where the porous medium was assumed to be homogenous. To account for the heterogeneity existing in the actual formations, we designed a series of experiments in controlled ways to introduce spatial variations of permeability. By measuring the mass transfer efficiency under different conditions, our experiments provide a new way to assess the

  1. Natural flow and vertical heterogeneities in a sedimentary geothermal reservoir (Paris Basin, France): Geochemical investigations

    SciTech Connect

    Criaud, Annie, Fouassier, Philippe; Fouillac, Christian; Brach, Michel

    1988-01-01

    Three geothermal wells tapping the Dogger aquifer were studied in detail for their variations in chemical composition with time or conditions of exploitation. Analytical improvements for the determination of Cl, SO{sub 4}, Ca, Mg, Na and K make it possible to detect variations respectively of 0.15, 0.8, 0.6, 1.8, 1.8 and 1.4 %. Despite the fact that the natural flow may be important in some parts of the basin aquifer, we conclude that this factor is not responsible for the small variations noticed in mineralization within the one year survey period. The results concerning reactive and nonreactive species are best explained if a vertical heterogeneity of the chemistry of the fluid is assumed. A number of calcareous sub-layers, already demonstrated by geological studies, contribute to varying degrees to the production of the hot water. The changes in pumping rates, which are fixed according to external requirements, play a major role in the hydrodynamic and chemical disequilibrium of the wells. The consequences for the geothermal exploitations are emphasized.

  2. A computational investigation of the role of behavioral heterogeneities on cell cluster motion

    NASA Astrophysics Data System (ADS)

    Copenhagen, Katherine; Gov, Nir; Gopinathan, Ajay

    2015-03-01

    Collective motion of cells is a common occurence in many biological systems, including tissue develope- ment and repair, and tumor formation. Recent experiments have shown that malignant B and T lymphocytes form clusters in a chemical gradient of CCL19 which display three different phases: translational, rotational, and random. Could these phases be due to interactions between cells as well as chemotaxis of individuals? If so what types of local interactions can lead to the three phases seen in experiment? We model cell clusters with a continuous two dimensional agent based model. To form a single cell cluster which displays all three of the phases described above, cells interact with a Vicsek alignment interaction, a Lennard-Jones collision- avoidance and cohesiveness interaction, and a long range spring interaction to prevent fracture. By changing the behaviors of individual cells depending on the number of cells they are contacting, we are able to create clusters that occupy these phases with varying likelihood. Our results show that heterogeneous behaviors of individuals based on local environment can lead to novel phases seen in experiments.

  3. An investigation of genetic heterogeneity and linkage disequilibrium in 161 families with spinal muscular atrophy

    SciTech Connect

    Merette, C.; Gilliam, T.C.; Brzustowicz, L.M. ); Daniels, R.J.; Davies, K.E. ); Melki, J.; Munnich, A. ); Pericak-Vance, M.A. ); Siddique, T. ); Voosen, B. )

    1994-05-01

    The authors performed linkage analysis of 161 families with spinal muscular atrophy (SMA) in which affected individuals suffer from the intermediate or mild form of the disease (Types II or III). Markers for six loci encompassing the chromosome 5q11.2-q13.3 region were typed. The best map location for the disease locus was found to be between D5S6 and MAP1B. The corresponding 1 lod unit support interval is confined to this interval and spans 0.5 cM. The data strongly support the hypothesis of linkage heterogeneity (likelihood ratio, 1.14 [times] 10[sup 4]), with 5% of the families unlinked. Four families have a probability of less than 50% of segregating the SMA gene linked to the region 5q11.2-q13.3. A likelihood approach to test for linkage disequilibrium revealed no significant departure from Hardy-Weinberg equilibrium with any marker under study. 28 refs., 4 figs., 3 tabs.

  4. Intratumoral mediated immunosuppression is prognostic in genetically engineered murine models of glioma and correlates to immune therapeutic responses

    PubMed Central

    Kong, Ling-Yuan; Wu, Adam S.; Doucette, Tiffany; Wei, Jun; Priebe, Waldemar; Fuller, Gregory N.; Qiao, Wei; Sawaya, Raymond; Rao, Ganesh; Heimberger, Amy B.

    2010-01-01

    Purpose Pre-clinical murine model systems used for the assessment of therapeutics have not been predictive of human clinical responses, primarily because their clonotypic nature does not recapitulate the heterogeneous biology and immunosuppressive mechanisms of humans. Relevant model systems with mice that are immunologically competent are needed to evaluate the efficacy of therapeutic agents, especially immunotherapeutics. Experimental Design Using the RCAS/Ntv-a system, mice were engineered to co-express platelet-derived growth factor receptor (PDGF)-B + B-cell lymphoma (Bcl)-2 under the control of the glioneuronal-specific Nestin promoter. The degree and type of tumor-mediated immunosuppression was determined in these endogenously arising gliomas based upon the presence of macrophages and regulatory T cells (Tregs). The immunotherapeutic agent, WP1066, was tested in vivo to assess therapeutic efficacy and immune modulation. Results N-tva mice were injected with RCAS vectors to express PDGF-B + Bcl-2, resulting in both low- and high-grade gliomas. Consistent with observations in human high-grade gliomas, mice with high-grade gliomas also developed a marked intratumoral influx of macrophages that was influenced by tumor signal transducer and activator of transduction (STAT) 3 expression. The presence of intratumoral F4/80 macrophages was a negative prognosticator for long-term survival. In mice expressing both PDGF-B + Bcl-2 that were treated with WP1066, there was 55.5% increase in median survival time (P< 0.01), with an associated inhibition of intratumoral STAT3 and macrophages. Conclusions Although randomization is necessary for including mice in a therapeutic trial, these murine model systems are more suitable for testing therapeutics, and especially immune therapeutics, in the context of translational studies. PMID:20921210

  5. Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumors in vivo by label-free third-harmonic generation microscopy

    NASA Astrophysics Data System (ADS)

    Weng, Wei-Hung; Liao, Yi-Hua; Tsai, Ming-Rung; Wei, Ming-Liang; Huang, Hsin-Yi; Sun, Chi-Kuang

    2016-07-01

    Morphology and distribution of melanocytes are critical imaging information for the diagnosis of melanocytic lesions. However, how to image intratumoral melanocytes noninvasively in pigmented skin tumors is seldom investigated. Third-harmonic generation (THG) is shown to be enhanced by melanin, whereas high accuracy has been demonstrated using THG microscopy for in vivo differential diagnosis of nonmelanocytic pigmented skin tumors. It is thus desirable to investigate if label-free THG microscopy was capable to in vivo identify intratumoral melanocytes. In this study, histopathological correlations of label-free THG images with the immunohistochemical images stained with human melanoma black (HMB)-45 and cluster of differentiation 1a (CD1a) were made. The correlation results indicated that the intratumoral THG-bright dendritic-cell-like signals were endogenously derived from melanocytes rather than Langerhans cells (LCs). The consistency between THG-bright dendritic-cell-like signals and HMB-45 melanocyte staining showed a kappa coefficient of 0.807, 84.6% sensitivity, and 95% specificity. In contrast, a kappa coefficient of -0.37, 21.7% sensitivity, and 30% specificity were noted between the THG-bright dendritic-cell-like signals and CD1a staining for LCs. Our study indicates the capability of noninvasive label-free THG microscopy to differentiate intratumoral melanocytes from LCs, which is not feasible in previous in vivo label-free clinical-imaging modalities.

  6. Managing Local Swelling Following Intratumoral Electro-Chemo-Gene Therapy

    PubMed Central

    Cutrera, Jeffry; King, Glenn; Jones, Pamela; Gumpel, Elias; Xia, Xueqing

    2014-01-01

    Summary Delivering genes and other materials directly into the tumor tissue causes specifically localized and powerfully enhanced efficacy of treatments; however, these specific effects can cause rapid, drastic changes in the appearance, texture, and consistency of the tumor. These changes complicate clinical response measurements which can confound the results and render recurring treatments difficult to perform and clinical response measurements nearly impossible to accurately obtain. One of these complicating issues is local swelling. Here, we will demonstrate how swelling caused by intratumoral gene treatments can confound the clinical results and impede further treatments, and we will demonstrate an easy technique to help to overcome this potential hurdle. PMID:24510827

  7. Hemiballismus as a complication of an intratumoral chemotherapy catheter.

    PubMed

    Zuccarelli, Britton; Aalbers, Brian; Grabb, Paul

    2016-08-01

    We report an unusual case of delayed bilateral, right greater than left hemiballismus in a 15-year-old female patient with a history of a craniopharyngioma 2years following the insertion of a right intratumoral chemotherapy catheter. Following cyst decompression, the catheter was found to have changed position, traversing the basal ganglia structures, namely the right subthalamic nucleus. Her movement disorder near-completely resolved immediately following removal of the catheter. A review of the current literature and proposed pathophysiological mechanisms are discussed. PMID:26964474

  8. Preface of the "Symposium on Mathematical Models and Methods to investigate Heterogeneity in Cell and Cell Population Biology"

    NASA Astrophysics Data System (ADS)

    Clairambault, Jean

    2016-06-01

    This session investigates hot topics related to mathematical representations of cell and cell population dynamics in biology and medicine, in particular, but not only, with applications to cancer. Methods in mathematical modelling and analysis, and in statistical inference using single-cell and cell population data, should contribute to focus this session on heterogeneity in cell populations. Among other methods are proposed: a) Intracellular protein dynamics and gene regulatory networks using ordinary/partial/delay differential equations (ODEs, PDEs, DDEs); b) Representation of cell population dynamics using agent-based models (ABMs) and/or PDEs; c) Hybrid models and multiscale models to integrate single-cell dynamics into cell population behaviour; d) Structured cell population dynamics and asymptotic evolution w.r.t. relevant traits; e) Heterogeneity in cancer cell populations: origin, evolution, phylogeny and methods of reconstruction; f) Drug resistance as an evolutionary phenotype: predicting and overcoming it in therapeutics; g) Theoretical therapeutic optimisation of combined drug treatments in cancer cell populations and in populations of other organisms, such as bacteria.

  9. Investigating the spectral characteristics of backscattering from heterogeneous spherical nuclei using broadband finite-difference time-domain simulations

    NASA Astrophysics Data System (ADS)

    Chao, Guo-Shan; Sung, Kung-Bin

    2010-01-01

    Reflectance spectra measured from epithelial tissue have been used to extract size distribution and refractive index of cell nuclei for noninvasive detection of precancerous changes. Despite many in vitro and in vivo experimental results, the underlying mechanism of sizing nuclei based on modeling nuclei as homogeneous spheres and fitting the measured data with Mie theory has not been fully explored. We describe the implementation of a three-dimensional finite-difference time-domain (FDTD) simulation tool using a Gaussian pulse as the light source to investigate the wavelength-dependent characteristics of backscattered light from a nuclear model consisting of a nucleolus and clumps of chromatin embedded in homogeneous nucleoplasm. The results show that small-sized heterogeneities within the nuclei generate about five times higher backscattering than homogeneous spheres. More interestingly, backscattering spectra from heterogeneous spherical nuclei show periodic oscillations similar to those from homogeneous spheres, leading to high accuracy of estimating the nuclear diameter by comparison with Mie theory. In addition to the application in light scattering spectroscopy, the reported FDTD method could be adapted to study the relations between measured spectral data and nuclear structures in other optical imaging and spectroscopic techniques for in vivo diagnosis.

  10. Investigating the spectral characteristics of backscattering from heterogeneous spheroidal nuclei using broadband finite-difference time-domain simulations

    NASA Astrophysics Data System (ADS)

    Chao, Guo-Shan; Sung, Kung-Bin

    2010-02-01

    Backscattered light spectra have been used to extract size distribution of cell nuclei in epithelial tissues for noninvasive detection of precancerous lesions. In existing experimental studies, size estimation is achieved by assuming nuclei as homogeneous spheres or spheroids and fitting the measured data with models based on Mie theory. However, the validity of simplifying nuclei as homogeneous spheres has not been thoroughly examined. In this study, we investigate the spectral characteristics of backscattering from models of spheroidal nuclei under plane wave illumination using three-dimensional finite-difference time-domain (FDTD) simulation. A modulated Gaussian pulse is used to obtain wavelength dependent scattering intensity with a single FDTD run. The simulated model of nuclei consists of a nucleolus and randomly distributed chromatin condensation in homogeneous cytoplasm and nucleoplasm. The results show that backscattering spectra from spheroidal nuclei have similar oscillating patterns to those from homogeneous spheres with the diameter equal to the projective length of the spheroidal nucleus along the propagation direction. The strength of backscattering is enhanced in heterogeneous spheroids as compared to homogeneous spheroids. The degree of which backscattering spectra of heterogeneous nuclei deviate from Mie theory is highly dependent on the distribution of chromatin/nucleolus but not sensitive to nucleolar size, refractive index fluctuation or chromatin density.

  11. Heterogeneity of ERBB2 in gastric carcinomas: a study of tissue microarray and matched primary and metastatic carcinomas.

    PubMed

    Cho, Eun Yoon; Park, Kyeongmee; Do, Ingu; Cho, Junhun; Kim, Jiyun; Lee, Jeeyun; Kim, Seonwoo; Kim, Kyoung-Mee; Sohn, Tae Sung; Kang, Won Ki; Kim, Sung

    2013-05-01

    Trastuzumab in association with systemic cytotoxic chemotherapy is a therapeutic option for patients with advanced or metastatic ERBB2+ gastric carcinoma. The status of the ERBB2 overexpression or gene amplification is an important predictive marker in gastric cancer. However, it is controversial whether the primary tumor is representative of distant metastases in terms of ERBB2 status. Quadruplicated tissue microarrays from formalin-fixed paraffin-embedded tissues from 498 advanced primary gastric carcinomas and 97 matched metastatic lymph nodes were investigated by immunohistochemistry with HercepTest and silver in situ hybridization. For further comparison, another set of 41 paired primary and distant metastatic gastric carcinomas were also tested. Intratumoral heterogeneity was defined as different results between tissue microarray cores. ERBB2-positivity was observed in 52 gastric carcinomas (10%) and was not associated with recurrence of disease or survival of patients. In ERBB2-positive primary gastric carcinomas, heterogeneous ERBB2 overexpression was observed in 21/63 (33%) gastric carcinomas and heterogeneous ERBB2 gene amplification in 14/62 (23%) cases. Repeated immunohistochemistry and silver in situ hybridization in representative paraffin tumor blocks confirmed focal ERBB2 overexpression and ERBB2 gene amplification and did not change the final results. Discrepancies in ERBB2 results between primary and paired metastatic lymph nodes were observed in 11% of cases by immunohistochemistry and 7% by silver in situ hybridization. Out of the 41 paired primary and distant metastases, 5 (12%) cases were ERBB2-positive, and discrepancy was observed in one case. Intratumoral heterogeneity and discrepant ERBB2 results in primary and metastatic tumor are not uncommon in gastric carcinoma. Results of silver in situ hybridization showed less frequent heterogeneity compared with immunohistochemistry. Wherever possible, ERBB2 immunohistochemistry testing should be

  12. Effects of intratumoral injection of I-125 iododeoxyuridine on Ehrlich ascites carcinoma

    SciTech Connect

    Hong, S.S.; Ford, E.H.; Alfieri, A.A.; Bravo, S. )

    1989-11-01

    Intratumoral injection of I-125 iododeoxyuridine (IUdR), saline solution, and oil suspension was investigated using Ehrlich ascites tumors in the thighs of mice. The oil suspension was more effective in tumor growth delay than was the saline solution. Single injection of the oil suspension at the dose of 12.5 microCi resulted in 21.5 days growth delay, whereas 50 microCi of the saline solution resulted in 11.5 days growth delay relative to control growth delay. At 40 days after treatment, higher radioactivities were observed in the tumor and the skin of the mice treated with the oil suspension, which represented the prolongation of I-125 IUdR oil suspension within the tumor. No normal tissue toxicities were observed.

  13. Flow microcalorimetry investigation of the influence of surfactants on a heterogeneous aerobic culture.

    PubMed Central

    Beaubien, A; Keita, L; Jolicoeur, C

    1987-01-01

    The influence of various surfactants on the biological activity of a mixed aerobic culture has been investigated by using flow microcalorimetry. The response of the culture to the addition of homologous n-alkylcarboxylates (C2 to C16) and n-alkylpyridinium bromides (C11 to C14) has been examined under endogenous and substrate saturation conditions, and inhibitory concentrations (MIC or the concentration which decreased the initial activity (heat flux) of the culture by 50%) were determined for each state. Under both conditions, the n-alkylpyridinium bromides were found to be more toxic than the n-alkylcarboxylates of identical chain length, thus confirming that the head group of the amphiphiles plays an important role in the microbial toxicity of surfactants. The relationship observed between the concentration at which 50% of the activity is lost and the chain length of the surfactant further confirms that cellular toxicity is also dependent on surfactant hydrophobicity. In relation to the biodegradability of surfactants in mixed aerobic cultures, the low concentration effects of n-alkylcarboxylates on endogenous culture were investigated in some detail. There appear to be compounded indications that these surfactants are rapidly metabolized by the microorganisms of the mixed culture, at least for homologs lower than C10. PMID:3426221

  14. Investigating the influence of subsurface heterogeneity on chemical weathering in the critical zone using high resolution reactive transport models

    NASA Astrophysics Data System (ADS)

    Pandey, S.; Rajaram, H.

    2014-12-01

    The critical zone (CZ) represents a major life-sustaining realm of the terrestrial surface. The processes controlling the development and transformation of the CZ are important to continued health of the planet as human influence continues to grow. The CZ encompasses the shallow subsurface, a region of reaction, unsaturated flow, and transport. Chemical weathering in the subsurface is one of the important processes involved in the formation and functioning of the CZ. We present two case studies of reactive transport modeling to investigate the influence of subsurface heterogeneity and unsaturated flow on chemical weathering processes in the CZ. The model is implemented using the reactive transport code PFLOTRAN. Heterogeneity in subsurface flow is represented using multiple realizations of conductive fracture networks in a hillslope cross-section. The first case study is motivated by observations at the Boulder Creek Critical Zone Observatory (BCCZO) including extensive hydrologic and geochemical datasets. The simulations show that fractures greatly enhance weathering as compared to a homogeneous porous medium. Simulations of north-facing slope hydrology with prolonged snowmelt pulses also increases weathering rates, showing the importance of slope aspect on weathering intensity. Recent work elucidates deteriorating water quality caused by climate change in the CZ of watersheds where acid rock drainage (ARD) occurs. The more complex reactions of ARD require a customized kinetic reaction module with PFLOTRAN. The second case study explores the mechanisms by which changes in hydrologic forcing, air and ground temperatures, and water table elevations influence ARD. For instance, unreacted pyrite exposed by a water table drop was shown to produce a 125% increase in annual pyrite oxidization rate, which provides one explanation for increased ARD.

  15. Bimodality of intratumor Ki67 expression is an independent prognostic factor of overall survival in patients with invasive breast carcinoma.

