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Sample records for affect tumor development

  1. Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation.

    PubMed

    Rodriguez-Puebla, Marcelo L; Miliani de Marval, Paula L; LaCava, Margaret; Moons, David S; Kiyokawa, Hiroaki; Conti, Claudio J

    2002-08-01

    Most human tumors have mutations that result in deregulation of the cdk4/cyclin-Ink4-Rb pathway. Overexpression of D-type cyclins or cdk4 and inactivation of Ink4 inhibitors are common in human tumors. Conversely, lack of cyclin D1 expression results in significant reduction in mouse skin and mammary tumor development. However, complete elimination of tumor development was not observed in these models, suggesting that other cyclin/cdk complexes play an important role in tumorigenesis. Here we described the effects of cdk4 deficiency on mouse skin proliferation and tumor development. Cdk4 deficiency resulted in a 98% reduction in the number of tumors generated through the two-stage carcinogenesis model. The absence of cdk4 did not affect normal keratinocyte proliferation and both wild-type and cdk4 knockout epidermis are equally affected after topical treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in epidermal hyperplasia. In similar fashion, cdk4 knockout keratinocytes proliferated well in an in vivo model of wound-induced proliferation. Biochemical studies in mouse epidermis showed that cdk6 activity increased twofold in cdk4-deficient mice compared to wild-type siblings. These results suggest that therapeutic approaches to inhibit cdk4 activity could provide a target to inhibit tumor development with minimal or no effect in normal tissue.

  2. cdk4 Deficiency Inhibits Skin Tumor Development but Does Not Affect Normal Keratinocyte Proliferation

    PubMed Central

    Rodriguez-Puebla, Marcelo L.; Miliani de Marval, Paula L.; LaCava, Margaret; Moons, David S.; Kiyokawa, Hiroaki; Conti, Claudio J.

    2002-01-01

    Most human tumors have mutations that result in deregulation of the cdk4/cyclin-Ink4-Rb pathway. Overexpression of D-type cyclins or cdk4 and inactivation of Ink4 inhibitors are common in human tumors. Conversely, lack of cyclin D1 expression results in significant reduction in mouse skin and mammary tumor development. However, complete elimination of tumor development was not observed in these models, suggesting that other cyclin/cdk complexes play an important role in tumorigenesis. Here we described the effects of cdk4 deficiency on mouse skin proliferation and tumor development. Cdk4 deficiency resulted in a 98% reduction in the number of tumors generated through the two-stage carcinogenesis model. The absence of cdk4 did not affect normal keratinocyte proliferation and both wild-type and cdk4 knockout epidermis are equally affected after topical treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in epidermal hyperplasia. In similar fashion, cdk4 knockout keratinocytes proliferated well in an in vivo model of wound-induced proliferation. Biochemical studies in mouse epidermis showed that cdk6 activity increased twofold in cdk4-deficient mice compared to wild-type siblings. These results suggest that therapeutic approaches to inhibit cdk4 activity could provide a target to inhibit tumor development with minimal or no effect in normal tissue. PMID:12163365

  3. Inhibition of polyamine oxidase activity affects tumor development during the maize-Ustilago maydis interaction.

    PubMed

    Jasso-Robles, Francisco Ignacio; Jiménez-Bremont, Juan Francisco; Becerra-Flora, Alicia; Juárez-Montiel, Margarita; Gonzalez, María Elisa; Pieckenstain, Fernando Luis; García de la Cruz, Ramón Fernando; Rodríguez-Kessler, Margarita

    2016-05-01

    Ustilago maydis is a biotrophic plant pathogenic fungus that leads to tumor development in the aerial tissues of its host, Zea mays. These tumors are the result of cell hypertrophy and hyperplasia, and are accompanied by the reprograming of primary and secondary metabolism of infected plants. Up to now, little is known regarding key plant actors and their role in tumor development during the interaction with U. maydis. Polyamines are small aliphatic amines that regulate plant growth, development and stress responses. In a previous study, we found substantial increases of polyamine levels in tumors. In the present work, we describe the maize polyamine oxidase (PAO) gene family, its contribution to hydrogen peroxide (H2O2) production and its possible role in tumor development induced by U. maydis. Histochemical analysis revealed that chlorotic lesions and maize tumors induced by U. maydis accumulate H2O2 to significant levels. Maize plants inoculated with U. maydis and treated with the PAO inhibitor 1,8-diaminooctane exhibit a notable reduction of H2O2 accumulation in infected tissues and a significant drop in PAO activity. This treatment also reduced disease symptoms in infected plants. Finally, among six maize PAO genes only the ZmPAO1, which encodes an extracellular enzyme, is up-regulated in tumors. Our data suggest that H2O2 produced through PA catabolism by ZmPAO1 plays an important role in tumor development during the maize-U. maydis interaction.

  4. Cell surface fucosylation does not affect development of colon tumors in mice with germline Smad3 mutation

    PubMed Central

    Domino, Steven E.; Karnak, David M.; Hurd, Elizabeth A.

    2006-01-01

    Background/Aims: Neoplasia-related alterations in cell surface α(1,2)fucosylated glycans have been reported in multiple tumors including colon, pancreas, endometrium, cervix, bladder, lung, and choriocarcinoma. Spontaneous colorectal tumors from mice with a germline null mutation of transforming growth factor-β signaling gene Smad3 (Madh3) were tested for α(1,2)fucosylated glycan expression. Methods: Ulex Europaeus Agglutinin-I lectin staining, fucosyltransferase gene northern blot analysis, and a cross of mutant mice with Fut2 and Smad3 germline mutations were performed. Results: Spontaneous colorectal tumors from Smad3 (-/-) homozygous null mice were found to express α(1,2)fucosylated glycans in an abnormal pattern compared to adjacent nonneoplastic colon. Northern blot analysis of α(1,2)fucosyltransferase genes Fut1 and Fut2 revealed that Fut2, but not Fut1, steady-state mRNA levels were significantly increased in tumors relative to adjacent normal colonic mucosa. Mutant mice with a Fut2-inactivating germline mutation were crossed with Smad3 targeted mice. In Smad3 (-/-)/Fut2 (-/-) double knock-out mice, UEA-I lectin staining was eliminated from colon and colon tumors, however, the number and size of tumors present by 24 weeks of age did not vary regardless of the Fut2 genotype. Conclusions: In this model of colorectal cancer, cell surface α(1,2)fucosylation does not affect development of colon tumors. PMID:17264540