    PubMed

    Laurinavicius, Arvydas; Plancoulaine, Benoit; Rasmusson, Allan; Besusparis, Justinas; Augulis, Renaldas; Meskauskas, Raimundas; Herlin, Paulette; Laurinaviciene, Aida; Abdelhadi Muftah, Abir A; Miligy, Islam; Aleskandarany, Mohammed; Rakha, Emad A; Green, Andrew R; Ellis, Ian O

    2016-04-01

    Proliferative activity, assessed by Ki67 immunohistochemistry (IHC), is an established prognostic and predictive biomarker of breast cancer (BC). However, it remains under-utilized due to lack of standardized robust measurement methodologies and significant intratumor heterogeneity of expression. A recently proposed methodology for IHC biomarker assessment in whole slide images (WSI), based on systematic subsampling of tissue information extracted by digital image analysis (DIA) into hexagonal tiling arrays, enables computation of a comprehensive set of Ki67 indicators, including intratumor variability. In this study, the tiling methodology was applied to assess Ki67 expression in WSI of 152 surgically removed Ki67-stained (on full-face sections) BC specimens and to test which, if any, Ki67 indicators can predict overall survival (OS). Visual Ki67 IHC estimates and conventional clinico-pathologic parameters were also included in the study. Analysis revealed linearly independent intrinsic factors of the Ki67 IHC variance: proliferation (level of expression), disordered texture (entropy), tumor size and Nottingham Prognostic Index, bimodality, and correlation. All visual and DIA-generated indicators of the level of Ki67 expression provided significant cutoff values as single predictors of OS. However, only bimodality indicators (Ashman's D, in particular) were independent predictors of OS in the context of hormone receptor and HER2 status. From this, we conclude that spatial heterogeneity of proliferative tumor activity, measured by DIA of Ki67 IHC expression and analyzed by the hexagonal tiling approach, can serve as an independent prognostic indicator of OS in BC patients that outperforms the prognostic power of the level of proliferative activity. PMID:26818835

  16. Lung tumor microenvironment induces specific gene expression signature in intratumoral NK cells.

    PubMed

    Gillard-Bocquet, Mélanie; Caer, Charles; Cagnard, Nicolas; Crozet, Lucile; Perez, Mikael; Fridman, Wolf Herman; Sautès-Fridman, Catherine; Cremer, Isabelle

    2013-01-01

    Natural killer (NK) cells are able to recognize and kill tumor cells, however whether they contribute to tumor immunosurveillance is still debated. Our previous studies demonstrated the presence of NK cells in human lung tumors. Their comparison with NK cells from non-tumoral lung tissues and with blood NK cells from the same individuals revealed a decreased expression of some NK receptors and impaired ex vivo cytotoxic functions occurring specifically in NK cells isolated from the tumor microenvironment. The aim of the present study was to characterize the transcriptional profile of such intratumoral NK cells, by comparative microarray analysis of sorted NK cells isolated from non-tumoral (Non-Tum-NK) and tumoral (Tum-NK) lung tissues of 12 Non-Small Cell Lung Cancer patients. Our results reveal a specific gene expression signature of Tum-NK cells particularly in activation processes and cytotoxicity, confirming that tumor environment induces modifications in NK cells biology. Indeed, intratumoral NK cells display higher expression levels of NKp44, NKG2A, Granzymes A and K, and Fas mRNA. A particular pattern of receptors involved in chemotaxis was also observed, with an overexpression of CXCR5 and CXCR6, and a lower expression of CX3CR1 and S1PR1 genes in Tum-NK as compared to Non-Tum-NK cells. The precise identification of the molecular pathways modulated in the tumor environment will help to decipher the role of NK cells in tumor immunosurveillance and will open future investigations to manipulate their antitumoral functions. PMID:23382731

  17. A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme.

    PubMed

    de Aquino, Priscila F; Carvalho, Paulo Costa; Nogueira, Fábio C S; da Fonseca, Clovis Orlando; de Souza Silva, Júlio Cesar Thomé; Carvalho, Maria da Gloria da Costa; Domont, Gilberto B; Zanchin, Nilson I T; Fischer, Juliana de Saldanha da Gama

    2016-01-01

    Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient's GBM but obtained from two surgeries a year's time apart. Our analysis also included GBM's fragments from different anatomical regions. Our quantitative proteomic strategy employed 4-plex iTRAQ peptide labeling followed by a four-step strong cation chromatographic separation; each fraction was then analyzed by reversed-phase nano-chromatography coupled on-line with an Orbitrap-Velos mass spectrometer. Unsupervised clustering grouped the proteomic profiles into four major distinct groups and showed that most changes were related to the tumor's anatomical region. Nevertheless, we report differentially abundant proteins from GBM's fragments of the same region but obtained 1 year apart. We discuss several key proteins (e.g., S100A9) and enriched pathways linked with GBM such as the Ras pathway, RHO GTPases activate PKNs, and those related to apoptosis, to name a few. As far as we know, this is the only report that compares GBM fragments proteomic profiles from the same patient. Ultimately, our results fuel the forefront of scientific discussion on the importance in exploring the richness of subproteomes within a single tissue sample for a better understanding of the disease, as each tumor is unique. PMID:27597932

  18. A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme

    PubMed Central

    de Aquino, Priscila F.; Carvalho, Paulo Costa; Nogueira, Fábio C. S.; da Fonseca, Clovis Orlando; de Souza Silva, Júlio Cesar Thomé; Carvalho, Maria da Gloria da Costa; Domont, Gilberto B.; Zanchin, Nilson I. T.; Fischer, Juliana de Saldanha da Gama

    2016-01-01

    Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM. For this, we profiled tumor fragments from the profound region of the same patient’s GBM but obtained from two surgeries a year’s time apart. Our analysis also included GBM‘s fragments from different anatomical regions. Our quantitative proteomic strategy employed 4-plex iTRAQ peptide labeling followed by a four-step strong cation chromatographic separation; each fraction was then analyzed by reversed-phase nano-chromatography coupled on-line with an Orbitrap-Velos mass spectrometer. Unsupervised clustering grouped the proteomic profiles into four major distinct groups and showed that most changes were related to the tumor’s anatomical region. Nevertheless, we report differentially abundant proteins from GBM’s fragments of the same region but obtained 1 year apart. We discuss several key proteins (e.g., S100A9) and enriched pathways linked with GBM such as the Ras pathway, RHO GTPases activate PKNs, and those related to apoptosis, to name a few. As far as we know, this is the only report that compares GBM fragments proteomic profiles from the same patient. Ultimately, our results fuel the forefront of scientific discussion on the importance in exploring the richness of subproteomes within a single tissue sample for a better understanding of the disease, as each tumor is unique. PMID:27597932

  19. Intratumoral Morphologic and Molecular Heterogeneity of Rhabdoid Renal Cell Carcinoma: Challenges for Personalized Therapy

    PubMed Central

    Singh, Rajesh R.; Murugan, Paari; Patel, Lalit R.; Voicu, Horatiu; Yoo, Suk-Young; Majewski, Tadeusz; Mehrotra, Meenakshi; Wani, Khalida; Tannir, Nizar; Karam, Jose A.; Jonasch, Eric; Wood, Christopher G.; Creighton, Chad J.; Medeiros, L. Jeffrey; Broaddus, Russell R.; Tamboli, Pheroze; Baggerly, Keith A.; Aldape, Kenneth D.; Czerniak, Bogdan; Luthra, Rajyalakshmi; Sircar, Kanishka

    2015-01-01

    Rhabdoid histology in clear cell renal cell carcinoma is associated with a poor prognosis. The prognosis of patients with clear cell renal cell carcinoma may also be influenced by molecular alterations. The aim of this study was to evaluate the association between histologic features and salient molecular changes in rhabdoid clear cell renal cell carcinoma. We macrodissected the rhabdoid and clear cell epithelioid components from 12 cases of rhabdoid clear cell renal cell carcinoma. We assessed cancer related mutations from 8 cases using a clinical next generation exome sequencing platform. The transcriptome of rhabdoid clear cell renal cell carcinoma (n=8) and non-rhabdoid clear cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene expression microarray. VHL (63%) showed identical mutations in all regions from the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the rhabdoid but not the epithelioid component and were mutually exclusive in 3/3 cases and 1 case, respectively. SETD2 (63%) mutations were discordant between different histologic regions in 2/5 cases, with mutations called only in the epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid clear cell renal cell carcinoma was distinct from advanced stage and high grade clear cell renal cell carcinoma. The diverse histologic components of rhabdoid clear cell renal cell carcinoma, however, showed a similar transcriptomic program, including a similar prognostic gene expression signature. Rhabdoid clear cell renal cell carcinoma is transcriptomically distinct and shows a high rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver mutations in clear cell renal cell carcinoma are often discordant across different morphologic regions whereas the gene expression program is relatively stable. Molecular profiling of clear cell renal cell carcinoma may improve by assessing for gene expression and sampling tumor foci from different histologic regions. PMID:26111976

  20. Shades of T790M – intratumor heterogeneity in EGFR mutant lung cancer

    PubMed Central

    Ichihara, Eiki; Lovly, Christine M.

    2015-01-01

    Summary In the setting of recent exciting clinical results and numerous on-going trials, Piotrowska and colleagues explore mechanisms of acquired resistance to the mutant specific EGFR inhibitor, rociletinib, and demonstrate that loss of T790M, EGFR amplification, and small cell transformation are all clinically relevant mechanisms of drug resistance. They provide a new paradigm for using quantitative assessment of the ratio EGFR T790M/activation mutation allele frequency to prognosticate responses to rociletinib and also demonstrate that plasma based assessments of circulating tumor DNA can be used to monitor drug response and the emergence of drug resistance. PMID:26152920

  1. Investigating the influence of subgrid scale soil moisture heterogeneity on surface heat fluxes in large-scale models: hydrology versus meteorology

    NASA Astrophysics Data System (ADS)

    van Heerwaarden, C.; Mellado, J.; Vila-Guerau Arellano, J.

    2011-12-01

    Subgrid scale soil moisture heterogeneity needs to be taken into account in large-scale models. Due to the nonlinear relationship between soil moisture content and the stomatal resistance of plants, a nonuniform distribution of precipitation water leads to a different area-averaged la- tent and sensible heat flux, than a case in which the precpitation water is uniformly distributed. At the same time, heterogeneity in soil moisture at the surface results in a heterogeneous input of heat and moisture into the atmosphere, which can be a source of wind circulations. These circulations can modify the surface fluxes as well, as they result in a more effective ventilation of the land surface and in modified surface fluxes due to horizontal transport of heat and moisture. To be able to model correct surface fluxes in large-scale models, both the hydrological and meteorological influences of soil moisture heterogeneity need to be taken into account. It is, however, not sure how the magnitudes of the influences compare. In this study we use DNS and LES simulations with an interactive land surface to compare the hydrological with the meteorological effects of soil moisture heterogeneity to be able to determine where the focus should be in improving large-scale models. In the comparison, we take into account different patterns of heterogeneity that vary in size and magnitude and we investigate the differences between day and night.

  2. An investigation into heterogeneity in a single vein-type uranium ore deposit: Implications for nuclear forensics.

    PubMed

    Keatley, A C; Scott, T B; Davis, S; Jones, C P; Turner, P

    2015-12-01

    Minor element composition and rare earth element (REE) concentrations in nuclear materials are important as they are used within the field of nuclear forensics as an indicator of sample origin. However recent studies into uranium ores and uranium ore concentrates (UOCs) have shown significant elemental and isotopic heterogeneity from a single mine site such that some sites have shown higher variation within the mine site than that seen between multiple sites. The elemental composition of both uranium and gangue minerals within ore samples taken along a single mineral vein in South West England have been measured and reported here. The analysis of the samples was undertaken to determine the extent of the localised variation in key elements. Energy Dispersive X-ray spectroscopy (EDS) was used to analyse the gangue mineralogy and measure major element composition. Minor element composition and rare earth element (REE) concentrations were measured by Electron Probe Microanalysis (EPMA). The results confirm that a number of key elements, REE concentrations and patterns used for origin location do show significant variation within mine. Furthermore significant variation is also visible on a meter scale. In addition three separate uranium phases were identified within the vein which indicates multiple uranium mineralisation events. In light of these localised elemental variations it is recommended that representative sampling for an area is undertaken prior to establishing the REE pattern that may be used to identify the originating mine for an unknown ore sample and prior to investigating impact of ore processing on any arising REE patterns. PMID:26301831

  3. An Analysis Framework for Investigating the Trade-offs Between System Performance and Energy Consumption in a Heterogeneous Computing Environment

    SciTech Connect

    Friese, Ryan; Khemka, Bhavesh; Maciejewski, Anthony A; Siegel, Howard Jay; Koenig, Gregory A; Powers, Sarah S; Hilton, Marcia M; Rambharos, Rajendra; Okonski, Gene D; Poole, Stephen W

    2013-01-01

    Rising costs of energy consumption and an ongoing effort for increases in computing performance are leading to a significant need for energy-efficient computing. Before systems such as supercomputers, servers, and datacenters can begin operating in an energy-efficient manner, the energy consumption and performance characteristics of the system must be analyzed. In this paper, we provide an analysis framework that will allow a system administrator to investigate the tradeoffs between system energy consumption and utility earned by a system (as a measure of system performance). We model these trade-offs as a bi-objective resource allocation problem. We use a popular multi-objective genetic algorithm to construct Pareto fronts to illustrate how different resource allocations can cause a system to consume significantly different amounts of energy and earn different amounts of utility. We demonstrate our analysis framework using real data collected from online benchmarks, and further provide a method to create larger data sets that exhibit similar heterogeneity characteristics to real data sets. This analysis framework can provide system administrators with insight to make intelligent scheduling decisions based on the energy and utility needs of their systems.

  4. Intratumoral Agreement of High-Resolution Magic Angle Spinning Magnetic Resonance Spectroscopic Profiles in the Metabolic Characterization of Breast Cancer

    PubMed Central

    Park, Vivian Youngjean; Yoon, Dahye; Koo, Ja Seung; Kim, Eun-Kyung; Kim, Seung Il; Choi, Ji Soo; Park, Seho; Park, Hyung Seok; Kim, Suhkmann; Kim, Min Jung

    2016-01-01

    Abstract High-resolution magic angle spinning (HR-MAS) magnetic resonance (MR) spectroscopy data may serve as a biomarker for breast cancer, with only a small volume of tissue sample required for assessment. However, previous studies utilized only a single tissue sample from each patient. The aim of this study was to investigate whether intratumoral location and biospecimen type affected the metabolic characterization of breast cancer assessed by HR-MAS MR spectroscopy This prospective study was approved by the institutional review board and informed consent was obtained. Preoperative core-needle biopsies (CNBs), central, and peripheral surgical tumor specimens were prospectively collected under ultrasound (US) guidance in 31 patients with invasive breast cancer. Specimens were assessed with HR-MAS MR spectroscopy. The reliability of metabolite concentrations was evaluated and multivariate analysis was performed according to intratumoral location and biospecimen type. There was a moderate or higher agreement between the relative concentrations of 94.3% (33 of 35) of metabolites in the center and periphery, 80.0% (28 of 35) of metabolites in the CNB and central surgical specimens, and 82.9% (29 of 35) of metabolites between all 3 specimen types. However, there was no significant agreement between the concentrations of phosphocholine (PC) and phosphoethanolamine (PE) in the center and periphery. The concentrations of several metabolites (adipate, arginine, fumarate, glutamate, PC, and PE) had no significant agreement between the CNB and central surgical specimens. In conclusion, most HR-MAS MR spectroscopic data do not differ based on intratumoral location or biospecimen type. However, some metabolites may be affected by specimen-related variables, and caution is recommended in decision-making based solely on metabolite concentrations, particularly PC and PE. Further validation through future studies is needed for the clinical implementation of these biomarkers based

  5. Investigation of early water breakthrough and the likely effectiveness of water shut-off treatments in heterogeneous carbonate reservoirs

    NASA Astrophysics Data System (ADS)

    Alblooshi, Younes

    Progressive percentage of total fluid produced in the oil industry is formation brine. Ever, increasing water cut will reduce oil recovery, diminish wells' productivity and increase cost of eventual artificial lift and produced water handling. This study investigates the problem of early water development in layered and heterogeneous reservoirs and determines the effect of various reservoir parameters on the development of water front movement in the presence of thief zones. A water injection in a line-staggered pattern was simulated to analyze these effects on the water breakthrough time, WBTT, and the evolution of water front in the thief zone. To achieve this, sensitivity analysis is conducted to investigate and determine the effect of some reservoir parameters that would explain the experience of having unpredicted advancement of injected water resulting in early water breakthrough and high water cut wells. These reservoir parameters included layers' horizontal permeability, Kv/Kh ratio, thickness of high permeability layers, water gravity effect, oil API gravity effect, and injection/production rate ratio (or IPR). Threshold of these parameters beyond which its effect would be constant is also determined to help operators to better estimate the water breakthrough time and hence better decision making process in waterflooding projects. Moreover, water shut-off, WSO, treatments are simulated to determine their effectiveness in delaying the water breakthrough time, and reducing water cut percentages for maximum possible time, under different thief zones' conditions. Extreme thief zone cases are selected from the first part of the study for this purpose. Also, the optimum WSO treatment thickness is identified at which a maximum delay in time is achieved which yields to best treatment practices in the fields. Finally, this study summarizes the applicability of these WSO treatment methods, and it identifies the level of effectiveness based on specific given

  6. Investigating Population Heterogeneity and Interaction Effects of Covariates: The Case of a Large-Scale Assessment for Teacher Licensure in Saudi Arabia

    ERIC Educational Resources Information Center

    Dimitrov, Dimiter M.; Al-Saud, Faisal Abdullah Al-Mashari; Alsadaawi, Abdullah Saleh

    2015-01-01

    This article investigates the population heterogeneity of test data for the case of teacher licensure assessments in Saudi Arabia. The results from factor mixture modeling of the data (N = 15,962) on the construct of "promoting learning" revealed the presence of two latent classes of examinees based on their performance profiles across…

  7. Intratumoral hemorrhage in a patient with cerebellar hemangioblastoma: a case report and review.

    PubMed

    Wang, Zhen; Hu, Jun; Xu, Liang; Malaguit, Jay; Chen, Sheng

    2015-01-01

    Spontaneous hemorrhage is rarely associated with hemangioblastomas. Intratumoral hemorrhage occurring in cerebellar hemangioblastomas is more rare. A 25-year-old man was admitted to our hospital with headache. We found a round cystic lesion with solid part in the right cerebellum. The lesion was resected. The final pathological diagnosis was hemangioblastomas. The radiological features of this case were similar to normal hemangioblastomas, whereas our histological examination showed the occurrence of the intratumoral hemorrhage. If the hemangioblastoma ruptures in our case, the outcome of the patient will be worse. It is difficult to identify the intratumoral hemorrhage of hemangioblastomas and quite dangerous if it is diagnosed late. Diagnosing an intratumoral hemorrhage of hemangioblastomas still needs a further discussion. Genetic screening may help us make an early diagnosis. Furthermore, the mechanism about intratumoral hemorrhage of hemangioblastomas remains unknown. The mutation of D6Mit135 gene on chromosome 6 may be responsible for the vascular dilation and hemorrhage induction in the hemangioblastomas. Tumor size, upregulation of vascular endothelial growth factor, spinalradicular location, and solid type are also factors relating to the hemorrhage of hemangioblastomas. The purpose of reporting our case is 2-fold: to remind clinicians to consider the possibility of internal hemorrhaging while diagnosing this disease, and provide a starting point to discuss mechanisms regarding the intratumoral hemorrhage of hemangioblastomas. PMID:25634201

  8. Numerical Investigation of the Main Characteristics of Heat and Mass Transfer while Heating the Heterogeneous Water Droplet in the Hot Gases

    NASA Astrophysics Data System (ADS)

    Piskunov, Maxim V.; Shcherbinina, Anastasia A.; Vysokomornaya, Olga V.