  5. CDK2 activation in mouse epidermis induces keratinocyte proliferation but does not affect skin tumor development.

    PubMed

    Macias, Everardo; Miliani de Marval, Paula L; De Siervi, Adriana; Conti, Claudio J; Senderowicz, Adrian M; Rodriguez-Puebla, Marcelo L

    2008-08-01

    It has been widely assumed that elevated CDK2 kinase activity plays a contributory role in tumorigenesis. We have previously shown that mice overexpressing CDK4 under control of the keratin 5 promoter (K5CDK4 mice) develop epidermal hyperplasia and increased susceptibility to squamous cell carcinomas. In this model, CDK4 overexpression results in increased CDK2 activity associated with the noncatalytic function of CDK4, sequestration of p21(Cip1) and p27(Kip1). Furthermore, we have shown that ablation of Cdk2 reduces Ras-Cdk4 tumorigenesis, suggesting that increased CDK2 activity plays an important role in Ras-mediated tumorigenesis. To investigate this hypothesis, we generated two transgenic mouse models of elevated CDK2 kinase activity, K5Cdk2 and K5Cdk4(D158N) mice. The D158N mutation blocks CDK4 kinase activity without interfering with its binding capability. CDK2 activation via overexpression of CDK4(D158N), but not of CDK2, resulted in epidermal hyperplasia. We observed elevated levels of p21(Cip1) in K5Cdk2, but not in K5Cdk4(D158N), epidermis, suggesting that CDK2 overexpression elicits a p21(Cip1) response to maintain keratinocyte homeostasis. Surprisingly, we found that neither CDK2 overexpression nor the indirect activation of CDK2 enhanced skin tumor development. Thus, although the indirect activation of CDK2 is sufficient to induce keratinocyte hyperproliferation, activation of CDK2 alone does not induce malignant progression in Ras-mediated tumorigenesis.

  6. CDK2 Activation in Mouse Epidermis Induces Keratinocyte Proliferation but Does Not Affect Skin Tumor Development

    PubMed Central

    Macias, Everardo; Miliani de Marval, Paula L.; De Siervi, Adriana; Conti, Claudio J.; Senderowicz, Adrian M.; Rodriguez-Puebla, Marcelo L.

    2008-01-01

    It has been widely assumed that elevated CDK2 kinase activity plays a contributory role in tumorigenesis. We have previously shown that mice overexpressing CDK4 under control of the keratin 5 promoter (K5CDK4 mice) develop epidermal hyperplasia and increased susceptibility to squamous cell carcinomas. In this model, CDK4 overexpression results in increased CDK2 activity associated with the noncatalytic function of CDK4, sequestration of p21Cip1 and p27Kip1. Furthermore, we have shown that ablation of Cdk2 reduces Ras-Cdk4 tumorigenesis, suggesting that increased CDK2 activity plays an important role in Ras-mediated tumorigenesis. To investigate this hypothesis, we generated two transgenic mouse models of elevated CDK2 kinase activity, K5Cdk2 and K5Cdk4D158N mice. The D158N mutation blocks CDK4 kinase activity without interfering with its binding capability. CDK2 activation via overexpression of CDK4D158N, but not of CDK2, resulted in epidermal hyperplasia. We observed elevated levels of p21Cip1 in K5Cdk2, but not in K5Cdk4D158N, epidermis, suggesting that CDK2 overexpression elicits a p21Cip1 response to maintain keratinocyte homeostasis. Surprisingly, we found that neither CDK2 overexpression nor the indirect activation of CDK2 enhanced skin tumor development. Thus, although the indirect activation of CDK2 is sufficient to induce keratinocyte hyperproliferation, activation of CDK2 alone does not induce malignant progression in Ras-mediated tumorigenesis. PMID:18599613

  7. How does cancer cell metabolism affect tumor migration and invasion?

    PubMed

    Han, Tianyu; Kang, De; Ji, Daokun; Wang, Xiaoyu; Zhan, Weihua; Fu, Minggui; Xin, Hong-Bo; Wang, Jian-Bin

    2013-01-01

    Cancer metastasis is the major cause of cancer-associated death. Accordingly, identification of the regulatory mechanisms that control whether or not tumor cells become "directed walkers" is a crucial issue of cancer research. The deregulation of cell migration during cancer progression determines the capacity of tumor cells to escape from the primary tumors and invade adjacent tissues to finally form metastases. The ability to switch from a predominantly oxidative metabolism to glycolysis and the production of lactate even when oxygen is plentiful is a key characteristic of cancer cells. This metabolic switch, known as the Warburg effect, was first described in 1920s, and affected not only tumor cell growth but also tumor cell migration. In this review, we will focus on the recent studies on how cancer cell metabolism affects tumor cell migration and invasion. Understanding the new aspects on molecular mechanisms and signaling pathways controlling tumor cell migration is critical for development of therapeutic strategies for cancer patients.

  8. Tumor necrosis factor-alpha during neonatal brain development affects anxiety- and depression-related behaviors in adult male and female mice.

    PubMed

    Babri, Shirin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

    2014-03-15

    A nascent literature suggests that neonatal infection is a risk factor for the development of brain, behavior and hypothalamic-pituitary-adrenal axis which can affect anxiety- and depression-related behaviors in later life. It has been documented that neonatal infection raises the concentrations of tumor necrosis factor-alpha (TNF-α) in neonate rodents and such infections may result in neonatal brain injury, at least in part, through pro-inflammatory cytokines. In addition, previous studies have shown that TNF-α is involved in cellular differentiation, neurogenesis and programmed cell death during the development of the central nervous system. We investigated for the first time whether neonatal exposure to TNF-α can affect body weight, stress-induced corticosterone (COR), anxiety- and depression-related behaviors in adult mice. In the present study, neonatal mice were treated to recombinant mouse TNF-α (0.2, 0.4, 0.7 and 1 μg/kg) or saline on postnatal days 3 and 5, then adult male and female mice were exposed to different behavioral tests. The results indicated that neonatal TNF-α treatment reduced body weight in neonatal period in both sexes. In addition, this study presents findings indicating that high doses of TNF- increase stress-induced COR levels, anxiety- and depression-related behaviors in adult males, but increase levels of anxiety without significantly influencing depression in adult female mice [corrected]. Our findings suggest that TNF-α exposure during neonatal period can alter brain and behavior development in a dose and sex-dependent manner in mice.

  9. Tumor necrosis factor-alpha during neonatal brain development affects anxiety- and depression-related behaviors in adult male and female mice.

    PubMed

    Babri, Shirin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

    2014-03-15

    A nascent literature suggests that neonatal infection is a risk factor for the development of brain, behavior and hypothalamic-pituitary-adrenal axis which can affect anxiety- and depression-related behaviors in later life. It has been documented that neonatal infection raises the concentrations of tumor necrosis factor-alpha (TNF-α) in neonate rodents and such infections may result in neonatal brain injury, at least in part, through pro-inflammatory cytokines. In addition, previous studies have shown that TNF-α is involved in cellular differentiation, neurogenesis and programmed cell death during the development of the central nervous system. We investigated for the first time whether neonatal exposure to TNF-α can affect body weight, stress-induced corticosterone (COR), anxiety- and depression-related behaviors in adult mice. In the present study, neonatal mice were treated to recombinant mouse TNF-α (0.2, 0.4, 0.7 and 1 μg/kg) or saline on postnatal days 3 and 5, then adult male and female mice were exposed to different behavioral tests. The results indicated that neonatal TNF-α treatment reduced body weight in neonatal period in both sexes. In addition, this study presents findings indicating that high doses of TNF- increase stress-induced COR levels, anxiety- and depression-related behaviors in adult males, but increase levels of anxiety without significantly influencing depression in adult female mice [corrected]. Our findings suggest that TNF-α exposure during neonatal period can alter brain and behavior development in a dose and sex-dependent manner in mice. PMID:24398264

  10. Metformin selectively affects human glioblastoma tumor-initiating cell viability

    PubMed Central

    Würth, Roberto; Pattarozzi, Alessandra; Gatti, Monica; Bajetto, Adirana; Corsaro, Alessandro; Parodi, Alessia; Sirito, Rodolfo; Massollo, Michela; Marini, Cecilia; Zona, Gianluigi; Fenoglio, Daniela; Sambuceti, Gianmario; Filaci, Gilberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio

    2013-01-01

    Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect. PMID:23255107

  11. Cross-talk between tumors can affect responses to therapy

    PubMed Central

    Devaud, Christel; John, Liza B; Westwood, Jennifer A; Yong, Carmen SM; Beavis, Paul A; Schwendener, Reto A; Darcy, Phillip K; Kershaw, Michael H

    2015-01-01

    Advanced stages of cancer often involve multiple tumors in different locations in the body. These tumors are associated with a microenvironment that can influence tumor responses to immunotherapy. Whether tumors and their disparate microenvironment can interact together at distance in a multiple tumor setting, through a form of cross-talk, and affect their responses to immunotherapy has never been described. Our study investigated the cross-talk between two tumors with disparate microenvironments in a mouse model. We demonstrated that immunosuppressive visceral tumors could influence distant subcutaneous (SC) tumors to render them resistant to immunotherapy. We observed distinct modifications in the SC tumor microenvironment following cross-talk with kidney tumors that exhibit a type-2 macrophage-related immunosuppressive microenvironment. Indeed, when a concomitant kidney tumor was present in the mouse, the SC tumors were highly infiltrated with M2 macrophages and had a reduced T cell and NK cell effector immune profile. Finally, blocking the M2-associated chemokine CCL2 or depleting macrophages, significantly improved the effect of immunotherapy on growth of SC tumors in the presence of concomitant kidney tumors. This work emphasizes the potential negative influence that a tumor, with a strong immunosuppressive microenvironment, can exert on distant tumors that would normally be treatment-responsive. This report may lead to a new vision of the prioritization in the treatment of advanced metastatic cancer. PMID:26140251

  12. Factors affecting intellectual outcome in pediatric brain tumor patients

    SciTech Connect

    Ellenberg, L.; McComb, J.G.; Siegel, S.E.; Stowe, S.

    1987-11-01

    A prospective study utilizing repeated intellectual testing was undertaken in 73 children with brain tumors consecutively admitted to Childrens Hospital of Los Angeles over a 3-year period to determine the effect of tumor location, extent of surgical resection, hydrocephalus, age of the child, radiation therapy, and chemotherapy on cognitive outcome. Forty-three patients were followed for at least two sequential intellectual assessments and provide the data for this study. Children with hemispheric tumors had the most general cognitive impairment. The degree of tumor resection, adequately treated hydrocephalus, and chemotherapy had no bearing on intellectual outcome. Age of the child affected outcome mainly as it related to radiation. Whole brain radiation therapy was associated with cognitive decline. This was especially true in children below 7 years of age, who experienced a very significant loss of function after whole brain radiation therapy.

  13. Genetic background affects susceptibility to tumoral stem cell reprogramming

    PubMed Central

    García-Ramírez, Idoia; Ruiz-Roca, Lucía; Martín-Lorenzo, Alberto; Blanco, Óscar; García-Cenador, María Begoña; García-Criado, Francisco Javier; Vicente-Dueñas, Carolina; Sánchez-García, Isidro

    2013-01-01

    The latest studies of the interactions between oncogenes and its target cell have shown that certain oncogenes may act as passengers to reprogram tissue-specific stem/progenitor cell into a malignant cancer stem cell state. In this study, we show that the genetic background influences this tumoral stem cell reprogramming capacity of the oncogenes using as a model the Sca1-BCRABLp210 mice, where the type of tumor they develop, chronic myeloid leukemia (CML), is a function of tumoral stem cell reprogramming. Sca1-BCRABLp210 mice containing FVB genetic components were significantly more resistant to CML. However, pure Sca1-BCRABLp210 FVB mice developed thymomas that were not seen in the Sca1-BCRABLp210 mice into the B6 background. Collectively, our results demonstrate for the first time that tumoral stem cell reprogramming fate is subject to polymorphic genetic control. PMID:23839033

  14. [Development of the affect system].