    2016-02-01

    The processes of heat and evaporation of heterogeneous water droplet with solid (by the example of carbon) inclusion in hot (from 800 K to 1500 K) gases were investigated by the developed models of heat and mass transfer. We defined the limited conditions, characteristics of the droplet and the gas medium which are sufficient for implementing the "explosive" destruction of heterogeneous droplet due to intensive vaporization on an inner interface, and intensive evaporation of liquid from an external (free) droplet surface. The values of the main characteristic of the process (period from start of heating to "explosive" destruction) obtained in response to using various heat and mass transfer models were compared.

  9. Current Approaches for Improving Intratumoral Accumulation and Distribution of Nanomedicines

    PubMed Central

    Durymanov, Mikhail O; Rosenkranz, Andrey A; Sobolev, Alexander S

    2015-01-01

    The ability of nanoparticles and macromolecules to passively accumulate in solid tumors and enhance therapeutic effects in comparison with conventional anticancer agents has resulted in the development of various multifunctional nanomedicines including liposomes, polymeric micelles, and magnetic nanoparticles. Further modifications of these nanoparticles have improved their characteristics in terms of tumor selectivity, circulation time in blood, enhanced uptake by cancer cells, and sensitivity to tumor microenvironment. These “smart” systems have enabled highly effective delivery of drugs, genes, shRNA, radioisotopes, and other therapeutic molecules. However, the resulting therapeutically relevant local concentrations of anticancer agents are often insufficient to cause tumor regression and complete elimination. Poor perfusion of inner regions of solid tumors as well as vascular barrier, high interstitial fluid pressure, and dense intercellular matrix are the main intratumoral barriers that impair drug delivery and impede uniform distribution of nanomedicines throughout a tumor. Here we review existing methods and approaches for improving tumoral uptake and distribution of nano-scaled therapeutic particles and macromolecules (i.e. nanomedicines). Briefly, these strategies include tuning physicochemical characteristics of nanomedicines, modulating physiological state of tumors with physical impacts or physiologically active agents, and active delivery of nanomedicines using cellular hitchhiking. PMID:26155316

  10. Factors Controlling the Pharmacokinetics, Biodistribution and Intratumoral Penetration of Nanoparticles

    PubMed Central

    Ernsting, Mark J.; Murakami, Mami; Roy, Aniruddha; Li, Shyh-Dar

    2014-01-01

    Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided. PMID:24075927

  11. Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

    PubMed Central

    Diaz-Cano, Salvador J.

    2012-01-01

    Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning. PMID:22408433

  12. Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development

    PubMed Central

    Blakeley, Jaishri; Portnow, Jana

    2014-01-01

    Importance of the field: Many promising targeted agents and combination therapies are being investigated for brain cancer. However, the results from recent clinical trials have been disappointing. A better understanding of the disposition of drug in the brain early in drug development would facilitate appropriate channeling of new drugs into brain cancer clinical trials. Areas covered in this review: Barriers to successful drug activity against brain cancer and issues affecting intratumoral drug concentrations are reviewed. The use of the microdialysis technique for extracellular fluid (ECF) sampling and its application to drug distribution studies in brain are reviewed using published literature from 1995 to the present. The benefits and limitations of microdialysis for performing neuorpharmacokinetic (nPK) and neuropharmacodynamic (nPD) studies are discussed. What the reader will gain: The reader will gain an appreciation of the challenges involved in identifying agents likely to have efficacy in brain cancer, an understanding of the general principles of microdialysis, and the power and limitations of using this technique in early drug development for brain cancer therapies. Take home message: A major factor preventing efficacy of anti-brain cancer drugs is limited access to tumor. Intracerebral microdialysis allows sampling of drug in the brain ECF. The resulting nPK/nPD data can aid in the rational selection of drugs for investigation in brain tumor clinical trials. PMID:20969450

  13. An Efficient Referencing And Sample Positioning System To Investigate Heterogeneous Substances With Combined Microfocused Synchrotron X-ray Techniques

    SciTech Connect

    Spangenberg, Thomas; Goettlicher, Joerg; Steininger, Ralph

    2009-01-29

    A referencing and sample positioning system has been developed to transfer object positions measured with an offline microscope to a synchrotron experimental station. The accuracy should be sufficient to deal with heterogeneous samples on micrometer scale. Together with an online fluorescence mapping visualisation the optical alignment helps to optimize measuring procedures for combined microfocused X-ray techniques.

  14. Investigating the Heterogeneous Interaction of VOCs with Natural Atmospheric Particles: Adsorption of Limonene and Toluene on Saharan Mineral Dusts.

    PubMed

    Romanías, Manolis N; Ourrad, Habib; Thévenet, Frédéric; Riffault, Véronique

    2016-03-01

    The heterogeneous interaction of limonene and toluene with Saharan dusts was investigated under dark conditions, pressure of 1 atm, and temperature 293 K. The mineral dust samples were collected from six different regions along the Sahara desert, extending from Tunisia to the western Atlantic coastal areas of Morocco, and experiments were carried out with the smallest sieved fractions, that is, inferior to 100 μm. N2 sorption measurements, granulometric analysis, and X-ray fluorescence and diffraction (XRF and XRD) measurements were conducted to determine the physicochemical properties of the particles. The chemical characterization showed that dust originating from mideastern Sahara has a significantly higher SiO2 content (∼ 82%) than dust collected from the western coastal regions where the SiO2 relative abundance was ∼ 50%. A novel experimental setup combining diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), selected-ion flow-tube mass spectrometry (SIFT-MS), and long path transmission Fourier transform infrared spectroscopy (FTIR) allowed us to follow both the adsorbed and gas phases. The kinetic adsorption/desorption measurements were performed using purified dry air as bath gas, exposing each dust surface to 10 ppm of the selective volatile organic compound (VOC). The adsorption of limonene was independent of the SiO2 content, given the experimental uncertainties, and the coverage measurements ranged between (10 and 18) × 10(13) molecules cm(-2). Experimental results suggest that other metal oxides that could possibly influence dust acidity may enhance the adsorption of limonene. On the contrary, in the case of toluene, the adsorption capacities of the Saharan samples increased with decreasing SiO2 content; however, the coverage measurements were significantly lower than those of limonene and ranged between (2 and 12) × 10(13) molecules cm(-2). Flushing the surface with purified dry air showed that VOC desorption is not a

  15. Radiofrequency Ablation Before Intratumoral Injection of 131I-chTNT Improves the Tumor-to-Normal Tissue Ratio in Solid VX2 Tumor

    PubMed Central

    Zheng, Shu-Guang; Lu, Ming-De; Yue, Dian-Chao; Xie, Xiao-Yan; Liu, Guang-Jian

    2013-01-01

    Abstract Purpose This study was aimed to investigate whether the tumor necrosis induced by radiofrequency ablation (RFA) can improve the ratio of tumor-to-normal tissue (T/NT) after intratumoral injection of 131I-chTNT. Materials and Method Eighteen New Zealand rabbits bearing VX2 tumor on the thigh were randomly divided into two treatment groups (control group: intratumoral injection of 131I-chTNT alone; RFA group: RFA + intratumoral injection of 131I-chTNT 3 days after RFA) and each group was further divided into three subgroups I, II, and III (1–2 cm, 2–3 cm, and 3–4 cm in maximum diameter, respectively), by the tumor size. SPECT was performed to evaluate the T/NT on days 1, 8, and 15 after 131I-chTNT injection. Results After treatment, all rabbits underwent the SPECT whole-body scan and the T/NT was analyzed. The results showed that T/NT in the RFA group (55.45±41.83) was significantly higher compared with the control group (7.23±5.61) (F=18.89, p=0.001). Meanwhile, a linear ascending trend was found for T/NT in the RFA group along with the follow-up time (r=0.47, p=0.01). The tumor size or the dose of 131I-TNT injection had no significant effect on the variation of T/NT in both groups (p>0.05). Conclusion RFA before intratumoral injection of 131I-chTNT can dramatically improve T/NT, demonstrating the potential application of this combination therapy. PMID:23964639

  16. The prognostic advantage of preoperative intratumoral injection of OK-432 for gastric cancer patients

    PubMed Central

    Gochi, A; Orita, K; Fuchimoto, S; Tanaka, N; Ogawa, N

    2001-01-01

    To investigate, by a multi-institutional randomized trial, the prognostic significance of the augmentation of tumour-infiltrating lymphocytes (TILs) by preoperative intratumoral injection of OK-432 (OK-432 it), a bacterial biological response modifier, in patients with gastric cancer. The 10-year survival and disease-free survival were examined and analysis of the factors showing survival benefit was performed. 370 patients who had undergone curative resection of gastric cancer were enrolled in this study and followed up for 10 years postoperatively. Patients were randomized into either an OK-432 it group or a control group. Ten Klinishe Einheit (KE) of OK-432 was endoscopically injected at 1 to 2 weeks before the operation in the OK-432 it group. Both groups received the same adjuvant chemoimmunotherapy consisting of a bolus injection of mitomycin C (0.4 mg kg−1i.v.) and administration of tegafur and OK-432 from postoperative day 14 up to 1 year later. Tegafur (600 mg day−1) was given orally and OK-432 (5 KE/2 weeks) was injected intradermally for a maintenance therapy. The TILs grades in resected tumour specimens and presence of metastasis and metastatic pattern in dissected lymph nodes were examined. Multivariate analysis was performed to determine the efficacy of OK-432 it on prognostic factors. All patients were followed up for 10 years. The overall 5- and 10-year survival rates and disease-free survival rates of the OK-432 it group were not significantly higher than those of the control group. However, OK-432 it significantly increased the 5- and 10-year survival rates of patients with stage IIIA + IIIB, moderate lymph node metastasis (pN2), and positive TILs. OK-432 it was most effective at prolonging the survival of patients who had both positive TILs and lymph node metastasis. The OK-432 it group with positive TILs showed a significant decrease in metastatic lymph node frequency and in the number of lymph node micro- metastatic foci when compared to

  17. Intratumoral application of standardized mistletoe extracts down regulates tumor weight via decreased cell proliferation, increased apoptosis and necrosis in a murine model.

    PubMed

    Beuth, J; Ko, H L; Schneider, H; Tawadros, S; Kasper, H U; Zimst, H; Schierholz, J M

    2006-01-01

    The cytotoxic in vitro activity of standardized mistletoe extracts (ME) was examined by established assays towards the human ductal breast carcinoma cell line BT474. A dose-dependent (optimum 25 mg/mL medium) and significantly (p < 0.05) enhanced cytotoxic activity towards the BT474 cells was demonstrated. In vivo experiments on the antitumor activity of ME-A and ME-M were performed in a BALB/c-mouse / BT474 ductal breast carcinoma model. ME-A and ME-M were intratumorally administered according to an application schedule which was found to be optimal concerning dosage and time of administration. Standardized intratumoral application of ME-A and ME-M induced a significantly (p < 0.05) decreased tumor weight in experimental mice. Histological investigations were performed comprising analysis of mitosis and proliferation rates (Ki67 expression), as well as necrosis and apoptosis induction (ssDNA detection). As compared to tumors of control mice with intratumoral phosphate-buffered saline (PBS) injections, tumors of the ME-A and ME-M treated groups showed a decreased cell proliferation rate, as well as an increased cell necrosis and apoptosis rate. Standardized mistletoe extracts, interfering with defined tumor cell functions, e.g., proliferation, necrosis and apoptosis, may have an impact on local cancer treatment. PMID:17201168

  18. HIF-1alpha Expression Profile in Intratumoral and Peritumoral Inflammatory Cells as a Prognostic Marker for Squamous Cell Carcinoma of the Oral Cavity

    PubMed Central

    Mendes, Suzanny Oliveira; dos Santos, Marcelo; Peterle, Gabriela Tonini; Maia, Lucas de Lima; Stur, Elaine; Agostini, Lidiane Pignaton; de Carvalho, Marcos Brasilino; Tajara, Eloiza Helena; Louro, Iúri Drumond; Trivilin, Leonardo Oliveira; da Silva-Conforti, Adriana Madeira Álvares

    2014-01-01

    The HIF-1 transcriptional complex is responsible for controlling transcription of over 100 genes involved in cell hypoxia response. HIF-1alpha subunit is stabilized in hypoxia conditions, creating the HIF-1 nuclear transcription factor. In inflammatory cells, high HIF-1alpha expression induces lymphocytic immunosuppression, decreasing tumoral antigen recognition, which promotes tumor growth. The present work investigated the relationship between HIF-1alpha expression in lymphocytes populating the intratumoral and peritumoral region of 56 patients with oral cancer. Our data indicates a prognostic value for this expression. High HIF-1alpha expression in peritumoral inflammatory cells is significantly related to worse patient outcome, whereas high expression in the intratumoral lymphoid cells correlates with a better prognosis. A risk profile indicating the chance of disease relapse and death was designed based on HIF-1alpha expression in tumoral inflammatory cells, defining low, intermediate and high risks. This risk profile was able to determine that high HIF-1alpha expression in peritumoral cells correlates with worse prognosis, independently of intratumoral expression. Low HIF-1alpha in tumor margins and high expression in the tumor was considered a low risk profile, showing no cases of disease relapse and disease related death. Intermediate risk was associated with low expression in tumor and tumor margins. Our results suggest that HIF-1alpha expression in tumor and peritumoral inflammatory cells may play an important role as prognostic tumor marker. PMID:24416312

  19. Application of a proapoptotic peptide to intratumorally spreading cancer therapy

    PubMed Central

    Chen, Renwei; Braun, Gary B; Luo, Xiuquan; Sugahara, Kazuki N.; Teesalu, Tambet; Ruoslahti, Erkki

    2013-01-01

    Bit1 is a pro-apoptotic mitochondrial protein associated with anoikis. Upon cell detachment, Bit1 is released into the cytoplasm and triggers caspase-independent cell death. Bit1 consists of 179 amino acids; the C-terminal two thirds of the molecule functions as a peptidyl-tRNA hydrolase, while the N-terminus contains a mitochondrial localization signal. Here, we localize the cell death domain (CDD) to the N-terminal 62 amino acids of Bit1 by transfecting cells with truncated Bit1 cDNA constructs. CDD was more potent in killing cells than the full-length Bit1 protein when equivalent amounts of cDNA were transfected. To develop Bit1 CDD into a cancer therapeutic we engineered a recombinant protein consisting of the CDD fused to iRGD, which is a tumor-specific peptide with unique tumor-penetrating and cell-internalizing properties. iRGD-CDD internalized into cultured tumor cells through a neuropilin-1-activated pathway and triggered cell death. Importantly, iRGD-CDD spread extensively within the tumor when injected intratumorally into orthotopically implanted breast tumors in mice. Repeated treatment with iRGD-CDD strongly inhibited tumor growth, resulting in an average reduction of 77% in tumor volume and eradication of some tumors. The caspase independence of Bit1-induced cell death makes CDD a potentially attractive anti-cancer agent because tumor resistance to the main mechanisms of apoptosis is circumvented. Using iRGD to facilitate the spreading of a therapeutic agent throughout the tumor mass may be a useful adjunct to local therapy of tumors that are surgically inoperable or difficult to treat systemically. PMID:23248118

  20. Application of normal mode theory to seismic source and structure problems: Seismic investigations of upper mantle lateral heterogeneity. Ph.D. Thesis

    NASA Technical Reports Server (NTRS)

    Okal, E. A.

    1978-01-01

    The theory of the normal modes of the earth is investigated and used to build synthetic seismograms in order to solve source and structural problems. A study is made of the physical properties of spheroidal modes leading to a rational classification. Two problems addressed are the observability of deep isotropic seismic sources and the investigation of the physical properties of the earth in the neighborhood of the Core-Mantle boundary, using SH waves diffracted at the core's surface. Data sets of seismic body and surface waves are used in a search for possible deep lateral heterogeneities in the mantle. In both cases, it is found that seismic data do not require structural differences between oceans and continents to extend deeper than 250 km. In general, differences between oceans and continents are found to be on the same order of magnitude as the intrinsic lateral heterogeneity in the oceanic plate brought about by the aging of the oceanic lithosphere.

  1. Comparison of circulating and intratumoral regulatory T cells in patients with renal cell carcinoma.

    PubMed

    Asma, Gati; Amal, Gorrab; Raja, Marrakchi; Amine, Derouiche; Mohammed, Chebil; Amel, Ben Ammar Elgaaied

    2015-05-01

    The clear evidence that tumor-infiltrating lymphocytes (TIL) exists in the tumor microenvironment raises the question why renal cell carcinoma (RCC) progresses. Numerous studies support the implication of CD4(+)CD25(high) regulatory T (Treg) cells in RCC development. We aimed in this study to characterize the phenotype and function of circulating and intratumoral Treg cells of RCC patient in order to evaluate their implication in the inhibition of the local antitumor immune response. Our results demonstrate that the proportion of Treg in TIL was, in average, similar to that found in circulating CD4(+) T cells of patients or healthy donors. However, intratumoral Treg exhibit a marked different phenotype when compared with the autologous circulating Treg. A higher CD25 mean level, HLA-DR, Fas, and GITR, and a lower CD45RA expression were observed in intratumoral Treg, suggesting therefore that these cells are effector in the tumor microenvironment. Additionally, intratumoral Treg showed a higher inhibitory function on autologous CD4(+)CD25(-) T cells when compared with circulating Treg that may be explained by an overexpression of FoxP3 transcription factor. These findings suggest that intratumoral Treg could be major actors in the impairment of local antitumor immune response for RCC patients. PMID:25563193

  2. Investigation of interaction between the Pt(II) ions and aminosilane-modified silica surface in heterogeneous system

    NASA Astrophysics Data System (ADS)

    Nowicki, Waldemar; Gąsowska, Anna; Kirszensztejn, Piotr

    2016-05-01

    UV-vis spectroscopy measurements confirmed the reaction in heterogeneous system between Pt(II) ions and ethylenediamine type ligand, n-(2-aminoethyl)-3-aminopropyl-trimethoxysilane, immobilized at the silica surface. The formation of complexes is a consequence of interaction between the amine groups from the ligand grafted onto SiO2 and ions of platinum. A potentiometric titration technique was to determine the stability constants of complexes of Pt(II) with immobilized insoluble ligand (SG-L), on the silica gel. The results show the formation of three surface complexes of the same type (PtHSG-L, Pt(HSG-L)2, PtSG-L) with SG-L ligand, in a wide range of pH for different Debye length. The concentration distribution of the complexes in a heterogeneous system is evaluated.

  3. Endogenous molecular network reveals two mechanisms of heterogeneity within gastric cancer

    PubMed Central

    Li, Site; Zhu, Xiaomei; Liu, Bingya; Wang, Gaowei; Ao, Ping

    2015-01-01

    Intratumor heterogeneity is a common phenomenon and impedes cancer therapy and research. Gastric cancer (GC) cells have generally been classified into two heterogeneous cellular phenotypes, the gastric and intestinal types, yet the mechanisms of maintaining two phenotypes and controlling phenotypic transition are largely unknown. A qualitative systematic framework, the endogenous molecular network hypothesis, has recently been proposed to understand cancer genesis and progression. Here, a minimal network corresponding to such framework was found for GC and was quantified via a stochastic nonlinear dynamical system. We then further extended the framework to address the important question of intratumor heterogeneity quantitatively. The working network characterized main known features of normal gastric epithelial and GC cell phenotypes. Our results demonstrated that four positive feedback loops in the network are critical for GC cell phenotypes. Moreover, two mechanisms that contribute to GC cell heterogeneity were identified: particular positive feedback loops are responsible for the maintenance of intestinal and gastric phenotypes; GC cell progression routes that were revealed by the dynamical behaviors of individual key components are heterogeneous. In this work, we constructed an endogenous molecular network of GC that can be expanded in the future and would broaden the known mechanisms of intratumor heterogeneity. PMID:25962957

  4. [Investigation of molecular-genetic heterogeneity of clematis plants (Clematis L.) obtained by organogenesis and somatic embryogenesis in vitro].

    PubMed

    Mitrofanova, I V; Galaev, A V; Sivolap, Iu M

    2003-01-01

    Genome variability of in vitro micropropagated Clematis plants was established. The optimum concentrations of BAP and zeatin in the culture medium regulating in vitro morphogenetic processes in clematis explants cv. Serenada Kryma were determined. Molecular-genetic analysis of Clematis plants obtained via in vitro somatic embryogenesis and organogenesis was carried out. Using ISSR primers 105 amplicons have been revealed, six of them were polymorphic. The mean index of heterogeneity of clematis plants was 5.7%. PMID:15067940

  5. Investigating the influence of aquifer heterogeneity on the potential for thermal free convection in the Yarragadee Aquifer, Western Australia

    NASA Astrophysics Data System (ADS)

    Irvine, Dylan J.; Sheldon, Heather A.; Simmons, Craig T.; Werner, Adrian D.; Griffiths, Cedric M.

    2015-02-01

    The potential for thermal convection in aquifers is strongly influenced by permeability. Permeability is highly heterogeneous within aquifers, and spatial distributions of permeability are rarely well constrained by measurements, making it difficult to determine the potential for thermal convection in a given aquifer. In this study, this difficulty is overcome through the use of a stratigraphic forward model (SFM). The SFM simulates the processes of deposition, burial and compaction of the aquifer, yielding a geologically plausible permeability field that is conditioned through measured permeability-porosity relationships. The aim of this study is to determine the influence of aquifer heterogeneity on the potential for thermal convection in the Yarragadee Aquifer, Western Australia. Permeability distributions from the SFM of the Yarragadee Aquifer are analysed through calculation of the thermal Rayleigh number (a stability criterion) from vertically averaged permeability, and numerical hydrothermal simulations with permeability distributions taken from the SFM. Results from the numerical simulations demonstrate that thermal convection can occur with the inclusion of geologically informed heterogeneity. These findings are supported by Rayleigh number calculations that indicate that convection is most likely to occur on the eastern side of the aquifer where it is thick and has high average permeability.

  6. Translational Implications of Tumor Heterogeneity

    PubMed Central

    Jamal-Hanjani, Mariam; Quezada, Sergio A.; Larkin, James; Swanton, Charles

    2015-01-01

    Advances in next-generation sequencing and bioinformatics have led to an unprecedented view of the cancer genome and its evolution. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins, and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression and the risk of disease relapse. However, the significance of subclonal mutations, in particular mutations in driver genes, and their evolution through time and their dynamics in response to cancer therapies, is yet to be determined. The necessary tools are now available to prospectively determine whether clonal heterogeneity can be used as a biomarker of clinical outcome, and to what extent subclonal somatic alterations might influence clinical outcome. Studies that employ longitudinal tissue sampling, integrating both genomic and clinical data, have the potential to reveal the subclonal composition and track the evolution of tumors in order to address these questions, and to begin to define the breadth of genetic diversity in different tumor types, and its relevance to patient outcome. Such studies may provide further evidence for novel drug resistance mechanisms informing novel combinatorial, adaptive and tumour immune-therapies placed within the context of tumor evolution. PMID:25770293

  7. Acute brainstem compression by intratumoral hemorrhages in an intracranial hypoglossal schwannoma.

    PubMed

    Inoue, Hiromasa; Nakagawa, Yasuhisa; Ikemura, Mayumi; Usugi, Eri; Kiyofuji, Yuma; Nata, Masayuki

    2013-09-01

    A 77-year-old female in the hospital was found tachycardic and hypothermic by a nurse, and the patient's respiration subsequently ceased. Forensic autopsy revealed an intracranial cystic tumor that would have compressed the brainstem. On microscopic examination, the tumor was diagnosed as an Antoni A schwannoma growth, and recent multiple intratumoral hemorrhages in the intracranial schwannoma were observed, suggesting the sudden enlargement of the intracranial schwannoma due to intratumoral hemorrhaging. Accordingly, we diagnosed the cause of death as brainstem compression induced by the intratumoral hemorrhaging in the intracranial schwannoma. Meanwhile, a rhinopharyngeal tumor was also detected by the autopsy, which was compatible with an antemortem diagnosis of a dumbbell-shaped hypoglossal schwannoma. PMID:23541888

  8. Intratumoral iron oxide nanoparticle hyperthermia and radiation cancer treatment

    NASA Astrophysics Data System (ADS)

    Hoopes, P. J.; Strawbridge, R. R.; Gibson, U. J.; Zeng, Q.; Pierce, Z. E.; Savellano, M.; Tate, J. A.; Ogden, J. A.; Baker, I.; Ivkov, R.; Foreman, A. R.

    2007-02-01

    The potential synergism and benefit of combined hyperthermia and radiation for cancer treatment is well established, but has yet to be optimized clinically. Specifically, the delivery of heat via external arrays /applicators or interstitial antennas has not demonstrated the spatial precision or specificity necessary to achieve appropriate a highly positive therapeutic ratio. Recently, antibody directed and possibly even non-antibody directed iron oxide nanoparticle hyperthermia has shown significant promise as a tumor treatment modality. Our studies are designed to determine the effects (safety and efficacy) of iron oxide nanoparticle hyperthermia and external beam radiation in a murine breast cancer model. Methods: MTG-B murine breast cancer cells (1 x 106) were implanted subcutaneous in 7 week-old female C3H/HeJ mice and grown to a treatment size of 150 mm3 +/- 50 mm3. Tumors were then injected locally with iron oxide nanoparticles and heated via an alternating magnetic field (AMF) generator operated at approximately 160 kHz and 400 - 550 Oe. Tumor growth was monitored daily using standard 3-D caliper measurement technique and formula. specific Mouse tumors were heated using a cooled, 36 mm diameter square copper tube induction coil which provided optimal heating in a 1 cm wide region in the center of the coil. Double dextran coated 80 nm iron oxide nanoparticles (Triton Biosystems) were used in all studies. Intra-tumor, peri-tumor and rectal (core body) temperatures were continually measured throughout the treatment period. Results: Preliminary in vivo nanoparticle-AMF hyperthermia (167 KHz and 400 or 550 Oe) studies demonstrated dose responsive cytotoxicity which enhanced the effects of external beam radiation. AMF associated eddy currents resulted in nonspecific temperature increases in exposed tissues which did not contain nanoparticles, however these effects were minor and not injurious to the mice. These studies also suggest that iron oxide nanoparticle

  9. A new ghost-node method for linking different models and initial investigations of heterogeneity and nonmatching grids

    USGS Publications Warehouse

    Dickinson, J.E.; James, S.C.; Mehl, S.; Hill, M.C.; Leake, S.A.; Zyvoloski, G.A.; Faunt, C.C.; Eddebbarh, A.-A.

    2007-01-01

    A flexible, robust method for linking parent (regional-scale) and child (local-scale) grids of locally refined models that use different numerical methods is developed based on a new, iterative ghost-node method. Tests are presented for two-dimensional and three-dimensional pumped systems that are homogeneous or that have simple heterogeneity. The parent and child grids are simulated using the block-centered finite-difference MODFLOW and control-volume finite-element FEHM models, respectively. The models are solved iteratively through head-dependent (child model) and specified-flow (parent model) boundary conditions. Boundary conditions for models with nonmatching grids or zones of different hydraulic conductivity are derived and tested against heads and flows from analytical or globally-refined models. Results indicate that for homogeneous two- and three-dimensional models with matched grids (integer number of child cells per parent cell), the new method is nearly as accurate as the coupling of two MODFLOW models using the shared-node method and, surprisingly, errors are slightly lower for nonmatching grids (noninteger number of child cells per parent cell). For heterogeneous three-dimensional systems, this paper compares two methods for each of the two sets of boundary conditions: external heads at head-dependent boundary conditions for the child model are calculated using bilinear interpolation or a Darcy-weighted interpolation; specified-flow boundary conditions for the parent model are calculated using model-grid or hydrogeologic-unit hydraulic conductivities. Results suggest that significantly more accurate heads and flows are produced when both Darcy-weighted interpolation and hydrogeologic-unit hydraulic conductivities are used, while the other methods produce larger errors at the boundary between the regional and local models. The tests suggest that, if posed correctly, the ghost-node method performs well. Additional testing is needed for highly

  10. Ionic arrest of segmental motion and emergence of spatio-temporal heterogeneity: A fluorescence investigation of (polyethylene glycol + electrolyte) composites

    NASA Astrophysics Data System (ADS)

    Guchhait, Biswajit; Biswas, Ranjit

    2013-03-01

    Temperature dependent steady state and time resolved fluorescence measurements have been performed to explore the interaction and dynamics in polymer-electrolyte composite of the following general formula: [0.85 PEG + 0.15{f KNO3+ (1-f) LiNO3}], with f denoting fraction of potassium ion in the 0.15 mol electrolyte present in the medium. Poly(ethylene glycol) with number-averaged molecular weight of 300 (PEG300) has been employed as polymer and C153 as the fluorescent probe. Substantial excitation wavelength dependence of probe fluorescence emission in presence of electrolyte suggests presence of spatial heterogeneity which vanishes either upon raising temperature or removing the electrolyte. This has been interpreted as arising from the cation-induced arrest of polymer segmental motion. Temporal heterogeneity in these composites is manifested via fractional viscosity dependence of average solvation and rotation rates of the dissolved probe. Viscosity decoupling of these rates in composites is found to depend on cation identity and is also reflected via the corresponding activation energies. The degree of decoupling differs between solvation and rotation, inducing an analogy to the observations made in deeply supercooled liquids. In addition, conformity to hydrodynamic predictions is recovered by measuring f dependent solute rotation at higher temperatures. Several complimentary but different experiments are suggested to re-examine the mechanism proposed here, based on the fluorescence results, for the emergence of spatio-temporal heterogeneity in these composites and its disappearance either in the absence of any electrolyte or at higher temperatures.

  11. Zebrafish as a model to assess cancer heterogeneity, progression and relapse

    PubMed Central

    Blackburn, Jessica S.; Langenau, David M.

    2014-01-01

    Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays. PMID:24973745

  12. Investigation of network heterogeneities in filled, trimodal, highly functional PDMS networks by 1H Multiple Quantum NMR

    SciTech Connect

    Maxwell, R; Gjersing, E; Chinn, S; Giuliani, J; Herberg, J; Eastwood, E; Bowen, D; Stephens, T

    2007-03-20

    The segmental order and dynamics of polymer network chains in a filled, tri-modal silicone foam network have been studied by static 1H Multiple Quantum (MQ) NMR methods to gain insight into the structure property relationships. The foam materials were synthesized with two different types of crosslinks, with functionalities, {phi}, of 4 and near 60. The network chains were composed of distributions of high, low, and medium molecular weight chains. Crosslinking was accomplished by standard acid catalyzed reactions. MQ NMR methods have detected domains with residual dipolar couplings (<{Omega}{sub d}>) of near 4 kRad/s and 1 kRad/s assigned to (a) the shorter polymer chains and chains near the multifunctional (f=60) crosslinking sites and to (b) the longer polymer chains far from these sites. Three structural variables were systematically varied and the mechanical properties via compression and distributions of residual dipolar couplings measured in order to gain insight in to the network structural motifs that contribute significantly to the composite properties. The partitioning of and the average values of the residual dipolar couplings for the two domains were observed to be dependent on formulation variable and provided increased insight into the network structure of these materials which are unavailable from swelling and spin-echo methods. The results of this study suggest that the domains with high crosslink density contribute significantly to the high strain modulus, while the low crosslink density domains do not. This is in agreement with theories and experimental studies on silicone bimodal networks over the last 20 years. In-situ MQ-NMR of swollen sample suggests that the networks deform heterogeneously and non-affinely. The heterogeneity of the deformation process was observed to depend on the amount of the high functionality crosslinking site PMHS. The NMR experiments shown here provide increased ability to characterize multimodal networks of typical

  13. Experimental investigation of supercritical CO2 trapping mechanisms at the Intermediate Laboratory Scale in well-defined heterogeneous porous media

    SciTech Connect

    Trevisan, Luca; Pini, Ronny; Cihan, Abdullah; Birkholzer, Jens T.; Zhou, Quanlin; Illangasekare, Tissa H.

    2014-12-31

    The heterogeneous nature of typical sedimentary formations can play a major role in the propagation of the CO2 plume, eventually dampening the accumulation of mobile phase underneath the caprock. From core flooding experiments, it is also known that contrasts in capillary threshold pressure due to different pore size can affect the flow paths of the invading and displaced fluids and consequently influence the build- up of non-wetting phase (NWP) at interfaces between geological facies. The full characterization of the geologic variability at all relevant scales and the ability to make observations on the spatial and temporal distribution of the migration and trapping of supercritical CO2 is not feasible from a practical perspective. To provide insight into the impact of well-defined heterogeneous systems on the flow dynamics and trapping efficiency of supercritical CO2 under drainage and imbibition conditions, we present an experimental investigation at the meter scale conducted in synthetic sand reservoirs packed in a quasi-two-dimensional flow-cell. Two immiscible displacement experiments have been performed to observe the preferential entrapment of NWP in simple heterogeneous porous media. The experiments consisted of an injection, a fluid redistribution, and a forced imbibition stages conducted in an uncorrelated permeability field and a homogeneous base case scenario. We adopted x-ray attenuation analysis as a non-destructive technique that allows a precise measurement of phase saturations throughout the entire flow domain. By comparing a homogeneous and a heterogeneous scenario we have identified some important effects that can be attributed to capillary barriers, such as dampened plume advancement, higher non-wetting phase saturations, larger contact area between the injected and displaced phases, and a larger range of non-wetting phase saturations.

  14. Intratumoral expression of cyclooxygenase-2 (COX-2) is a negative prognostic marker for patients with cutaneous melanoma.

    PubMed

    Kuźbicki, Łukasz; Lange, Dariusz; Stanek-Widera, Agata; Chwirot, Barbara W

    2016-10-01

    Because of the well-known heterogeneity of melanomas, prognosis of the disease is often difficult to assess even for lesions classified in similar stages. The aim of this study was to assess the usefulness of COX-2 as a melanoma prognostic marker and to establish an optimum algorithm for analysis of COX-2 expression levels in lesions of interest. Expression of COX-2 was detected immunohistochemically in standard sections of formalin-fixed paraffin-embedded tissue samples of 85 primary melanomas, 36 lymph node metastases, and five skin metastases including 39 cases of paired primary and metastatic lesions obtained from the same patient. Enhanced expression of COX-2 in primary melanomas is an indicator of poorer prognosis. A significant correlation was found between high expression of COX-2 in primary lesions and shorter survival. The enhancement of COX-2 expression is also positively correlated with other prognostic factors such as tumor thickness and infiltration level, ulceration, high mitotic index, more invasive histologic type, vertical growth phase, and lymph node metastasis. On the whole, the results suggest that intratumoral expression of COX-2 is a strong negative prognostic marker for patients with melanoma. Moreover, our work shows that a simple and objective immunohistochemical scoring algorithm involving the determination of only a percentage fraction of positively stained cells is sufficient to obtain the prognostic information. PMID:27391144

  15. Hyaluronidase Expression by an Oncolytic Adenovirus Enhances Its Intratumoral Spread and Suppresses Tumor Growth

    PubMed Central

    Guedan, Sonia; Rojas, Juan José; Gros, Alena; Mercade, Elena; Cascallo, Manel; Alemany, Ramon

    2010-01-01

    Successful virotherapy requires efficient virus spread within tumors. We tested whether the expression of hyaluronidase, an enzyme which dissociates the extracellular matrix (ECM), could enhance the intratumoral distribution of an oncolytic adenovirus and improve its therapeutic activity. As a proof of concept, we demonstrated that intratumoral coadministration of hyaluronidase in mice-bearing tumor xenografts improves the antitumor activity of an oncolytic adenovirus. Next, we constructed a replication-competent adenovirus expressing a soluble form of the human sperm hyaluronidase (PH20) under the control of the major late promoter (MLP) (AdwtRGD-PH20). Intratumoral treatment of human melanoma xenografts with AdwtRGD-PH20 resulted in degradation of hyaluronan (HA), enhanced viral distribution, and induced tumor regression in all treated tumors. Finally, the PH20 cDNA was inserted in an oncolytic adenovirus that selectively kills pRb pathway-defective tumor cells. The antitumoral activity of the novel oncolytic adenovirus expressing PH20 (ICOVIR17) was compared to that of the parental virus ICOVIR15. ICOVIR17 showed more antitumor efficacy following intratumoral and systemic administration in mice with prestablished tumors, along with an improved spread of the virus within the tumor. Importantly, a single intravenous dose of ICOVIR17 induced tumor regression in 60% of treated tumors. These results indicate that ICOVIR17 is a promising candidate for clinical testing. PMID:20442708

  16. Vitamin D Enhances the Efficacy of Irinotecan through miR-627-Mediated Inhibition of Intratumoral Drug Metabolism.

    PubMed

    Sun, Meiyan; Zhang, Qunshu; Yang, Xiaoyu; Qian, Steven Y; Guo, Bin

    2016-09-01

    Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D-regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4-mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer cells. We show that calcitriol enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. When miR-627 is inhibited, calcitriol fails to enhance the activity of irinotecan. In addition, overexpression of miR-627 or siRNA knockdown of CYP3A4 enhanced the efficacy of irinotecan in growth inhibition and apoptosis induction. In contrast, overexpression of CYP3A4 abolished the effects of calcitriol on the activity of irinotecan. Using a nude mouse xenograft model, we demonstrated that calcitriol inhibited CYP3A4 and enhanced the in vivo antitumor activity of irinotecan without causing side effects. Our study identified a novel target for improving cancer therapy, i.e., modulating the intratumoral CYP3A4-mediated drug metabolism with vitamin D. This strategy could enhance the therapeutic efficacy without eliciting the side effects. Mol Cancer Ther; 15(9); 2086-95. ©2016 AACR. PMID:27458137

  17. PEG-rIL-10 treatment decreases FoxP3(+) Tregs despite upregulation of intratumoral IDO.

    PubMed

    Chan, Ivan H; Wu, Victoria; Bilardello, Melissa; Jorgenson, Brett; Bal, Harminder; McCauley, Scott; Van Vlasselaer, Peter; Mumm, John B

    2016-07-01

    IL-10 has been classically defined as a broad-spectrum immunosuppressant and is thought to facilitate the development of regulatory CD4(+) T cells. IL-10 is believed to represent one of the major suppressive factors secreted by IDO(+)FoxP3(+)CD4(+) Tregs. Contrary to this view, we have previously reported that PEGylated recombinant IL-10 (PEG-rIL-10) treatment of mice induces potent IFNγ and CD8(+) T-cell-dependent antitumor immunity. This hypothesis is currently being tested in clinical trials and we have reported that treatment of cancer patients with PEG-rHuIL-10 results in inhibition and regression of tumor growth as well as increased serum IFNγ. We have continued to assess PEG-rIL-10's pleiotropic effects and report that treatment of tumor-bearing mice and humans with PEG-rIL-10 increases intratumoral indoleamine 2, 3-dioxygenase (IDO) in an IFNγ-dependent manner. This should result in an increase in Tregs, but paradoxically our data illustrate that PEG-rIL-10 treatment of mice reduces intratumoral FoxP3(+)CD4(+) T cells in an IDO-independent manner. Additional investigation indicates that PEG-rIL-10 inhibits TGFβ/IL-2-dependent in vitro polarization of FoxP3(+)CD4(+) Tregs and potentiates IFNγ(+)T-bet(+)CD4(+) T cells. These data suggest that rather than acting as an immunosuppressant, PEG-rIL-10 may counteract the FoxP3(+)CD4(+) Treg suppressive milieu in tumor-bearing mice and humans, thereby further facilitating PEG-rIL-10's potent antitumor immunity. PMID:27622052

  18. Intratumoral Mistletoe (Viscum album L) Therapy in Patients With Unresectable Pancreas Carcinoma: A Retrospective Analysis.