    PubMed

    Moser, U; Von Zeppelin, I

    1996-01-01

    The authors show that the development of the affect system commences with affects of an exclusively communicative nature. These regulate the relationship between subject and object. On a different plane they also provide information on the feeling of self deriving from the interaction. Affect is seen throughout as a special kind of information. One section of the article is given over to intensity regulation and early affect defenses. The development of cognitive processes leads to the integration of affect systems and cognitive structures. In the pre-conceptual concretistic phase, fantasies change the object relation in such a way as to make unpleasant affects disappear. Only at a later stage do fantasies acquire the capacity to deal with affects. Ultimately, the affect system is grounded on an invariant relationship feeling. On a variety of different levels it displays the features typical of situation theory and the theory of the representational world, thus making it possible to entertain complex object relations. In this process the various planes of the affect system are retained and practised. Finally, the authors discuss the consequences of their remarks for the understanding of psychic disturbances and the therapies brought to bear on them. PMID:8584745

  15. Molecular biology and genetics affecting pediatric solid tumors.

    PubMed

    Lugo-Vicente, H

    2000-01-01

    Since the discovery of oncogenes more than 20 years ago, it has been proven that cancer is a genetically determined disease. Multiple genetic alteration occurs during the course of an illness for neoplasia to develop. Transformation of positive cell growth regulators (oncogenes) and inactivations of negative cell growth regulators (tumor suppressor genes) merge to express a malignant phenotype. These genetic alterations occur as chromosomal translocations, deletions, inversion, amplification or point mutation. The objective of this review is to introduce basic concepts of molecular biology and describe the molecular genetics and biologic clinical findings of the most important solid malignant tumors in children, namely Neuroblastoma, Wilms and Rhabdomyosarcoma. It is the oncology surgeons responsibility to learn basic molecular genetics and tumor biology to provide rational and appropriate care in the setting of multidisciplinary management. Identifications of new oncogenes will continue to be important milestones in diagnosis, early detection of tumor recurrence, and as potential targets for gene therapy. Fusion proteins generated by mutated translocations are true tumor specific antigens and potential targets for therapy. The predicament is that they are proteins needing therapeutic manipulation within the tumor cell nuclei. Technological advances in molecular and genetics will develop tools necessary to manipulate the cell nuclear DNA and target cancer cell.

  16. Genes affected by mouse mammary tumor virus (MMTV) proviral insertions in mouse mammary tumors are deregulated or mutated in primary human mammary tumors

    PubMed Central

    Callahan, Robert; Mudunuri, Uma; Bargo, Sharon; Raafat, Ahmed; McCurdy, David; Boulanger, Corinne; Lowther, William; Stephens, Robert; Luke, Brian T.; Stewart, Claudia; Wu, Xiaolin; Munroe, David; Smith, Gilbert H.

    2012-01-01

    The accumulation of mutations is a contributing factor in the initiation of premalignant mammary lesions and their progression to malignancy and metastasis. We have used a mouse model in which the carcinogen is the mouse mammary tumor virus (MMTV) which induces clonal premalignant mammary lesions and malignant mammary tumors by insertional mutagenesis. Identification of the genes and signaling pathways affected in MMTV-induced mouse mammary lesions provides a rationale for determining whether genetic alteration of the human orthologues of these genes/pathways may contribute to human breast carcinogenesis. A high-throughput platform for inverse PCR to identify MMTV-host junction fragments and their nucleotide sequences in a large panel of MMTV-induced lesions was developed. Validation of the genes affected by MMTV-insertion was carried out by microarray analysis. Common integration site (CIS) means that the gene was altered by an MMTV proviral insertion in at least two independent lesions arising in different hosts. Three of the new genes identified as CIS for MMTV were assayed for their capability to confer on HC11 mouse mammary epithelial cells the ability for invasion, anchorage independent growth and tumor development in nude mice. Analysis of MMTV induced mammary premalignant hyperplastic outgrowth (HOG) lines and mammary tumors led to the identification of CIS restricted to 35 loci. Within these loci members of the Wnt, Fgf and Rspo gene families plus two linked genes (Npm3 and Ddn) were frequently activated in tumors induced by MMTV. A second group of 15 CIS occur at a low frequency (2-5 observations) in mammary HOGs or tumors. In this latter group the expression of either Phf19 or Sdc2 was shown to increase HC11 cells invasion capability. Foxl1 expression conferred on HC11 cells the capability for anchorage-independent colony formation in soft agar and tumor development in nude mice. The published transcriptome and nucleotide sequence analysis of gene

  17. Chemokines in tumor development and progression

    SciTech Connect

    Mukaida, Naofumi; Baba, Tomohisa

    2012-01-15

    Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking. Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression.

  18. Environmental issues affecting CCT development

    SciTech Connect

    Reidy, M.

    1997-12-31

    While no final legislative schedule has been set for the new Congress, two issues with strong environmental ramifications which are likely to affect the coal industry seem to top the list of closely watched debates in Washington -- the Environmental Protection Agency`s proposed new ozone and particulate matter standards and utility restructuring. The paper discusses the background of the proposed standards, public comment, the Congressional review of regulations, other legislative options, and utility restructuring.

  19. HFE polymorphisms affect survival of brain tumor patients.

    PubMed

    Lee, Sang Y; Slagle-Webb, Becky; Sheehan, Jonas M; Zhu, Junjia; Muscat, Joshua E; Glantz, Michael; Connor, James R

    2015-03-01

    The HFE (high iron) protein plays a key role in the regulation of body iron. HFE polymorphisms (H63D and C282Y) are the common genetic variants in Caucasians. Based on frequency data, both HFE polymorphisms have been associated with increased risk in a number of cancers. The prevalence of the two major HFE polymorphisms in a human brain tumor patient populations and the impact of HFE polymorphisms on survival have not been studied. In the present study, there is no overall difference in survival by HFE genotype. However, male GBM patients with H63D HFE (H63D) have poorer overall survival than wild type HFE (WT) male GBM (p = 0.03). In GBM patients with the C282Y HFE polymorphism (C282Y), female patients have poorer survival than male patients (p = 0.05). In addition, female metastatic brain tumor patients with C282Y have shorter survival times post diagnosis than WT patients (p = 0.02) or male metastatic brain tumor patients with C282Y (p = 0.02). There is a tendency toward a lower proportion of H63D genotype in GBM patients than a non-tumor control group (p = 0.09) or other subtypes of brain tumors. In conclusion, our study suggests that HFE genotype impacts survival of brain tumor patients in a gender specific manner. We previously reported that glioma and neuroblastoma cell lines with HFE polymorphisms show greater resistance to chemo and radiotherapy. Taken together, these data suggest HFE genotype is an important consideration for evaluating and planning therapeutic strategies in brain tumor patients.