    PubMed

    Schad, Friedemann; Atxner, Jan; Buchwald, Dirk; Happe, Antje; Popp, Stephan; Kröz, Matthias; Matthes, Harald

    2014-07-01

    Pancreatic carcinoma remains one of the main causes for cancer-related death. Intratumoral application of anticancer agents is discussed as a promising method for solid tumors such as pancreatic cancer. Endoscopic ultrasound provides a good tool to examine and treat the pancreas. European mistletoe (Viscum album L) is a phytotherapeutic commonly used in integrative oncology in Central Europe. Its complementary use seeks to induce immunostimulation and antitumoral effects as well as alleviate chemotherapeutic side effects. Intratumoral mistletoe application has induced local tumor response in various cancer entities. This off-label use needs to be validated carefully in terms of safety and benefits. Here we report on 39 patients with advanced, inoperable pancreatic cancer, who received in total 223 intratumoral applications of mistletoe, endoscopic ultrasound guided or under transabdominal ultrasound control. No severe procedure-related events were reported. Adverse drug reactions were mainly increased body temperature or fever in 14% and 11% of the applications, respectively. Other adverse drug reactions, such as pain or nausea, occurred in less than 7% of the procedures. No severe adverse drug reaction was recorded. Patients received standard first- and second-line chemotherapy and underwent adequate palliative surgical interventions as well as additive subcutaneous and partly intravenous mistletoe application. A median survival of 11 months was observed for all patients, or 11.8 and 8.3 months for stages III and IV, respectively. Due to the multimodal therapeutic setting and the lack of a control group, the effect of intratumoral mistletoe administration alone remains unclear. This retrospective analysis suggests that intratumoral-applicated mistletoe might contribute to improve survival of patients with pancreatic cancer. In conclusion, the application is feasible and safe, and its efficacy should be evaluated in a randomized controlled trial. PMID:24363283

  19. Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor.

    PubMed

    Mukerji, Ratul; Schaal, Jeffrey; Li, Xinghai; Bhattacharyya, Jayanta; Asai, Daisuke; Zalutsky, Michael R; Chilkoti, Ashutosh; Liu, Wenge

    2016-02-01

    In an attempt to spatiotemporally control both tumor retention and the coverage of anticancer agents, we developed a photoradiation-controlled intratumoral depot (PRCITD) driven by convection enhanced delivery (CED). This intratumoral depot consists of recombinant elastin-like polypeptide (ELP) containing periodic cysteine residues and is conjugated with a photosensitizer, chlorin-e6 (Ce6) at the N-terminus of the ELP. We hypothesized that this cysteine-containing ELP (cELP) can be readily crosslinked through disulfide bonds upon exposure to oxidative agents, specifically the singlet oxygen produced during photodynamic stimulation. Upon intratumoral injection, CED drives the distribution of the soluble polypeptide freely throughout the tumor interstitium. Formation and retention of the depot was monitored using fluorescence molecular tomography imaging. When imaging shows that the polypeptide has distributed throughout the entire tumor, 660-nm light is applied externally at the tumor site. This photo-radiation wavelength excites Ce6 and generates reactive oxygen species (ROS) in the presence of oxygen. The ROS induce in situ disulfide crosslinking of the cysteine thiols, stabilizing the ELP biopolymer into a stable therapeutic depot. Our results demonstrate that this ELP design effectively forms a hydrogel both in vitro and in vivo. These depots exhibit high stability in subcutaneous tumor xenografts in nude mice and significantly improved intratumoral retention compared to controls without crosslinking, as seen by fluorescent imaging and iodine-125 radiotracer studies. The photodynamic therapy provided by the PRCITD was found to cause significant tumor inhibition in a Ce6 dose dependent manner. Additionally, the combination of PDT and intratumoral radionuclide therapy co-delivered by PRCITD provided a greater antitumor effect than either monotherapy alone. These results suggest that the PRCITD could provide a stable platform for delivering synergistic, anti

  20. Structural and functional investigation of graphene oxide–Fe3O4 nanocomposites for the heterogeneous Fenton-like reaction

    PubMed Central

    Zubir, Nor Aida; Yacou, Christelle; Motuzas, Julius; Zhang, Xiwang; Diniz da Costa, João C.

    2014-01-01

    Graphene oxide–iron oxide (GO–Fe3O4) nanocomposites were synthesised by co-precipitating iron salts onto GO sheets in basic solution. The results showed that formation of two distinct structures was dependent upon the GO loading. The first structure corresponds to a low GO loading up to 10 wt%, associated with the beneficial intercalation of GO within Fe3O4 nanoparticles and resulting in higher surface area up to 409 m2 g−1. High GO loading beyond 10 wt% led to the aggregation of Fe3O4 nanoparticles and the undesirable stacking of GO sheets. The presence of strong interfacial interactions (Fe-O-C bonds) between both components at low GO loading lead to 20% higher degradation of Acid Orange 7 than the Fe3O4 nanoparticles in heterogeneous Fenton-like reaction. This behaviour was attributed to synergistic structural and functional effect of the combined GO and Fe3O4 nanoparticles. PMID:24699690

  1. An investigation into the accuracy of Acuros(TM) BV in heterogeneous phantoms for a (192)Ir HDR source using LiF TLDs.

    PubMed

    Manning, Siobhan; Nyathi, Thulani

    2014-09-01

    The aim of this study was to evaluate the accuracy of the new Acuros(TM) BV algorithm using well characterized LiF:Mg,Ti TLD 100 in heterogeneous phantoms. TLDs were calibrated using an (192)Ir source and the AAPM TG-43 calculated dose. The Tölli and Johansson Large Cavity principle and Modified Bragg Gray principle methods confirm the dose calculated by TG-43 at a distance of 5 cm from the source to within 4 %. These calibrated TLDs were used to measure the dose in heterogeneous phantoms containing air, stainless steel, bone and titanium. The TLD results were compared with the AAPM TG-43 calculated dose and the Acuros calculated dose. Previous studies by other authors have shown a change in TLD response with depth when irradiated with an (192)Ir source. This TLD depth dependence was assessed by performing measurements at different depths in a water phantom with an (192)Ir source. The variation in the TLD response with depth in a water phantom was not found to be statistically significant for the distances investigated. The TLDs agreed with Acuros(TM) BV within 1.4 % in the air phantom, 3.2 % in the stainless steel phantom, 3 % in the bone phantom and 5.1 % in the titanium phantom. The TLDs showed a larger discrepancy when compared to TG-43 with a maximum deviation of 9.3 % in the air phantom, -11.1 % in the stainless steel phantom, -14.6 % in the bone phantom and -24.6 % in the titanium phantom. The results have shown that Acuros accounts for the heterogeneities investigated with a maximum deviation of -5.1 %. The uncertainty associated with the TLDs calibrated in the PMMA phantom is ±8.2 % (2SD). PMID:24866931

  2. Investigating the functional heterogeneity of the default mode network using coordinate-based meta-analytic modeling

    PubMed Central

    Laird, Angela R.; Eickhoff, Simon B.; Li, Karl; Robin, Donald A.; Glahn, David C.; Fox, Peter T.

    2010-01-01

    The default mode network (DMN) comprises a set of regions that exhibit ongoing, intrinsic activity in the resting state and task-related decreases in activity across a range of paradigms. However, DMN regions have also been reported as task-related increases, either independently or coactivated with other regions in the network. Cognitive subtractions and the use of low-level baseline conditions have generally masked the functional nature of these regions. Using a combination of activation likelihood estimation, which assesses statistically significant convergence of neuroimaging results, and tools distributed with the BrainMap database, we identified core regions in the DMN and examined their functional heterogeneity. Meta-analytic coactivation maps of task-related increases were independently generated for each region, which included both within-DMN and non-DMN connections. Their functional properties were assessed using behavioral domain metadata in BrainMap. These results were integrated to determine a DMN connectivity model that represents the patterns of interactions observed in task-related increases in activity across diverse tasks. Sub-network components of this model were identified, and behavioral domain analysis of these cliques yielded discrete functional properties, demonstrating that components of the DMN are differentially specialized. Affective and perceptual cliques of the DMN were identified, as well as the cliques associated with a reduced preference for motor processing. In summary, we used advanced coordinate-based meta-analysis techniques to explicate behavior and connectivity in the default mode network; future work will involve applying this analysis strategy to other modes of brain function, such as executive function or sensorimotor systems. PMID:19923283

  3. Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts

    PubMed Central

    Kemper, Kristel; Krijgsman, Oscar; Cornelissen-Steijger, Paulien; Shahrabi, Aida; Weeber, Fleur; Song, Ji-Ying; Kuilman, Thomas; Vis, Daniel J; Wessels, Lodewyk F; Voest, Emile E; Schumacher, Ton NM; Blank, Christian U; Adams, David J; Haanen, John B; Peeper, Daniel S

    2015-01-01

    The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAFV600E metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient’s melanoma. PMID:26105199

  4. αB-Crystallin: A Hybrid Solid-Solution State NMR Investigation Reveals Structural Aspects of the Heterogeneous Oligomer

    PubMed Central

    Jehle, Stefan; van Rossum, Barth; Stout, Joseph R.; Noguchi, Satoshi R.; Falber, Katja; Rehbein, Kristina; Oschkinat, Hartmut; Klevit, Rachel E.; Rajagopal, Ponni

    2009-01-01

    Summary Atomic level structural information on αB-Crystallin (αB), a prominent member of the small Heat Shock Protein (sHSP) family has been a challenge to obtain due its polydisperse, oligomeric nature. We show that magic-angle spinning solid-state NMR can be used to obtain high-resolution information on ∼ 580 kDa human αB assembled from 175-residue, 20 kDa subunits. An ∼100-residue α-crystallin domain is common to all sHSPs and solution-state NMR was performed on two different α-crystallin domain constructs isolated from αB. In vitro, the chaperone-like activities of full-length αB and the isolated α-crystallin domain are identical. Chemical shifts of the backbone and the Cβ resonances have been obtained for residues 64-162 (α-crystallin domain plus part of the C-terminus) in αB and the isolated α-crystallin domain by solid- and solution-state NMR, respectively. Both sets of data strongly predict six β-strands in the α-crystallin domain. A majority of residues in the α-crystallin domain have similar chemical shifts in both solid- and solution-state indicating a similar structure for the domain in its isolated and oligomeric forms. Sites of inter-subunit interaction are identified from chemical shift differences that cluster to specific regions of the α-crystallin domain. Multiple signals are observed for the resonances of M68 in the oligomer, identifying the region containing this residue as existing in heterogeneous environments within αB. Evidence for a novel dimerization motif in the human α-crystallin domain is obtained by a comparison of (i) solid- and solution-state chemical shift data and (ii) 1H-15N HSQC spectra as a function of pH. The isolated α-crystallin domain undergoes a dimer-monomer transition over the pH range of 7.5 to 6.8. This steep pH-dependent switch may be important for αB to function optimally, e.g., to preserve the filament integrity of cardiac muscle proteins such as actin and desmin during cardiac ischemia which

  5. αB-Crystallin. A Hybrid Solid-State/Solution-State NMR Investigation Reveals Structural Aspects of the Heterogeneous Oligomer

    SciTech Connect

    Jehle, Stefan; van Rossum, Barth; Stout, Joseph R.; Noguchi, Satoshi M.; Falber, Katja; Rehbein, Kristina; Oschkinat, Hartmut; Klevit, Rachel E.; Rajagopal, Ponni

    2008-11-14

    Atomic-level structural information on αB-Crystallin (αB), a prominent member of the small heat-shock protein family, has been a challenge to obtain due its polydisperse oligomeric nature. We show that magic-angle spinning solid-state NMR can be used to obtain high-resolution information on an ~580-kDa human αB assembled from 175-residue 20-kDa subunits. An ~100-residue α-crystallin domain is common to all small heat-shock proteins, and solution-state NMR was performed on two different α- crystallin domain constructs isolated from αB. In vitro, the chaperone-like activities of full-length αB and the isolated α-crystallin domain are identical. Chemical shifts of the backbone and Cβ resonances have been obtained for residues 64–162 (α-crystallin domain plus part of the C-terminus) in αB and the isolated α-crystallin domain by solid-state and solution-state NMR, respectively. Both sets of data strongly predict six β-strands in the α-crystallin domain. A majority of residues in the α-crystallin domain have similar chemical shifts in both solid-state and solution-state, indicating similar structures for the domain in its isolated and oligomeric forms. Sites of intersubunit interaction are identified from chemical shift differences that cluster to specific regions of the α-crystallin domain. Multiple signals are observed for the resonances of M68 in the oligomer, identifying the region containing this residue as existing in heterogeneous environments within αB. Evidence for a novel dimerization motif in the human α-crystallin domain is obtained by a comparison of (i) solid-state and solution-state chemical shift data and (ii) 1H–15N heteronuclear single quantum coherence spectra as a function of pH. The isolated α-crystallin domain undergoes a dimer–monomer transition over the pH range 7.5–6.8. This steep pHdependent switch may be important for αB to function optimally (e.g., to preserve the filament integrity

  6. Mitoxantrone-loaded albumin microspheres for localized intratumoral chemotherapy of breast cancer

    NASA Astrophysics Data System (ADS)

    Almond, Brett Anthony

    The safety and efficacy of conventional chemotherapy is limited by its toxicity. The direct intratumoral injection of free or microsphere-loaded antineoplastic drugs is a promising modality for the treatment of solid tumors. Intratumoral chemotherapy delivers high localized doses of cytotoxic drugs to the tumor tissues than does systemic (intravenous) chemotherapy and it decreases systemic drug concentrations and toxicities. The use of drug-loaded microspheres also provides a prolonged release of drug into the surrounding tumor tissues, increasing exposure of the neoplasm to therapeutic levels of the cytotoxic drug. Mitoxantrone and 5-fluorouracil-loaded albumin microspheres were synthesized. The microspheres were synthesized using a suspension crosslinking technique and a glutardehyde crosslinking agent. The particle-size distribution of the microspheres was controlled by adjusting the emulsion energy and the concentration of cellulose acetate butyrate, the emulsion stabilization agent. Both microsphere size and crosslink density (glutaraldehyde concentration) were found to affect the in vitro release of loaded drugs in in vitro infinite sink conditions. The in vivo efficacy and toxicity of intratumoral chemotherapy with free and microsphere-loaded mitoxantrone were evaluated in a 16/C murine mammary adenocarcinoma model. Intratumoral chemotherapy with free mitoxantrone significantly improved survival and decreased toxicity compared to intravenously delivered drug. The efficacy of two size distributions of mitoxantrone-loaded albumin microspheres, corresponding to mean diameters of 5 to 10 mum and 20 to 40 mum, were evaluated delivered both alone and in combination with free mitoxantrone. Intratumoral injection of mitoxantrone-loaded microspheres was found to allow the safe delivery of increased doses compared to free drug. The maximum tolerated doses were approximately 40 mg/kg compared to 12 mg/kg, respectively. Intratumoral chemotherapy using free and

  7. Decreased intratumoral Foxp3 Tregs and increased dendritic cell density by neoadjuvant chemotherapy associated with favorable prognosis in advanced gastric cancer

    PubMed Central

    Hu, Min; Li, Kai; Maskey, Ninu; Xu, Zhigao; Peng, Chunwei; Wang, Bicheng; Li, Yan; Yang, Guifang

    2014-01-01

    Although neoadjuvant chemotherapy (NACT) has been increasingly used to improve the outcome of advanced gastric cancer (GC) for decades, its precise efficacy has been difficult to evaluate yet. Abundant studies have investigated the predictive factors that represent the effect of NACT on advanced GC. In the present study, the intratumoral infiltration of regulatory T cells (Tregs) and dendritic cells (DCs) response to NACT in advanced GC and their correlation with prognosis were evaluated. Infiltration of Tregs (marked by Foxp3) and DCs (marked by S-100) in 102 advanced GC specimens with or without NACT was measured using immunohistochemical method. Intratumoral infiltration of Foxp3 Tregs was significantly lower and DC density was significantly higher in NACT group than that in nNACT group (P=0.007, P=0.002, respectively). Infiltration of Foxp3 Tregs was significantly associated with tumor invasion depth (P<0.001). The DC density was significantly correlated with histopathologic type (P=0.035), invasion depth (P=0.002), TNM stage (P=0.018), and lymph node metastasis (P<0.001). There was no significant difference of patient’s OS between NACT and nNACT groups (P=0.452); however, patients treated with NACT had longer OS with lower infiltration of Foxp3 Tregs (P<0.001) and higher infiltration of DCs (P=0.010). Univariate and multivariate analyses indicated that infiltration of Foxp3 Tregs and DCs were independent prognostic factors (P=0.002, P=0.003, respectively). The results demonstrated that NACT could decrease intratumoral Foxp3 Tregs infiltration and increase DCs density, and that infiltration of Foxp3 Tregs and DCs may serve as novel prognostic biomarkers of human GC. PMID:25197340

  8. Investigation Gender/Ethnicity Heterogeneity in Course Management System Use in Higher Education by Utilizing the MIMIC Model

    ERIC Educational Resources Information Center

    Li, Yi

    2012-01-01

    This study focuses on the issue of learning equity in colleges and universities where teaching and learning have come to depend heavily on computer technologies. The study uses the Multiple Indicators Multiple Causes (MIMIC) latent variable model to quantitatively investigate whether there is a gender /ethnicity difference in using computer based…

  9. Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis

    PubMed Central

    Natrajan, Rachael; Sailem, Heba; Mardakheh, Faraz K.; Arias Garcia, Mar; Tape, Christopher J.; Dowsett, Mitch; Bakal, Chris; Yuan, Yinyin

    2016-01-01

    Background The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters. Methods and Findings We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10−4, hazard ratio = 1.47, 95% CI 1.17–1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26–2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size. Conclusions To

  10. Heterogeneous expression of zinc-finger E-box-binding homeobox 1 plays a pivotal role in metastasis via regulation of miR-200c in epithelial-mesenchymal transition.