  20. Novel glycosaminoglycan biosynthetic inhibitors affect tumor-associated angiogenesis

    PubMed Central

    Raman, Karthik; Ninomiya, Masayuki; Nguyen, Thao Kim Nu; Tsuzuki, Yasuhiro; Koketsu, Mamoru; Kuberan, Balagurunathan

    2011-01-01

    Heparan sulfate proteoglycans (HSPGs) are essential players in several steps of tumor-associated angiogenesis. As co-receptors for several pro-angiogenic factors such as VEGF and FGF, HSPGs regulate receptor-ligand interactions and play a vital role in signal transduction. Previously, we have employed an enzymatic strategy to show the importance of cell surface HSPGs in endothelial tube formation in vitro. We have recently found several fluoro-xylosides that can selectively inhibit proteoglycan synthesis in endothelial cells. The current study demonstrates that these fluoro-xylosides are effective inhibitors of endothelial tube formation in vitro using a matrigel based assay to simulate tumor-associated angiogenesis. These first generation scaffolds offer a promising stepping-stone to the discovery of more potent fluoro-xylosides that can effectively neutralize tumor growth. PMID:21094131

  1. Cell differentiation within a yeast colony: metabolic and regulatory parallels with a tumor-affected organism.

    PubMed

    Cáp, Michal; Stěpánek, Luděk; Harant, Karel; Váchová, Libuše; Palková, Zdena

    2012-05-25

    Nutrient sensing and metabolic reprogramming are crucial for metazoan cell aging and tumor growth. Here, we identify metabolic and regulatory parallels between a layered, multicellular yeast colony and a tumor-affected organism. During development, a yeast colony stratifies into U and L cells occupying the upper and lower colony regions, respectively. U cells activate a unique metabolism controlled by the glutamine-induced TOR pathway, amino acid-sensing systems (SPS and Gcn4p) and signaling from mitochondria with lowered respiration. These systems jointly modulate U cell physiology, which adapts to nutrient limitations and utilize the nutrients released from L cells. Stress-resistant U cells share metabolic pathways and other similar characteristics with tumor cells, including the ability to proliferate. L cells behave similarly to stressed and starving cells, which activate degradative mechanisms to provide nutrients to U cells. Our data suggest a nutrient flow between both cell types, resembling the Cori cycle and glutamine-NH(4)(+) shuttle between tumor and healthy metazoan cells.

  2. Factors Affecting Outcomes in Patients Treated Surgically for Upper Extremity Tumors and Tumor-Like Lesions

    PubMed Central

    Otero, Jesse E; Graves, Christopher M; TeKippe, Ashley; Buckwalter, Joseph A; Miller, Benjamin J

    2013-01-01

    There is little data available regarding outcomes of patients who have undergone surgery for tumors of the upper extremity. Functional data after surgery for upper extremity tumors would aid in guiding patient expectations in the peri-operative period. The purpose of this study was to identify patient, tumor, and surgery-related characteristics associated with patient-reported physical and emo-tional function before and after surgery for tumors of the upper extremity. Pre- and post-operative mental and physical Medical Outcomes Study Short Form 36 (SF-36) scores were collected from 79 patients with benign and malignant neoplasms of the upper extremity. A retrospective chart review was performed to ascertain whether tumor behavior, type, location, patient sex, age, surgical specimen size, or type of surgery were correlated with differing outcomes. Our outcome measure was patient-reported physi-cal and mental score (SF-36) at less than one year, one to two years, and greater than two years post-operatively. We found that patients with tumors proximal to the elbow and patients with right-sided tumors had statistically significantly lower post-operative physical scores at minimum two-year follow-up (p=0.02). Additionally, lower physical scores were associated with age greater than 50 (p=0.03) and tumor resection rather than curettage (p=0.01). The subset of patients with hereditary multiple exostoses had significantly lower post-operative physical scores than other patient sub-populations. There was no difference in physical function after surgery between patients with benign and malig-nant tumors, patients with tumors larger than 5 cm and less than 5 cm in greatest dimension, and patients with bone versus soft tissue tumors. Inter-estingly, we found that there was no difference in mental function scores between any comparisons. Our results suggest that patient age, tumor location, and type of surgery are correlated with patient-reported physical function following sur

  3. Stromal Integrin α11β1 Affects RM11 Prostate and 4T1 Breast Xenograft Tumors Differently

    PubMed Central

    Skogstrand, Trude; Sortland, Kristina; Schmid, Marei Caroline; Reed, Rolf K.; Stuhr, Linda

    2016-01-01

    Purpose It has been implied that the collagen binding integrin α11β1 plays a role in carcinogenesis. As still relatively little is known about how the stromal integrin α11β1 affects different aspects of tumor development, we wanted to examine the direct effects on primary tumor growth, fibrosis, tumor interstitial fluid pressure (PIF) and metastasis in murine 4T1 mammary and RM11 prostate tumors, using an in vivo SCID integrin α11-deficient mouse model. Methods Tumor growth was measured using a caliper, PIF by the wick-in-needle technique, activated fibroblasts by α-SMA immunofluorescence staining and fibrosis by transmission electron microscopy and picrosirius-red staining. Metastases were evaluated using hematoxylin and eosin stained sections. Results RM11 tumor growth was significantly reduced in the SCID integrin α11-deficient (α11-KO) compared to in SCID integrin α11 wild type (WT) mice, whereas there was no similar effect in the 4T1 tumor model. The 4T1 model demonstrated an alteration in collagen fibril diameter in the integrin α11-KO mice compared to WT, which was not found in the RM11 model. There were no significant differences in the amount of activated fibroblasts, total collagen content, collagen organization or PIF in the tumors in integrin α11-deficient mice compared to WT mice. There was also no difference in lung metastases between the two groups. Conclusion Deficiency of stromal integrin α11β1 showed different effects on tumor growth and collagen fibril diameter depending on tumor type, but no effect on tumor PIF or development of lung metastasis. PMID:26990302