    PubMed

    Muto, Yuta; Suzuki, Koichi; Kato, Takaharu; Tsujinaka, Shingo; Ichida, Kosuke; Takayama, Yuji; Fukui, Taro; Kakizawa, Nao; Watanabe, Fumiaki; Saito, Masaaki; Futsuhara, Kazushige; Noda, Hiroshi; Miyakura, Yasuyuki; Konishi, Fumio; Rikiyama, Toshiki

    2016-09-01

    Although epithelial-mesenchymal transition (EMT) has been implicated as the pivotal event in metastasis, there is insufficient evidence related to EMT in clinical settings. Intratumor heterogeneity may lead to underestimation of gene expression representing EMT. In the present study, we investigated the expression of EMT-associated genes and microRNAs in primary colorectal cancer while considering intratumor heterogeneity. One-hundred and thirty-three multiple spatially separated samples were obtained from 8 patients with metastatic colorectal cancers and 8 with non-metastatic colorectal cancers, from the tumor center (TC), invasive front (IF) and metastasis. Differences in gene and microRNA expression were investigated by microarray and quantitative reverse-transcription PCR. Gene expression microarray analysis detected 7920 sites showing differing levels of gene expression among the TC, IF and metastasis. Expression of the EMT-associated gene zinc-finger E-box-binding homeobox 1 (ZEB1) significantly increased in the IF (p<0.01). To exclude individual differences, the expression ratio between TC and IF in each tumor was applied to analysis. This approach enabled recognition of the activation of the VEGF and Wnt signaling pathways, which were involved in metastasis via promotion of EMT. While no activation of these pathways was seen at the TC, regardless of whether tumors were metastatic or non-metastatic, they were preferentially activated at the IF in metastatic tumors, where high ZEB1 expression was seen in connection with decreased miR-200c expression. Multiple sampling in a tumor revealed that heterogeneous ZEB1 expression induced by EMT-associated signaling pathways played a pivotal role in metastasis via regulation of miR-200c. PMID:27315529

  11. Therapeutic effect of intratumoral administration of DCs with conditional expression of combination of different cytokines

    PubMed Central

    Huang, Chun; Ramakrishnan, Rupal; Trkulja, Marko; Ren, Xiubao

    2015-01-01

    In this study, we tested the effect of intratumoral administration of dendritic cells (DCs) with inducible expression of different cytokines, using the novel Rheoswitch Therapeutic System on the experimental models of renal cell cancer (RENCA) and MethA sarcoma. Intratumoral injection of DCs, engineered to express IL-12, IL-21, or IFN-α, showed potent therapeutic effect against established tumor. This effect was associated with the induction of potent tumor antigen-specific CD8+ T-cell responses, as well as the infiltration of tumors with CD4+ and CD8+ T cells but not with the cytotoxic activity of DCs. Combination of i.t. administration of DCs, producing different cytokines, did not enhance the antitumor effect of therapy with single cytokine. These results indicate that RTS can be a potent tool for conditional topical cytokine delivery, in combination with DC administration. However, combination of different cytokines may not necessarily improve the outcome of treatment. PMID:22223258

  12. Heterogeneity of KRAS Mutation Status in Rectal Cancer

    PubMed Central

    Jo, Peter; König, Alexander; Schirmer, Markus; Kitz, Julia; Conradi, Lena-Christin; Azizian, Azadeh; Bernhardt, Markus; Wolff, Hendrik A.; Grade, Marian; Ghadimi, Michael; Ströbel, Philipp; Schildhaus, Hans-Ulrich; Gaedcke, Jochen

    2016-01-01

    Introduction Anti-EGFR targeted therapy is of increasing importance in advanced colorectal cancer and prior KRAS mutation testing is mandatory for therapy. However, at which occasions this should be performed is still under debate. We aimed to assess in patients with locally advanced rectal cancer whether there is intra-specimen KRAS heterogeneity prior to and upon preoperative chemoradiotherapy (CRT), and if there are any changes in KRAS mutation status due to this intervention. Materials and Methods KRAS mutation status analyses were performed in 199 tumor samples from 47 patients with rectal cancer. To evaluate the heterogeneity between different tumor areas within the same tumor prior to preoperative CRT, 114 biopsies from 34 patients (mean 3 biopsies per patient) were analyzed (pre-therapeutic intratumoral heterogeneity). For the assessment of heterogeneity after CRT residual tumor tissue (85 samples) from 12 patients (mean 4.2 tissue samples per patient) were analyzed (post-therapeutic intratumoral heterogeneity) and assessment of heterogeneity before and after CRT was evaluated in corresponding patient samples (interventional heterogeneity). Primer extension method (SNaPshot™) was used for initial KRAS mutation status testing for Codon 12, 13, 61, and 146. Discordant results by this method were reevaluated by using the FDA-approved KRAS Pyro Kit 24, V1 and the RAS Extension Pyro Kit 24, V1 Kit (therascreen® KRAS test). Results For 20 (43%) out of the 47 patients, a KRAS mutation was detected. With 12 out of 20, the majority of these mutations affected codon 35. We did not obtained evidence that CRT results in changes of the KRAS mutation pattern. In addition, no intratumoral heterogeneity in the KRAS mutational status could be proven. This was true for both the biopsies prior to CRT and the resection specimens thereafter. The discrepancy observed in some samples when using the SNaPshot™ assay was due to insufficient sensitivity of this technique upon

  13. Intraoperative Intratumoral Embolization of a Complex Recurrent Hemangiopericytoma: Technical Report and Review of the Literature.

    PubMed

    Ryttlefors, Mats; Latini, Francesco; Basma, Jaafar; Krisht, Ali F

    2016-07-01

    Objective Recurrent brain tumors represent a challenge for neurosurgeons because of the extensive blood loss and the time needed for surgical resection. Only a few hemostatic agents are useful to prevent the bleeding and thus facilitate the surgical resection. Fibrin sealant can be used to achieve sealing, tissue adherence, or hemostasis when other means of hemostasis are inadequate or inappropriate. We report the feasibility and positive effects of direct intratumoral injection of fibrin sealant during resection of a recurrent hemangiopericytoma. Material and Methods The intraoperative intratumoral injection of fibrin sealant changed the tumor properties of a recurrent hemangiopericytoma of the tentorium with infra- and supratentorial extension. From a loose friable briskly bleeding tumor, this complex lesion became a nonbleeding well-demarcated soft-firm tumor that could easily be dissected off the pial surface and totally resected without extensive bleeding. Results There are several benefits of intratumoral injection of fibrin sealant in hemangiopericytomas: (1) the extensive bleeding is diminished and blood loss minimized; (2) the restriction of the surgical view by the venous oozing is diminished, making the microsurgical dissection of the tumor capsule off the pial surface easier and safer; (3) the loose consistency of the tumor becomes firmer and facilitates the manipulation of the tumor and leads to a safer resection; and (4) a shorter operating time is needed. Conclusion The use of intratumoral fibrin glue injection is a safe and useful technique that could be used for hemostasis of highly vascularized tumors to facilitate a safer resection and to reduce blood loss. PMID:26270264

  14. Spatial distribution and antitumor activities after intratumoral injection of fragmented fibers with loaded hydroxycamptothecin.

    PubMed

    Wei, Jiaojun; Luo, Xiaoming; Chen, Maohua; Lu, Jinfu; Li, Xiaohong

    2015-09-01

    There was only a small percentage of drug delivered to tumors after systemic administration, and solid tumors also have many barriers to prevent drug penetration within tumors. In the current study, intratumoral injection of drug-loaded fiber fragments was proposed to overcome these barriers, allowing drug accumulation at the target site to realize the therapeutic efficacy. Fragmented fibers with hydroxycamptothecin (HCPT) loaded were constructed by cryocutting of aligned electrospun fibers, and the fiber lengths of 5 (FF-5), 20 (FF-20), and 50μm (FF-50) could be easily controlled by adjusting the slice thickness. Fragmented fibers were homogeneously dispersed into 2% sodium alginate solution, and could be smoothly injected through 26G1/2 syringe needles. FF-5, FF-20 and FF-50 fiber fragments indicated similar release profiles except a lower burst release from FF-50. In vitro viability tests showed that FF-5 and FF-20 fiber fragments caused higher cytotoxicity and apoptosis rates than FF-50. After intratumoral injection into murine H22 subcutaneous tumors, fragmented fibers with longer lengths indicated a higher accumulation into tumors and a better retention at the injection site, but showed less apparent diffusion within tumor tissues. In addition to the elimination of invasive surgery, HCPT-loaded fiber fragments showed superior in vivo antitumor activities and fewer side effects than intratumoral implantation of drug-loaded fiber mats. Compared with FF-5 and FF-50, FF-20 fiber fragments indicated optimal spatial distribution of HCPT within tumors and achieved the most significant effects on the animal survival, tumor growth inhibition and tumor cell apoptosis induction. It is suggested that the intratumoral injection of drug-loaded fiber fragments provided an efficient strategy to improve patient compliance, allow the retention of fragmented fibers and spatial distribution of drugs within tumor tissues to achieve a low systemic toxicity and an optimal

  15. Heterogeneous Catalysis.

    ERIC Educational Resources Information Center

    Miranda, R.

    1989-01-01

    Described is a heterogeneous catalysis course which has elements of materials processing embedded in the classical format of catalytic mechanisms and surface chemistry. A course outline and list of examples of recent review papers written by students are provided. (MVL)

  16. Synthesis and characterization of drug loaded albumin mesospheres for intratumoral chemotherapy

    NASA Astrophysics Data System (ADS)

    Freeman, Shema Taian

    Conventional chemotherapy is problematic due to toxic complications. Intratumoral (IT) drug delivery, offers a new, less toxic, potentially more effective treatment concept. The objectives of this research encompassed (1) an investigation of the synthesis of BSA mesospheres (MS) employing genipin (GEN) as a novel crosslinking agent, (2) comparison with glutaraldehyde (GTA) crosslinked mesosphere, (3) a study of process parameters to define conditions for the synthesis of 1-10microm drug loaded mesospheres, and (4) investigation of the drug delivery properties of such mesospheres for IT chemotherapy. Smooth, spherical BSA-MS, crosslinked with glutaraldehyde and genipin, were prepared in a dry particle size range of 1microm to 10microm. It was shown that increasing dispersion stirring rate, crosslinking time and GEN/BSA ratio led to a decrease in particle size and a narrower particle distribution. It was also shown that increasing crosslinking time, GEN/BSA ratio, BSA concentrations, GEN concentration slowed enzymatic degradation. Post-loading and in situ drug loading methods were studied for the incorporation of cyclophosphamide and cisplatin into mesospheres. Maximum post loading of cisplatin was 3.2% (w/w) and 2.6% (w/w) with GEN and with GTA crosslinking. For cyclophosphamide 8.2% (w/w) and 7.1% (w/w) loading was achieved with GEN and GTA respectively. In situ drug loaded MS genipin and glutaraldehyde crosslinked mesospheres were also synthesized with 1.8% (w/w) cisplatin (using GEN) and 1.2% (w/w) (using GTA). Maximum loading of 13.3% (w/w) was achieved for cyclophosphamide in genipin crosslinked mesospheres. The cytotoxicity of in situ loaded genipin and glutaraldehyde crosslinked cisplatin mesospheres was evaluated using a murine Lewis lung model. Both genipin and glutaraldehyde crosslinked BSA-cisplatin mesospheres proved to be cytotoxic during a 48 hour test. Ultimately a standard set of processing parameters (BSA concentration, CAB concentration, GEN

  17. Conjugation of pH-Responsive Nanoparticles to Neural Stem Cells Improves Intratumoral Therapy

    PubMed Central

    Mooney, Rachael; Weng, Yiming; Garcia, Elizabeth; Bhojane, Sukhada; Smith-Powell, Leslie; Kim, Seung U.; Annala, Alexander J.; Aboody, Karen S.; Berlin, Jacob M.

    2014-01-01

    Intratumoral drug delivery is an inherently appealing approach for concentrating toxic chemotherapies at the site of action. This mode of administration is currently used in a number of clinical treatments such as neoadjuvant, adjuvant, and even standalone therapies when radiation and surgery are not possible. However, even when injected locally, it is difficult to achieve efficient distribution of chemotherapeutics throughout the tumor. This is primarily attributed to the high interstitial pressure which results in gradients that drive fluid away from the tumor center. The stiff extracellular matrix also limits drug penetration throughout the tumor. We have previously shown that neural stem cells can penetrate tumor interstitium, actively migrating even to hypoxic tumor cores. When used to deliver therapeutics, these migratory neural stem cells result in dramatically enhanced tumor coverage relative to conventional delivery approaches. We recently showed that neural stem cells maintain their tumor tropic properties when surface-conjugated to nanoparticles. Here we demonstrate that this hybrid delivery system can be used to improve the efficacy of docetaxel-loaded nanoparticles when administered intratumorally. This was achieved by conjugating drug-loaded nanoparticles to the surface of neural stem cells using a bond that allows the stem cells to efficiently distribute nanoparticles throughout the tumor before releasing the drug for uptake by tumor cells. The modular nature of this system suggests that it could be used to improve the efficacy of many chemotherapy drugs after intratumoral administration. PMID:24952368

  18. Modified chitosan thermosensitive hydrogel enables sustained and efficient anti-tumor therapy via intratumoral injection.

    PubMed

    Jiang, Yingchun; Meng, Xuanyu; Wu, Zhenghong; Qi, Xiaole

    2016-06-25

    Thermosensitive in situ hydrogels are potential candidates to achieve intratumoral administration, nevertheless their weak mechanical strength always lead to serious drug leakage and burst. Herein, we developed a chitosan based thermosensitive hydrogel of high mechanical strength, which was modified by glutaraldehyde (GA) and polyvinyl alcohol (PVA), for intratumoral delivery of paclitaxel (PTX). The modified hydrogel system could achieve sol-gel transition at 35.79±0.4°C and exhibit a 7.03-fold greater mechanical strength compared with simple chitosan hydrogel. Moreover, the drug release of PTX loaded modified hydrogel in PBS (pH 7.4) was found to be extended to 13 days. After intratumoral administration in mice bearing H22 tumors, PTX-loaded modified hydrogels exhibited a 3.72-fold greater antitumor activity compared with Taxol(®). Overall, these modified hydrogel systems demonstrated to be a promising way to achieve efficient sustained release and enhanced anti-tumor therapy efficiency of anticancer drugs through in situ tumor injectable administration. PMID:27083815

  19. BRIEF COMMUNICATIONS: Investigation of the vibrational relaxation of CO2 molecules in a heterogeneous gas-cluster system

    NASA Astrophysics Data System (ADS)

    Vostrikov, A. A.; Mironov, S. G.; Rebrov, A. K.; Semyachkin, B. E.

    1981-06-01

    An investigation was made of the relaxation of monomers and clusters of carbon dioxide excited in a glow discharge maintained in a condensing supersonic free jet. Measurements were made of the intensity of the output radiation emitted from the 001 vibrational level of the CO2 molecule in a band at 4.3 μ, and also of the intensity and energy of the molecular beam. It was found that the relaxation of the excited monomers as a result of their collisions with clusters occurred at a rate much higher than the rate of VT relaxation in the gaseous phase, and it increased on increase in the average size of the cluster. The clusters which have received the excitation energy directly from the discharge and indirectly from monomers were found to lose this energy with time: in ≲1 msec the excitation was converted into heat and this resulted in partial evaporation of the clusters.

  20. Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

    PubMed Central

    Schreiner, Jens; Thommen, Daniela S.; Herzig, Petra; Bacac, Marina; Klein, Christian; Roller, Andreas; Belousov, Anton; Levitsky, Victor; Savic, Spasenija; Moersig, Wolfgang; Uhlenbrock, Franziska; Heinzelmann-Schwarz, Viola A.; Umana, Pablo; Pisa, Pavel; Lardinois, Didier; Müller, Philipp; Karanikas, Vaios; Zippelius, Alfred

    2016-01-01

    ABSTRACT T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1hi TILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1hi TILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1int and PD-1neg T-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1hi expressing cells; in contrast, patients with abundance of PD-1hi expressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1hi T-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction. PMID:27057429

  1. Single-cell profiling approaches to probing tumor heterogeneity.

    PubMed

    Khoo, Bee Luan; Chaudhuri, Parthiv Kant; Ramalingam, Naveen; Tan, Daniel Shao Weng; Lim, Chwee Teck; Warkiani, Majid Ebrahimi

    2016-07-15

    Tumor heterogeneity is a major hindrance in cancer classification, diagnosis and treatment. Recent technological advances have begun to reveal the true extent of its heterogeneity. Single-cell analysis (SCA) is emerging as an important approach to detect variations in morphology, genetic or proteomic expression. In this review, we revisit the issue of inter- and intra-tumor heterogeneity, and list various modes of SCA techniques (cell-based, nucleic acid-based, protein-based, metabolite-based and lipid-based) presently used for cancer characterization. We further discuss the advantages of SCA over pooled cell analysis, as well as the limitations of conventional techniques. Emerging trends, such as high-throughput sequencing, are also mentioned as improved means for cancer profiling. Collectively, these applications have the potential for breakthroughs in cancer treatment. PMID:26789729

  2. BRAFV600E immunopositive Melanomas Show Low Frequency of Heterogeneity and Association With Epithelioid Tumor Cells

    PubMed Central

    Verlinden, Ivana; van den Hurk, Karin; Clarijs, Ruud; Willig, Arjan P.; Stallinga, Cecile M.H.A.; Roemen, Guido M.J.M.; van den Oord, Joost J.; zur Hausen, Axel; Speel, Ernst-Jan M.; Winnepenninckx, Véronique J.L.

    2014-01-01

    Abstract Treatment of BRAFV600E-mutant melanoma by small molecule inhibitors that target BRAF or MEK kinases is increasingly used in clinical practice and significantly improve patient outcome. However, patients eventually become resistant and therapeutic improvement is required. Molecular diversity within individual tumors (intratumor heterogeneity) and between tumors within a single patient (intrapatient heterogeneity) poses a significant challenge to precision medicine. Using immunohistochemistry, we determined the extent of BRAFV600E intratumor and intrapatient heterogeneity and the influence of morphological heterogeneity in a large series of 171 melanomas of 81 patients. The BRAFV600E mutation rate found in our melanoma series is 44%, with none of 22 (0%) melanoma in situ, 23 of 56 (41%) primary tumors, 28 of 59 (48%) regional metastases, and 24 of 34 (71%) distant metastases harboring the mutation. In general, a diffuse homogeneous immunostaining was seen, even in tumors consisting of more than one cell type, that is, epithelioid, spindle, and/or small cell types. Nevertheless, BRAFV600E-mutant melanomas more often had a purely epithelioid cell population (P = 0.063), that is more evident among distant metastases (P = 0.014). Only two of 75 (3%) mutated specimens (one primary and one metastasis) displayed heterogeneous BRAFV600E expression. The primary tumor was also morphologically heterogeneous and exclusively displayed BRAFV600E in the epithelioid component, confirming an association between BRAFV600E and epithelioid cells. Twenty-eight of 30 patients (93%) had concordant BRAF mutation status between their tumors. Taken together, BRAFV600E intratumor and intrapatient heterogeneity in melanoma is diminutive, nevertheless, the identified exceptions will have important implications for the clinical management of this disease. PMID:25526463

  3. Non-selective oxidation of humic acid in heterogeneous aqueous systems: a comparative investigation on the effect of clay minerals.

    PubMed

    Kavurmaci, Sibel Sen; Bekbolet, Miray

    2014-01-01

    Application of photocatalysis for degradation of natural organic matter (NOM) has received wide interest during the last decades. Besides NOM, model compounds more specifically humic acids (HAs) were also studied. As a continuation of the previous research, TiO2 photocatalytic degradation of HA was investigated in the presence of clay minerals, i.e., montmorillonite (Mt) and kaolinite (Kt). Degradation of HA was expressed by the pseudo-first-order kinetic modelling of dissolved organic carbon (DOC) and UV-VIS parameters (Colour436 and UV254). A slight rate enhancement was attained for Colour436 and UV254 in the presence of either Mt or Kt. The presence of clay particles did not significantly change the DOC degradation rate of HA. The effect of ionic strength (Ca2+ loading from 5 x 10(-4) M to 5 x 1(-3) M) was also assessed for the photocatalytic degradation of sole HA and HA in the presence of either Mt or Kt. Following photocatalytic treatment, molecular size distribution profiles of HA were presented. Besides the effective removal of higher molecular size fractions (100 and 30 kDa fractions), transformation to lower molecular size fractions (<3 kDa) was more pronounced for sole HA rather than HA in the presence of clay minerals. Scanning electron microscopic images with the energy dispersive X-ray analysis confirmed the diversities in surface morphologies of the binary and ternary systems composed of HA, TiO2 and Mt or Kt both prior to and following photocatalysis. This study demonstrated that photocatalysis could be applicable for DOC degradation in the presence of clay minerals in natural waters. PMID:25145193

  4. Imaging the intratumoral-peritumoral extracellular pH gradient of gliomas.

    PubMed

    Coman, Daniel; Huang, Yuegao; Rao, Jyotsna U; De Feyter, Henk M; Rothman, Douglas L; Juchem, Christoph; Hyder, Fahmeed

    2016-03-01

    Solid tumors have an acidic extracellular pH (pHe ) but near neutral intracellular pH (pHi ). Because acidic pHe milieu is conducive to tumor growth and builds resistance to therapy, simultaneous mapping of pHe inside and outside the tumor (i.e., intratumoral-peritumoral pHe gradient) fulfills an important need in cancer imaging. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes shifts of non-exchangeable protons from macrocyclic chelates (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) or DOTP(8-) ) complexed with paramagnetic thulium (Tm(3) (+) ) ion, to generate in vivo pHe maps in rat brains bearing 9L and RG2 tumors. Upon TmDOTP(5-) infusion, MRI identified the tumor boundary by enhanced water transverse relaxation and BIRDS allowed imaging of intratumoral-peritumoral pHe gradients. The pHe measured by BIRDS was compared with pHi measured with (31) P-MRS. In normal tissue, pHe was similar to pHi , but inside the tumor pHe was lower than pHi . While the intratumoral pHe was acidic for both tumor types, peritumoral pHe varied with tumor type. The intratumoral-peritumoral pHe gradient was much larger for 9L than RG2 tumors because in RG2 tumors acidic pHe was found in distal peritumoral regions. The increased presence of Ki-67 positive cells beyond the RG2 tumor border suggested that RG2 was more invasive than the 9L tumor. These results indicate that extensive acidic pHe beyond the tumor boundary correlates with tumor cell invasion. In summary, BIRDS has sensitivity to map the in vivo intratumoral-peritumoral pHe gradient, thereby creating preclinical applications in monitoring cancer therapeutic responses (e.g., with pHe -altering drugs). Copyright © 2016 John Wiley & Sons, Ltd. PMID:26752688

  5. Radioactive 198Au-doped nanostructures with different shapes for in vivo analyses of their biodistribution, tumor uptake, and intratumoral distribution.

    PubMed

    Black, Kvar C L; Wang, Yucai; Luehmann, Hannah P; Cai, Xin; Xing, Wenxin; Pang, Bo; Zhao, Yongfeng; Cutler, Cathy S; Wang, Lihong V; Liu, Yongjian; Xia, Younan

    2014-05-27

    With Au nanocages as an example, we recently demonstrated that radioactive (198)Au could be incorporated into the crystal lattice of Au nanostructures for simple and reliable quantification of their in vivo biodistribution by measuring the γ radiation from (198)Au decay and for optical imaging by detecting the Cerenkov radiation. Here we extend the capability of this strategy to synthesize radioactive (198)Au nanostructures with a similar size but different shapes and then compare their biodistribution, tumor uptake, and intratumoral distribution using a murine EMT6 breast cancer model. Specifically, we investigated Au nanospheres, nanodisks, nanorods, and cubic nanocages. After PEGylation, an aqueous suspension of the radioactive Au nanostructures was injected into a tumor-bearing mouse intravenously, and their biodistribution was measured from the γ radiation while their tumor uptake was directly imaged using the Cerenkov radiation. Significantly higher tumor uptake was observed for the Au nanospheres and nanodisks relative to the Au nanorods and nanocages at 24 h postinjection. Furthermore, autoradiographic imaging was performed on thin slices of the tumor after excision to resolve the intratumoral distributions of the nanostructures. While both the Au nanospheres and nanodisks were only observed on the surfaces of the tumors, the Au nanorods and nanocages were distributed throughout the tumors. PMID:24766522

  6. Effect of intratumoral heterogeneity in oxygenation status on FMISO PET, autoradiography, and electrode PO {sub 2} measurements in murine tumors

    SciTech Connect

    Sorensen, Michael . E-mail: michael@pet.auh.dk; Horsman, Michael R.; Cumming, Paul; Munk, Ole Lajord; Keiding, Susanne

    2005-07-01

    Purpose: To explore conflicting results obtained when tumor hypoxia is assessed with Eppendorf electrode PO {sub 2} measurements and with positron emission tomography (PET) by use of [{sup 18}F]fluoromisonidazole (FMISO). Methods and Materials: We compared the 2 methods in conjunction with 2-[{sup 18}F]fluoro-2-deoxy-D-glucose (FDG) PET, dual-tracer ex vivo autoradiography (FMISO and 2-deoxy-D-[1-{sup 14}C]glucose (2DG)), and histology in 2 murine tumor models, the C3H mammary carcinoma and the SCCVII squamous cell carcinoma. Results: 2-[{sup 18}F]fluoro-2-deoxy-D-glucose (FDG)-PET showed tumor-to-reference tissue ratios of 3.5 in both tumor models after 2 hours. C3H mammary carcinoma reached an FMISO PET ratio of 11 after 3.5 hours. Autoradiography showed large confluent areas of FMISO and 2DG uptake. Median PO {sub 2} was 7 mm Hg and necrotic fraction was 10% to 30%. SCCVII squamous-cell carcinoma reached an FMISO PET tumor-to-reference tissue ratio of 2 after 2.5 hours. Autoradiography showed homogeneous 2DG uptake and scattered foci of high FMISO uptake. Median PO {sub 2} was 1 mm Hg and necrotic fraction was below 5%. Conclusions: Ex vivo dual-tracer autoradiography documented the ability of in vivo FMISO PET to distinguish between confluent areas of either viable tissue or necrosis. Electrode PO {sub 2} measurements could not be ascribed to specific areas in the tumors. Less uptake of FMISO in SCCVII squamous-cell carcinoma than in C3H mammary carcinoma could be caused by scattered foci versus confluent areas of viable hypoxic tissue in the 2 tumors, respectively.

  7. Comment on "Developing DCE-CT to quantify intra-tumor heterogeneity in breast tumors with differing angiogenic phenotype".

    PubMed

    Abramyuk, Andrij; Wolf, Gunter; Hietschold, Volker; Haberland, Ulrike; van den Hoff, Joerg; Abolmaali, Nasreddin

    2010-04-01

    In our comment some essential issues concerning determination of arterial input function (AIF), cardiac and respiratory related motion artifacts, contrast agent application and compartmental model fitting done by Cao et al., 2009 are discussed. PMID:20659827

  8. A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis

    PubMed Central

    Chao, Ming; Wu, Hao; Jin, Kai; Li, Bin; Wu, Jianjun; Zhang, Guangqiang; Yang, Gong; Hu, Xun

    2016-01-01

    Study design: Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) studies. Methods: The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor. Results: In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%–10.9%] vs 45.6% [28.9%–72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit. Conclusion: Bicarbonate markedly enhances the anticancer activity of TACE. Clinical trail registration: ChiCTR-IOR-14005319. DOI: http://dx.doi.org/10.7554/eLife.15691.001 PMID:27481188

  9. Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors

    PubMed Central

    Watson, Katherine D.; Lai, Chun-Yen; Qin, Shengping; Kruse, Dustin E.; Lin, Yueh-Chen; Seo, Jai Woong; Cardiff, Robert D.; Mahakian, Lisa M.; Beegle, Julie; Ingham, Elizabeth S.; Curry, Fitz-Roy; Reed, Rolf K.; Ferrara, Katherine W.

    2012-01-01

    Acquisition of the epithelial-mesenchymal transition (EMT) tumor phenotype is associated with impaired chemotherapeutic delivery and a poor prognosis. In this study, we investigated the application of therapeutic ultrasound methods available in the clinic to increase nanotherapeutic particle accumulation in epithelial and EMT tumors by labeling particles with a positron emission tomography tracer. Epithelial tumors were highly vascularized with tight cell-cell junctions, compared to EMT tumors where cells displayed an irregular, elongated shape with loosened cell-cell adhesions and a reduction in E-cadherin and cytokeratins 8/18 and 19. Without ultrasound, the accumulation of liposomal nanoparticles administered to tumors in vivo was ~1.5 times greater in epithelial tumors than EMT tumors. When ultrasound was applied, both nanoaccumulation and apparent tumor permeability were increased in both settings. Notably, ultrasound effects differed with thermal and mechanical indices, such that increasing the thermal ultrasound dose increased nanoaccumulation in EMT tumors. Taken together, our results illustrate how ultrasound can be used to enhance nanoparticle accumulation in tumors by reducing their intratumoral pressure and increasing their vascular permeability. PMID:22282664

  10. Intratumoral administration of a recombinant canarypox virus expressing interleukin 12 in patients with metastatic melanoma.

    PubMed

    Triozzi, Pierre L; Strong, Theresa V; Bucy, R Pat; Allen, Karen O; Carlisle, Ronda R; Moore, Susan E; Lobuglio, Albert F; Conry, Robert M

    2005-01-01

    The aim of this study was to evaluate the tolerability and activity of intratumoral administered human interleukin 12 encoded by a vector derived from the canarypox virus (ALVAC-IL-12). Nine patients with surgically incurable metastatic melanoma who had subcutaneous nodules available for injection were enrolled. ALVAC-IL-12 was administered by intratumoral injection on days 1, 4, 8, and 11. Tumor nodules greater than 2 cm in diameter were injected with 2 x 10(6) median tissue culture infectious doses (TCID(50)), and smaller tumors were injected with 1 x 10(6) TCID(50). The total dose per patient per time point ranged from 1 x 10(6) to 4 x 10(6) TCID(50). Toxicity was mild to moderate and consisted of inflammatory reactions at the injection site and fever associated with chills, myalgia, and fatigue. No dose-limiting toxicities occurred. Increases in IL-12 mRNA, and also increases in interferon gamma mRNA, were observed in ALVAC-IL-12-injected tumors compared with saline-injected control tumors in four of the nine patients. ALVAC-IL-12-injected tumors were also characterized by T cell infiltration. Three patients demonstrated increases in serum IL-12 and in interferon gamma levels. All patients developed neutralizing IgG antibody to the canarypox vector. One patient manifested a complete response of injected subcutaneous metastases and uninjected in-transit metastases. The intratumoral injection of ALVAC-IL-12 at these dose levels and according to this schedule was well tolerated and resulted in measurable biologic response in patients with metastatic melanoma. PMID:15703492

  11. Color Doppler Ultrasound and Gamma Imaging of Intratumorally Injected 500 nm Iron-Silica Nanoshells

    PubMed Central

    Liberman, Alexander; Wu, Zhe; Barback, Christopher V.; Viveros, Robert; Blair, Sarah L.; Ellies, Lesley G.; Vera, David R.; Mattrey, Robert F.; Kummel, Andrew C.; Trogler, William C.

    2013-01-01

    Perfluoropentane gas filled iron-silica nanoshells have been developed as stationary ultrasound contrast agents for marking tumors to guide surgical resection. It is critical to establish their long term imaging efficacy, as well as biodistribution. This work shows that 500 nm Fe-SiO2 nanoshells can be imaged by color Doppler ultrasound over the course of 10 days in Py8119 tumor bearing mice. The 500 nm non-biodegradable SiO2 and biodegradable Fe-SiO2 nanoshells were functionalized with diethylenetriamine pentaacetic acid (DTPA) ligand and radiolabeled with 111In3+ for biodistribution studies in nu/nu mice. The majority of radioactivity was detected in the liver and kidneys following intravenous (IV) administration of nanoshells to healthy animals. By contrast, after nanoshells were injected intratumorally, most of the radioactivity remained at the injection site; however, some nanoshells escaped into circulation and were distributed similarly as those given intravenously. For intratumoral delivery of nanoshells and IV delivery to healthy animals, little difference was seen between the biodistribution of SiO2 and biodegradable Fe-SiO2 nanoshells. However, when nanoshells were administered IV to tumor bearing mice, a significant increase was observed in liver accumulation of SiO2 nanoshells relative to biodegradable Fe-SiO2 nanoshells. Both SiO2 and Fe-SiO2 nanoshells accumulate passively in proportion to tumor mass, during intravenous delivery of nanoshells. This is the first report of the biodistribution following intratumoral injection of any biodegradable silica particle, as well as the first report demonstrating the utility of DTPA-111In labeling for studying silica nanoparticle biodistributions. PMID:23802554

  12. KIT oncogene inhibition drives intratumoral macrophage M2 polarization.

    PubMed

    Cavnar, Michael J; Zeng, Shan; Kim, Teresa S; Sorenson, Eric C; Ocuin, Lee M; Balachandran, Vinod P; Seifert, Adrian M; Greer, Jonathan B; Popow, Rachel; Crawley, Megan H; Cohen, Noah A; Green, Benjamin L; Rossi, Ferdinand; Besmer, Peter; Antonescu, Cristina R; DeMatteo, Ronald P

    2013-12-16

    Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers. PMID:24323358

  13. Investigation of heterogeneous asymmetric dihydroxylation over OsO{sub 4}-(QN){sub 2}PHAL catalysts of functionalized bimodal mesoporous silica with ionic liquid

    SciTech Connect

    Qiu, Shenjie; Sun, Jihong; Li, Yuzhen; Gao, Lin

    2011-08-15

    Highlights: {yields} Functionalized bimodal mesoporous silica with MTMSPIm{sup +}Cl{sup -}. {yields} Mesoporous catalyst immobilized with OsO{sub 4}-(QN){sub 2}PHAL. {yields} Catalysts for asymmetric dihydroxylation reaction with high yield and enatioselectivity. {yields} Recyclable catalysts. -- Abstract: A novel synthesis of the functionalized bimodal mesoporous silica with ionic liquid (FBMMs) was performed. After grafting 1-methyl-3-(trimethoxysilyl)propylimidazolium chloride onto the surface of bimodal mesoporous silicas, 1,4-bis(9-O-quininyl)phthalazine ((QN){sub 2}-PHAL) and K{sub 2}Os(OH){sub 4}.2H{sub 2}O were immobilized onto the modified FBMMs by adsorption or ionic exchange methods, and then, the asymmetric dihydroxylation reaction was carried out by using solid catalysts. Techniques such as X-ray diffraction, Fourier Transform Infrared spectroscopy, N{sub 2} adsorption and desorption were employed to characterize their structure and properties. The results showed that the mesoporous ordering degree of bimodal mesoporous silica decreased after functionalization and immobilization of OsO{sub 4}-(QN){sub 2}PHAL. Being very effective in asymmetric dihydroxylation with high yield and enantioselectivity, the prepared heterogeneous solid catalyst could be recycled for five times with little loss of enantioselectivity, with comparison of those results obtained in homophase system. Moreover, the effect of Osmium catalyst on asymmetric dihydroxylation was investigated.

  14. Heterogeneous nucleation of entrained eutectic Si in high purity melt spun Al-Si alloys investigated by entrained droplet technique and DSC

    NASA Astrophysics Data System (ADS)

    Li, J. H.; Albu, M.; Ludwig, T. H.; Hofer, F.; Arnberg, L.; Schumacher, P.

    2016-03-01

    Entrained droplet technique and DSC analyses were employed to investigate the influence of trace elements of Sr, Eu and P on the heterogeneous nucleation of entrained eutectic Si in high purity melt spun Al-5wt.% Si alloys. Sr and Eu addition was found to exert negative effects on the nucleation process, while an increased undercooling was observed. This can be attributed to the formation of phosphide compounds having a lower free energy and hence may preferentially form compared to AlP. Only a trace P addition was found to have a profound effect on the nucleation process. The nucleation kinetics is discussed on the basis of the classical nucleation theory and the free growth model, respectively. The estimated AlP patch size was found to be sufficient for the free growth of Si to occur within the droplets, which strongly indicates that the nucleation of Si on an AlP patch or AlP particle is a limiting step for free growth. The maximum nucleation site density within one droplet is directly related to the size distribution of AlP particles or AlP patches for Si nucleation, but is independent of the cooling rates. Although the nucleation conditions were optimized in entrained droplet experiments, the observed mechanisms are also valid at moderate cooling conditions, such as in shape casting.

  15. Smart design of intratumoral thermosensitive β-lapachone hydrogels by Artificial Neural Networks.

    PubMed

    Díaz-Rodríguez, P; Landin, M

    2012-08-20

    This study presents Artificial Neural Networks (ANN) as a tool for designing injectable intratumoral formulations of the anticancer drug β-lapachone. This methodology permits insight into the interactions between variables and determines the design space of the formulation without the restrictions of an experimental design. An ANN model for two critical parameters of the formulations; the amount of solubilized drug and gel temperature was developed and validated. The model allowed an understanding of interactions between ingredients in the formulation and the fundamental phenomena as the formation of polypseudorotaxanes to be detected and quantified. PMID:22613207

  16. Genetic heterogeneity in rhabdomyosarcoma revealed by SNP array analysis.

    PubMed

    Walther, Charles; Mayrhofer, Markus; Nilsson, Jenny; Hofvander, Jakob; Jonson, Tord; Mandahl, Nils; Øra, Ingrid; Gisselsson, David; Mertens, Fredrik

    2016-01-01

    Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Alveolar (ARMS) and embryonal (ERMS) histologies predominate, but rare cases are classified as spindle cell/sclerosing (SRMS). For treatment stratification, RMS is further subclassified as fusion-positive (FP-RMS) or fusion-negative (FN-RMS), depending on whether a gene fusion involving PAX3 or PAX7 is present or not. We investigated 19 cases of pediatric RMS using high resolution single-nucleotide polymorphism (SNP) array. FP-ARMS displayed, on average, more structural rearrangements than ERMS; the single FN-ARMS had a genomic profile similar to ERMS. Apart from previously known amplification (e.g., MYCN, CDK4, and MIR17HG) and deletion (e.g., NF1, CDKN2A, and CDKN2B) targets, amplification of ERBB2 and homozygous loss of ASCC3 or ODZ3 were seen. Combining SNP array with cytogenetic data revealed that most cases were polyploid, with at least one case having started as a near-haploid tumor. Further bioinformatic analysis of the SNP array data disclosed genetic heterogeneity, in the form of subclonal chromosomal imbalances, in five tumors. The outcome was worse for patients with FP-ARMS than ERMS or FN-ARMS (6/8 vs. 1/9 dead of disease), and the only children with ERMS showing intratumor diversity or with MYOD1 mutation-positive SRMS also died of disease. High resolution SNP array can be useful in evaluating genomic imbalances in pediatric RMS. PMID:26482321

  17. [Effect of doxorubicine and heterogenous electromagnetic and thermal fields on the nonlinear dynamics of carcinoma Guerin development].