  4. Role of several histone lysine methyltransferases in tumor development

    PubMed Central

    LI, JIFU; ZHU, SHUNQIN; KE, XIAO-XUE; CUI, HONGJUAN

    2016-01-01

    The field of cancer epigenetics has been evolving rapidly in recent decades. Epigenetic mechanisms include DNA methylation, histone modifications and microRNAs. Histone modifications are important markers of function and chromatin state. Aberrant histone methylation frequently occurs in tumor development and progression. Multiple studies have identified that histone lysine methyltransferases regulate gene transcription through the methylation of histone, which affects cell proliferation and differentiation, cell migration and invasion, and other biological characteristics. Histones have variant lysine sites for different levels of methylation, catalyzed by different lysine methyltransferases, which have numerous effects on human cancers. The present review focused on the most recent advances, described the key function sites of histone lysine methyltransferases, integrated significant quantities of data to introduce several compelling histone lysine methyltransferases in various types of human cancers, summarized their role in tumor development and discussed their potential mechanisms of action. PMID:26998265

  5. Life-Span Development of Affective Relationships.

    ERIC Educational Resources Information Center

    Takahashi, Keiko

    This paper presents a model of affective relationships and a review of a number of empirical studies based on the model. The fundamental aim of the model is to describe the life-span development of affective relationships, which are measured in terms of an individual's representation of a variety of significant interpersonal relationships. These…

  6. Loss of stromal JUNB does not affect tumor growth and angiogenesis.

    PubMed

    Braun, Jennifer; Strittmatter, Karin; Nübel, Tobias; Komljenovic, Dorde; Sator-Schmitt, Melanie; Bäuerle, Tobias; Angel, Peter; Schorpp-Kistner, Marina

    2014-03-15

    The transcription factor AP-1 subunit JUNB has been shown to play a pivotal role in angiogenesis. It positively controls angiogenesis by regulating Vegfa as well as the transcriptional regulator Cbfb and its target Mmp13. In line with these findings, it has been demonstrated that tumor cell-derived JUNB promotes tumor growth and angiogenesis. In contrast to JUNB's function in tumor cells, the role of host-derived stromal JUNB has not been elucidated so far. Here, we show that ablation of Junb in stromal cells including endothelial cells (ECs), vascular smooth muscle cells (SMCs) and fibroblasts does not affect tumor growth in two different syngeneic mouse models, the B16-F1 melanoma and the Lewis lung carcinoma model. In-depth analyses of the tumors revealed that tumor angiogenesis remains unaffected as assessed by measurements of the microvascular density and relative blood volume in the tumor. Furthermore, we could show that the maturation status of the tumor vasculature, analyzed by the SMC marker expression, α-smooth muscle actin and Desmin, as well as the attachment of pericytes to the endothelium, is not changed upon ablation of Junb. Taken together, these results indicate that the pro-angiogenic functions of stromal JUNB are well compensated with regard to tumor angiogenesis and tumor growth. PMID:24027048

  7. Environmental Factors Affecting Preschoolers' Motor Development

    ERIC Educational Resources Information Center

    Venetsanou, Fotini; Kambas, Antonis

    2010-01-01

    The process of development occurs according to the pattern established by the genetic potential and also by the influence of environmental factors. The aim of the present study was to focus on the main environmental factors affecting motor development. The review of the literature revealed that family features, such as socioeconomic status,…

  8. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt.

    PubMed

    Würth, Roberto; Pattarozzi, Alessandra; Gatti, Monica; Bajetto, Adirano; Corsaro, Alessandro; Parodi, Alessia; Sirito, Rodolfo; Massollo, Michela; Marini, Cecilia; Zona, Gianluigi; Fenoglio, Daniela; Sambuceti, Gianmario; Filaci, Gilberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio

    2013-01-01

    Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect.

  9. Factors Affecting the Quality of Staff Development.

    ERIC Educational Resources Information Center

    Purcell, Larry O.

    A review of the literature concerning the effectiveness and quality of staff development programs focuses on factors that affect the success of such programs. These factors include: individual concerns, training activities, applications, qualifications of consultants, scheduling, strategies, facilities, feedback, collaboration, and outcomes. It is…

  10. Toward Affective Development: A Program to Stimulate Psychological and Affective Development.

    ERIC Educational Resources Information Center

    Pearl, Linda F.

    1987-01-01

    Toward Affective Development (TAD), a 191-lesson program designed to stimulate psychological and affective development for third- through sixth-graders, can be used in special education, resource rooms, and remedial settings. TAD's five sections encompass: openness to experience, effects of emotions, group dynamics, individuality, and conflict…

  11. Recent developments in affective recommender systems

    NASA Astrophysics Data System (ADS)

    Katarya, Rahul; Verma, Om Prakash

    2016-11-01

    Recommender systems (RSs) are playing a significant role since 1990s as they provide relevant, personalized information to the users over the internet. Lots of work have been done in information filtering, utilization, and application related to RS. However, an important area recently draws our attention which is affective recommender system. Affective recommender system (ARS) is latest trending area of research, as publication in this domain are few and recently published. ARS is associated with human behaviour, human factors, mood, senses, emotions, facial expressions, body gesture and physiological with human-computer interaction (HCI). Due to this assortment and various interests, more explanation is required, as it is in premature phase and growing as compared to other fields. So we have done literature review (LR) in the affective recommender systems by doing classification, incorporate reputed articles published from the year 2003 to February 2016. We include articles which highlight, analyse, and perform a study on affective recommender systems. This article categorizes, synthesizes, and discusses the research and development in ARS. We have classified and managed ARS papers according to different perspectives: research gaps, nature, algorithm or method adopted, datasets, the platform on executed, types of information and evaluation techniques applied. The researchers and professionals will positively support this survey article for understanding the current position, research in affective recommender systems and will guide future trends, opportunity and research focus in ARS.