    PubMed

    Orel, V E; Dziatkovs'ka, I I; Nikolov, M O; Romanov, A V; Mel'nyk, Iu H; Dziatkovs'ka, N M

    2010-07-01

    While local hyperthermia application the intratumoral blood flow is enhancing, leading to oxygenation and vascular permeability for antitumoral medicines. The work objective was to investigate the dependence of the development kinetics in carcinoma Gereni (CG) from combined action of doxorubicin (DR) and the kind of thermal impact, a contact one--due to a contact delivery of heat from a water heater and without contact - due to the tumor electromagnetic irradiation (EMI) using heterogenous electromagnetic field (EMF). DR was injected to the animals in a mass concentration of 1,5 mg on 1 kg of their body mass. The DR injection, a contact heating and EMI were started on the 8th day after the tumor reinoculation and kept on conducting once a 2 days. The course had included 5 injections and/or 5 seances of a contact heating and/or EMF. The combined action of DR and EMI, using spatially heterogenous EMF of applicator in environment of physiological hyperthermia, have had influenced mostly the inhibition of a nonlinear dynamics in CG development. Antitumoral action of DR in the animals with CG was influenced by thermal and nonthermal effects, which were initiated by spatially heterogenous EMF. Nonlinear dynamics of a CG development in animals did not depend from horizontal direction of isolines of a spatially heterogenous EMF of inductive applicator towards the tumor and duration of the irradiation procedure (15 or 30 minutes) after DR injection. The data obtained were exploited in clinical practice for the inductothermy optimal regimes elaboration while conducting complex treatment of patients, suffering oncological diseases. PMID:20825095

  18. An Investigation of Homogeneous and Heterogeneous Sonochemistry for Destruction of Hazardous Waste - Final Report - 09/15/1996 - 09/14/2000

    SciTech Connect

    Hua, Inez

    2000-09-14

    During the last 20 years, various legislative acts have mandated the reduction and elimination of water and land pollution. In order to fulfill these mandates, effective control and remediation methods must be developed and implemented. The drawbacks of current hazardous waste control methods motivate the development of new technology, and the need for new technology is further driven by the large number of polluted sites across the country. This research explores the application and optimization of ultrasonic waves as a novel method by which aqueous contaminants are degraded. The primary objective of the investigation is to acquire a deeper fundamental knowledge of acoustic cavitation and cavitation chemistry, and in doing so, to ascertain how ultrasonic irradiation can be more effectively applied to environmental problems. Special consideration is given to the types of problems and hazardous chemical substrates found specifically at Department of Energy (DOE) sites. The experimental work is divided into five broad tasks, to be completed over a period of three years. The first task is to explore the significance of physical variables during sonolysis, such as ultrasonic frequency. The second aim is an understanding of sonochemical degradation kinetics and by-products, complemented by information from the detection of reactive intermediates with electron paramagnetic resonance. The sonolytic decomposition studies will focus on polychlorinated biphenyls (PCBs). Investigation of activated carbon regeneration during ultrasonic irradiation extends sonochemical applications in homogeneous systems to heterogeneous systems of environmental interest. Lastly, the physics and hydrodynamics of cavitation bubbles and bubble clouds will be correlated with sonochemical effects by performing high-speed photographic studies of acoustically cavitating aqueous solutions. The most important benefit will be fundamental information which will allow a more optimal application of

  19. Investigation of realistic PET simulations incorporating tumor patient's specificity using anthropomorphic models: Creation of an oncology database

    SciTech Connect

    Papadimitroulas, Panagiotis; Efthimiou, Nikos; Nikiforidis, George C.; Kagadis, George C.; Loudos, George; Le Maitre, Amandine; Hatt, Mathieu; Tixier, Florent; Visvikis, Dimitris

    2013-11-15

    Purpose: The GATE Monte Carlo simulation toolkit is used for the implementation of realistic PET simulations incorporating tumor heterogeneous activity distributions. The reconstructed patient images include noise from the acquisition process, imaging system's performance restrictions and have limited spatial resolution. For those reasons, the measured intensity cannot be simply introduced in GATE simulations, to reproduce clinical data. Investigation of the heterogeneity distribution within tumors applying partial volume correction (PVC) algorithms was assessed. The purpose of the present study was to create a simulated oncology database based on clinical data with realistic intratumor uptake heterogeneity properties.Methods: PET/CT data of seven oncology patients were used in order to create a realistic tumor database investigating the heterogeneity activity distribution of the simulated tumors. The anthropomorphic models (NURBS based cardiac torso and Zubal phantoms) were adapted to the CT data of each patient, and the activity distribution was extracted from the respective PET data. The patient-specific models were simulated with the Monte Carlo Geant4 application for tomography emission (GATE) in three different levels for each case: (a) using homogeneous activity within the tumor, (b) using heterogeneous activity distribution in every voxel within the tumor as it was extracted from the PET image, and (c) using heterogeneous activity distribution corresponding to the clinical image following PVC. The three different types of simulated data in each case were reconstructed with two iterations and filtered with a 3D Gaussian postfilter, in order to simulate the intratumor heterogeneous uptake. Heterogeneity in all generated images was quantified using textural feature derived parameters in 3D according to the ground truth of the simulation, and compared to clinical measurements. Finally, profiles were plotted in central slices of the tumors, across lines with

  20. Profile of differentially expressed intratumoral cytokines to predict the immune-polarizing side effects of tamoxifen in breast cancer treatment

    PubMed Central

    Li, Bailiang; Li, Yang; Wang, Xiao-Yu; Yan, Zi-Qiao; Liu, Huidi; Liu, Gui-Rong; Liu, Shu-Lin

    2015-01-01

    Factors within the tissue of breast cancer (BC) may shift the polarization of CD4+ T cells towards Th2 direction. This tendency can promote tumor development and be enhanced by the use of tamoxifen during the treatment. Thus, the patients with low levels of tumor-induced Th2 polarization prior to tamoxifen treatment may better endure the immune-polarizing side effects (IPSE) of tamoxifen and have better prognoses. Estimation of Th2 polarization status should help predict the IPSE among tamoxifen-treated patients and guide the use of tamoxifen among all BC patients before the tamoxifen therapy. Here, we report profiling of differentially expressed (DE) intratumoral cytokines as a signature to evaluate the IPSE of tamoxifen. The DE genes of intratumoral CD4+ T cells (CD4 DEGs) were identified by gene expression profiles of purified CD4+ T cells from BC patients and validated by profiling of cultured intratumoral CD4+ T cells. Functional enrichment analyses showed a directed Th2 polarization of intratumoral CD4+ T cells. To find the factors inducing the Th2 polarization of CD4+ T cells, we identified 995 common DE genes of bulk BC tissues (BC DEGs) by integrating five independent datasets. Five DE cytokines observed in bulk BC tissues with dysregulated receptors in the intratumoral CD4+ T cells were selected as the predictor of the IPSE of tamoxifen. The patients predicted to suffer low IPSE (low Th2 polarization) had a significantly lower distant relapse risk than the patients predicted to suffer high IPSE in independent datasets (n = 608; HR = 4.326, P = 0.000897; HR = 2.014, P = 0.0173; HR = 2.72, P = 0.04077). Patients predicted to suffer low IPSE would benefit from tamoxifen treatment (HR = 2.908, P = 0.03905). The DE intratumoral cytokines identified in this study may help predict the IPSE of tamoxifen and justify the use of tamoxifen in BC treatment. PMID:25973310

  1. Technique, pharmacokinetics, toxicity, and efficacy of intratumoral etanidazole and radiotherapy for treatment of spontaneous feline oral squamous cell carcinoma

    SciTech Connect

    Evans, S.M.; LaCreta, F.; Helfand, S.; VanWinkle, T.; Curran, W.J. Jr.; Brown, D.Q.; Hanks, G. )

    1991-04-01

    The histologic appearance, locoregional recurrence, and rate/site of metastases of spontaneous feline oral squamous cell carcinoma are similar to head and neck cancer in humans. A feasibility study of intratumoral Etanidazole, a hypoxic cell sensitizer, and radiation therapy were instituted in this model. Eleven cats with feline squamous cell carcinoma were treated with intratumoral Etanidazole and radiation therapy. Total Etanidazole doses were 1.5-24.0 gms/m2 (0.5-6.9 gms). The tumor partial response rate was 100% (11/11); the median volume regression was 70%. All cats have died as a result of tumor recurrence or tumor-related complications. Median survival was 116 days. Ten cats have been autopsied. Non-necrotic and necrotic tumor cells were identified at the treatment site in all cats. Pharmacokinetic studies were performed in six cats. Following intravenous infusion, the plasma elimination of the Etanidazole was biexponential. The systemic availability following intratumoral administration was 61.2 +/- 21.1%. Peak plasma Etanidazole levels were observed 14 minutes following intratumoral injection, after which elimination was biexponential. Thirty minutes following intratumoral Etanidazole administration, tumor Etanidazole levels were 62.8% of plasma levels. Feline squamous cell carcinoma appears to be a useful model of human head and neck cancer. Cats tolerate substantial doses of intratumoral and intravenous Etanidazole. Etanidazole and radiation therapy cause rapid regression, but not cure, of feline squamous cell carcinoma. There is a similarity between the intravenous kinetics of Etanidazole in humans and cats. Further studies in this model are planned.

  2. Interconnecting heterogeneous database management systems

    NASA Technical Reports Server (NTRS)

    Gligor, V. D.; Luckenbaugh, G. L.

    1984-01-01

    It is pointed out that there is still a great need for the development of improved communication between remote, heterogeneous database management systems (DBMS). Problems regarding the effective communication between distributed DBMSs are primarily related to significant differences between local data managers, local data models and representations, and local transaction managers. A system of interconnected DBMSs which exhibit such differences is called a network of distributed, heterogeneous DBMSs. In order to achieve effective interconnection of remote, heterogeneous DBMSs, the users must have uniform, integrated access to the different DBMs. The present investigation is mainly concerned with an analysis of the existing approaches to interconnecting heterogeneous DBMSs, taking into account four experimental DBMS projects.

  3. Political Jurisdictions in Heterogeneous Communities.

    ERIC Educational Resources Information Center

    Alesina, Alberto; Baqir, Reza; Hoxby, Caroline

    2004-01-01

    We investigate whether political jurisdictions form in response to the trade-off between economies of scale and the costs of a heterogeneous population. We consider heterogeneity in income, race, ethnicity, and religion, and we test the model using American school districts, school attendance areas, municipalities, and special districts. We find…

  4. Combination of cyclophosphamide, rituximab, and intratumoral CpG oligodeoxynucleotide successfully eradicates established B cell lymphoma.

    PubMed

    Betting, David J; Hurvitz, Sara A; Steward, Kristopher K; Yamada, Reiko E; Kafi, Kamran; van Rooijen, Nico; Timmerman, John M

    2012-09-01

    Rituximab plus chemotherapy is standard therapy for patients with non-Hodgkin B cell lymphoma, but often complete response or cure is not achieved. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) can improve antibody-dependent cellular cytotoxicity and adaptive antitumor immune responses. Using a syngeneic murine B cell lymphoma expressing human CD20 (38C13-huCD20), we previously demonstrated that rituximab plus intratumoral CpG, but not systemic CpG, could eradicate up to half of 7-day established 38C13-huCD20 tumors. However, larger 10-day established tumors could not be cured with this regimen. We thus hypothesized that cytoreduction with cyclophosphamide (Cy) before immunotherapy might permit eradication of these more advanced tumor burdens. Pretreatment with Cy resulted in tumor eradication from 83% of animals treated with rituximab/CpG, whereas Cy/CpG or Cy/rituximab treatments only cured 30% or 17%, respectively (P<0.005). Tumor eradication depended on natural killer cells, but not T cells, macrophages, or complement. Only mice treated with Cy/rituximab/CpG partially resisted rechallenge with tumor cells. Foxp3 Treg and CD11bGr1 myeloid suppressor cells persisted within lymphoid organs after therapy, possibly influencing the ability to establish adaptive tumor immunity. In conclusion, cytoreduction with Cy permitted the cure of large, established lymphomas not otherwise responsive to rituximab plus intratumoral CpG immunotherapy. PMID:22892450

  5. In vivo observing x-ray attenuation of intratumor injection of indocyanine green

    NASA Astrophysics Data System (ADS)

    Ye, Chang; Luo, Qingming; Liang, Wenxi; Lu, Jinling

    2003-12-01

    We report our experimental results of in vivo observing x-ray attenuation of intra-tumor injection of indocyanine green (ICG). An eight- to nine-week-old male BALB/c mouse weighting between 15 and 20 g is used in the experiments, which has been implanted with myeloma cell line (SP2/0) two week before. The system used to monitor the intratumor diffusion of ICG is a digital x-ray imaging system. It works at 33kVp, 0.3mAs, 4 seconds and 1.5×magnification. The objective of this research is to study the x-ray attenuation at different area, which represented by gray-scale value. Compare to the ROI in the tissue without ICG and ROI of black background in the image, there is an obvious change before and after injecting ICG in the tumor, which is the area ICG can diffuse to. It shows the feasibility of using digital x-ray imaging system to dynamically, effectively and noninterventionly monitor the diffusion of the ICG.

  6. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity

    PubMed Central

    Swanton, Charles; McGranahan, Nicholas; Starrett, Gabriel J.; Harris, Reuben S.

    2015-01-01

    Deep sequencing technologies are revealing the complexities of cancer evolution, casting light on mutational processes fuelling tumor adaptation, immune escape, and treatment resistance. Understanding mechanisms driving cancer diversity is a critical step toward developing strategies to attenuate tumor evolution and adaptation. One emerging mechanism fuelling tumor diversity and subclonal evolution is genomic DNA cytosine deamination catalyzed by APOBEC3B and at least one other APOBEC family member. Deregulation of APOBEC3 enzymes causes a general mutator phenotype that manifests as diverse and heterogeneous tumor subclones. Here we summarise knowledge of the APOBEC DNA deaminase family in cancer, and their role as driving forces for intratumor heterogeneity and a therapeutic target to limit tumor adaptation. PMID:26091828

  7. Investigation on relationship between epicentral distance and growth curve of initial P-wave propagating in local heterogeneous media for earthquake early warning system

    NASA Astrophysics Data System (ADS)

    Okamoto, Kyosuke; Tsuno, Seiji

    2015-10-01

    In the earthquake early warning (EEW) system, the epicenter location and magnitude of earthquakes are estimated using the amplitude growth rate of initial P-waves. It has been empirically pointed out that the growth rate becomes smaller as epicentral distance becomes far regardless of the magnitude of earthquakes. So, the epicentral distance can be estimated from the growth rate using this empirical relationship. However, the growth rates calculated from different earthquakes at the same epicentral distance mark considerably different values from each other. Sometimes the growth rates of earthquakes having the same epicentral distance vary by 104 times. Qualitatively, it has been considered that the gap in the growth rates is due to differences in the local heterogeneities that the P-waves propagate through. In this study, we demonstrate theoretically how local heterogeneities in the subsurface disturb the relationship between the growth rate and the epicentral distance. Firstly, we calculate seismic scattered waves in a heterogeneous medium. First-ordered PP, PS, SP, and SS scatterings are considered. The correlation distance of the heterogeneities and fractional fluctuation of elastic parameters control the heterogeneous conditions for the calculation. From the synthesized waves, the growth rate of the initial P-wave is obtained. As a result, we find that a parameter (in this study, correlation distance) controlling heterogeneities plays a key role in the magnitude of the fluctuation of the growth rate. Then, we calculate the regional correlation distances in Japan that can account for the fluctuation of the growth rate of real earthquakes from 1997 to 2011 observed by K-NET and KiK-net. As a result, the spatial distribution of the correlation distance shows locality. So, it is revealed that the growth rates fluctuate according to the locality. When this local fluctuation is taken into account, the accuracy of the estimation of epicentral distances from initial P

  8. Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer.

    PubMed

    Delitto, Daniel; Perez, Chelsey; Han, Song; Gonzalo, David H; Pham, Kien; Knowlton, Andrea E; Graves, Christina L; Behrns, Kevin E; Moldawer, Lyle L; Thomas, Ryan M; Liu, Chen; George, Thomas J; Trevino, Jose G; Wallet, Shannon M; Hughes, Steven J

    2015-12-01

    The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-γ (IFNγ) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNγ remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNγ response within and on key cells of the PC microenvironment was evaluated. IFNγ induced expression of human leukocyte antigen (HLA) class I and II on PC cell lines, primary pancreatic cancer epithelial cells (PPCE) and patient-derived tumor-associated stroma, concomitant with an upregulation of PDL1 in the absence of CD80 and CD86 expression. As expected, IFNγ also induced high levels of CXCL10 from all cell types. In addition, significantly higher levels of CXCL10 were observed in PC specimens compared to those from chronic pancreatitis, whereby intratumoral CXCL10 concentration was an independent predictor of poor survival. Immunohistochemical analysis revealed a subset of CXCR3-positive cancer cells in over 90 % of PC specimens, as well as on a subset of cultured PC cell lines and PPCE, whereby exposure to CXCL10 induced resistance to the chemotherapeutic gemcitabine. These findings suggest that IFNγ has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival. PMID:26423423

  9. Investigating the Impact of Surface Heterogeneity on the Convective Boundary Layer Over Urban Areas Through Coupled Large-Eddy Simulation and Remote Sensing

    NASA Technical Reports Server (NTRS)

    Dominguez, Anthony; Kleissl, Jan P.; Luvall, Jeffrey C.

    2011-01-01

    Large-eddy Simulation (LES) was used to study convective boundary layer (CBL) flow through suburban regions with both large and small scale heterogeneities in surface temperature. Constant remotely sensed surface temperatures were applied at the surface boundary at resolutions of 10 m, 90 m, 200 m, and 1 km. Increasing the surface resolution from 1 km to 200 m had the most significant impact on the mean and turbulent flow characteristics as the larger scale heterogeneities became resolved. While previous studies concluded that scales of heterogeneity much smaller than the CBL inversion height have little impact on the CBL characteristics, we found that further increasing the surface resolution (resolving smaller scale heterogeneities) results in an increase in mean surface heat flux, thermal blending height, and potential temperature profile. The results of this study will help to better inform sub-grid parameterization for meso-scale meteorological models. The simulation tool developed through this study (combining LES and high resolution remotely sensed surface conditions) is a significant step towards future studies on the micro-scale meteorology in urban areas.

  10. Investigation of the Neel Model of Thermal Activation in Heterogeneous Cobalt-Silver Alloy Films Through the Use of Dynamic Susceptibility Measurements

    NASA Astrophysics Data System (ADS)

    Slade, Steven Barclay

    Co-Ag heterogeneous alloys films having 5 at% Co are produced by sputtering and annealed after deposition to relieve stress and promote particle growth. X-ray diffraction suggests the as-deposited state consists of a single fcc alloy phase, with local density fluctuations resulting from the immiscible nature of Co and Ag leading to the formation of Co-rich and Ag-rich regions. Annealing is seen to drive progressive separation and growth of the Ag-rich and Co-rich areas. Characterizations of magnetic properties indicate the Co precipitates are ferromagnetically ordered and have a uniaxial anisotropy. A Curie-Weiss analysis of the inverse initial dc susceptibility indicates the as-deposited film has net antiferromagnetic interparticle magnetic interactions, while the annealed sample has non-interacting particles. Fitting the magnetization curves to a Langevin function with a lognormal volume distribution indicates the films have a narrow particle size distribution. The thermal activation behavior of the annealed sample is investigated through the use of dynamic susceptibility measurements made with a high sensitivity ac susceptometer and a SQUID magnetometer, which span 8 decades in frequency. The Neel model of thermal activation is first applied to the in-phase susceptibility data following a generally-accepted conventional analysis taken from the spin glass literature. Trends in the data are consistent with the Neel model, but values for the prefactor and the most probable energy barrier to reversal from this analysis are unphysical. A new method for applying the Neel model is presented, and allows, for the first time, correct application of this model to dynamic susceptibility data from a distributed system. This analysis of the dynamic susceptibility data yields physically meaningful results, provides a direct measure of the distribution of energy barriers, and derives a scaling relationship allowing data at different frequencies to be scaled onto a universal