  12. Characterization of the activities of actin-affecting drugs on tumor cell migration

    SciTech Connect

    Hayot, Caroline; Debeir, Olivier; Ham, Philippe van; Damme, Marc van; Kiss, Robert; Decaestecker, Christine . E-mail: cdecaes@ulb.ac.be

    2006-02-15

    Metastases kill 90% of cancer patients. It is thus a major challenge in cancer therapy to inhibit the spreading of tumor cells from primary tumor sites to those particular organs where metastases are likely to occur. Whereas the actin cytoskeleton is a key component involved in cell migration, agents targeting actin dynamics have been relatively poorly investigated. Consequently, valuable in vitro pharmacological tools are needed to selectively identify this type of agent. In response to the absence of any standardized process, the present work aims to develop a multi-assay strategy for screening actin-affecting drugs with anti-migratory potentials. To validate our approach, we used two cancer cell lines (MCF7 and A549) and three actin-affecting drugs (cytochalasin D, latrunculin A, and jasplakinolide). We quantified the effects of these drugs on the kinetics of actin polymerization in tubes (by means of spectrofluorimetry) and on the dynamics of actin cytoskeletons within whole cells (by means of fluorescence microscopy). Using quantitative videomicroscopy, we investigated the actual effects of the drugs on cell motility. Finally, the combined drug effects on cell motility and cell growth were evaluated by means of a scratch-wound assay. While our results showed concordant drug-induced effects on actin polymerization occurring in vitro in test tubes and within whole cells, the whole cell assay appeared more sensitive than the tube assay. The inhibition of actin polymerization induced by cytochalasin D was paralleled by a decrease in cell motility for both cell types. In the case of jasplakinolide, which induces actin polymerization, while it significantly enhanced the locomotion of the A549 cells, it significantly inhibited that of the MCF-7 ones. All these effects were confirmed by means of the scratch-wound assay except of the jasplakinolide-induced effects on MCF-7 cell motility. These later seemed compensated by an additional effect occurring during wound

  13. Evidence for involvement of phytochrome in tumor development on plants

    NASA Technical Reports Server (NTRS)

    Morrow, R. C.; Tibbitts, T. W.

    1988-01-01

    The regulation of nonpathogenic tumorous growths on tomato plants by red and far-red radiation was studied using leaf discs floated on water and irradiated from beneath. It was found that red light (600-700 nanometers) was required for the induction of tumors on tomato (Lycopersicon hirsutum Humb. & Bonpl. Plant Introduction LA 1625), while both blue (400-500 nanometers) and green (500-600 nanometers) light had little effect on tumor development. Detailed studies with red light demonstrated that tumor development increased with increasing photon flux and duration, though duration was the more significant factor. It was observed that tumor development could be prevented by the addition of far-red irradiance to red irradiance or by providing far-red irradiance immediately following red irradiance. The effectiveness of red and far-red irradiance in the regulation of tumor development indicates phytochrome involvement in this response. These findings should provide additional insight into the multiplicity of physiological factors regulating the development of nonpathogenic tumorous growths in plants.

  14. Developing Hierarchical Structures Integrating Cognition and Affect.

    ERIC Educational Resources Information Center

    Hurst, Barbara Martin

    Several categories of the affective domain are important to the schooling process. Schools are delegated the responsibility of helping students to clarify their esthetic, instrumental, and moral values. Three areas of affect are related to student achievement: subject-related affect, school-related affect, and academic self concept. In addition,…

  15. Tumor-derived death receptor 6 modulates dendritic cell development.

    PubMed

    DeRosa, David C; Ryan, Paul J; Okragly, Angela; Witcher, Derrick R; Benschop, Robert J

    2008-06-01

    Studies in murine models of cancer as well as in cancer patients have demonstrated that the immune response to cancer is often compromised. This paradigm is viewed as one of the major mechanisms of tumor escape. Many therapies focus on employing the professional antigen presenting dendritic cells (DC) as a strategy to overcome immune inhibition in cancer patients. Death receptor 6 (DR6) is an orphan member of the tumor necrosis factor receptor superfamily (TNFRSF21). It is overexpressed on many tumor cells and DR6(-/-) mice display altered immunity. We investigated whether DR6 plays a role in tumorigenesis by negatively affecting the generation of anti-tumor activity. We show that DR6 is uniquely cleaved from the cell surface of tumor cell lines by the membrane-associated matrix metalloproteinase (MMP)-14, which is often overexpressed on tumor cells and is associated with malignancy. We also demonstrate that >50% of monocytes differentiating into DC die when the extracellular domain of DR6 is present. In addition, DR6 affects the cell surface phenotype of the resulting immature DC and changes their cytokine production upon stimulation with LPS/IFN-gamma. The effects of DR6 are mostly amended when these immature DC are matured with IL-1beta/TNF-alpha, as measured by cell surface phenotype and their ability to present antigen. These results implicate MMP-14 and DR6 as a mechanism tumor cells can employ to actively escape detection by the immune system by affecting the generation of antigen presenting cells.

  16. The renal tumor morphological characteristics that affect surgical planning for laparoscopic or open partial nephrectomy.

    PubMed

    Funahashi, Yasuhito; Murotani, Kenta; Yoshino, Yasushi; Sassa, Naoto; Ishida, Shohei; Gotoh, Momokazu

    2015-02-01

    The purpose of this study is to investigate the morphological characteristics of renal tumors which affect the surgeons' decision-making for the selection of open or laparoscopic partial nephrectomy. We included 147 patients who underwent partial nephrectomy for renal masses with elective indications in this study. Laparoscopic partial nephrectomy (LPN) and open partial nephrectomy (OPN) were performed in 72 and 75 patients, respectively. Preoperative trans-sectional images were used to assess tumor characteristics such as tumor size, endophyticity, distance from the sinus, distance from the kidney equator, hilar designation, inside designation, and R.E.N.A.L. nephrometry score. Univariate logistic regression analyses demonstrated that tumor size, endophyticity, distance from the sinus, hilar designation, inside designation, and R.E.N.A.L. nephrometry score were associated with decision of laparoscopic partial nephrectomy. Among these factors, multiple regression analyses showed that endophyticity (odds ratio = 0.92, p = 0.007) and distance from the sinus (odds ratio = 1.201, p < 0.001) had statistically significant associations with the type of operation performed. ROC analyses demonstrated cut-off values of 16 mm for endophyticity (sensitivity 69%, specificity 77%) and of 4 mm for distance from the sinus (sensitivity 79%, specificity 65%) for predicting the selection of laparoscopic surgery. In conclusion, this study revealed that endophyticity and distance from the sinus were important for the surgical planning of partial nephrectomy.

  17. An important role of the hepcidin-ferroportin signaling in affecting tumor growth and metastasis.

    PubMed

    Guo, Wenli; Zhang, Shuping; Chen, Yue; Zhang, Daoqiang; Yuan, Lin; Cong, Haibo; Liu, Sijin

    2015-09-01

    Epidemiological and experimental studies have suggested that deregulated hepcidin-ferroportin (FPN) signaling is associated with the increased risk of cancers. However, the effects of deregulated hepcidin-FPN signaling on tumor behaviors such as metastasis and epithelial to mesenchymal transition (EMT) have not been closely investigated. In this study, LL/2 cancer cells were found to exhibit an impaired propensity to home into lungs, and a reduced ability to develop tumors was also demonstrated in lungs of Hamp1(-/-) mice. Moreover, hepatic hepcidin deficiency was found to considerably favor tumor-free survival in Hamp1(-/-) mice, compared with wild-type mice. These data thus underscored a contributive role of hepatic hepcidin in promoting lung cancer cell homing and fostering tumor progression. To explore the role of FPN in regulating tumor progression, we genetically engineered 4T1 cells with FPN over-expression upon induction by doxycycline. With this cell line, it was discovered that increased FPN expression reduced cell division and colony formation in vitro, without eliciting significant cell death. Analogously, FPN over-expression impeded tumor growth and metastasis to lung and liver in mice. At the molecular level, FPN over-expression was identified to undermine DNA synthesis and cell cycle progression. Importantly, FPN over-expression inhibited EMT, as reflected by the significant decrease of representative EMT markers, such as Snail1, Twist1, ZEB2, and vimentin. Additionally, there was also a reduction of lactate production in cells upon induction of FPN over-expression. Together, our results highlighted a crucial role of the hepcidin-FPN signaling in modulating tumor growth and metastasis, providing new evidence to understand the contribution of this signaling in cancers.

  18. Γ-aminobutyric acid receptors affect the progression and migration of tumor cells.

    PubMed

    Zhang, Xiaoxue; Du, Zuoyi; Liu, Jun; He, Jianxing

    2014-12-01

    Γ-aminobutyric acid (GABA) is a multifunctional molecule found in the nervous system and non-neuronal tissues. GABA receptors combine with GABA molecules and transmit signal stimuli into cells. In addition to traditional neurotransmission and regulation of secretion, GABA and GABA receptors are involved in cell differentiation and proliferation throughout peripheral organs, as well as in tumorigenesis. The exact mechanism of the GABAergic system in regulating tumor development is unclear, but many studies have revealed that GABA receptors exert critical regulative effects on tumor cell proliferation and migration. In this review, the molecular structure, distribution and biological function of GABA receptors associated with tumorigenesis are described. Recent advances in the elucidation of mechanisms underlying GABAergic signaling control over tumor growth are also discussed.

  19. Non-invasive thermal IR detection of breast tumor development in vivo

    NASA Astrophysics Data System (ADS)

    Case, Jason R.; Young, Madison A.; Dréau, D.; Trammell, Susan R.

    2015-03-01

    Lumpectomy coupled with radiation therapy and/or chemotherapy comprises the treatment of breast cancer for many patients. We are developing an enhanced thermal IR imaging technique that can be used in real-time to guide tissue excision during a lumpectomy. This novel enhanced thermal imaging method is a combination of IR imaging (8- 10 μm) and selective heating of blood (~0.5 °C) relative to surrounding water-rich tissue using LED sources at low powers. Post-acquisition processing of these images highlights temporal changes in temperature and is sensitive to the presence of vascular structures. In this study, fluorescent and enhanced thermal imaging modalities were used to estimate breast cancer tumor volumes as a function of time in 19 murine subjects over a 30-day study period. Tumor volumes calculated from fluorescent imaging follow an exponential growth curve for the first 22 days of the study. Cell necrosis affected the tumor volume estimates based on the fluorescent images after Day 22. The tumor volumes estimated from enhanced thermal imaging show exponential growth over the entire study period. A strong correlation was found between tumor volumes estimated using fluorescent imaging and the enhanced IR images, indicating that enhanced thermal imaging is capable monitoring tumor growth. Further, the enhanced IR images reveal a corona of bright emission along the edges of the tumor masses. This novel IR technique could be used to estimate tumor margins in real-time during surgical procedures.

  20. Cadmium affects retinogenesis during zebrafish embryonic development

    SciTech Connect

    Hen Chow, Elly Suk; Yu Hui, Michelle Nga; Cheng, Chi Wa; Cheng, Shuk Han

    2009-02-15

    Ocular malformations are commonly observed in embryos of aquatic species after exposure to toxicants. Using zebrafish embryos as the model organism, we showed that cadmium exposure from sphere stage (4 hpf) to end of segmentation stage (24 hpf) induced microphthalmia in cadmium-treated embryos. Embryos with eye defects were then assessed for visual abilities. Cadmium-exposed embryos were behaviorally blind, showing hyperpigmentation and loss of camouflage response to light. We investigated the cellular basis of the formation of the small eyes phenotype and the induction of blindness by studying retina development and retinotectal projections. Retinal progenitors were found in cadmium-treated embryos albeit in smaller numbers. The number of retinal ganglion cells (RGC), the first class of retinal cells to differentiate during retinogenesis, was reduced, while photoreceptor cells, the last batch of retinal neurons to differentiate, were absent. Cadmium also affected the propagation of neurons in neurogenic waves. The neurons remained in the ventronasal area and failed to spread across the retina. Drastically reduced RGC axons and disrupted optic stalk showed that the optic nerves did not extend from the retina beyond the chiasm into the tectum. Our data suggested that impairment in neuronal differentiation of the retina, disruption in RGC axon formation and absence of cone photoreceptors were the causes of microphthalmia and visual impairment in cadmium-treated embryos.

  1. Phase transition in tumor growth: I avascular development

    NASA Astrophysics Data System (ADS)

    Izquierdo-Kulich, E.; Rebelo, I.; Tejera, E.; Nieto-Villar, J. M.

    2013-12-01

    We propose a mechanism for avascular tumor growth based on a simple chemical network. This model presents a logistic behavior and shows a “second order” phase transition. We prove the fractal origin of the empirical logistics and Gompertz constant and its relation to mitosis and apoptosis rate. Finally, the thermodynamics framework developed demonstrates the entropy production rate as a Lyapunov function during avascular tumor growth.

  2. [The Role of SOCS in the Development of Tumors].

    PubMed

    Liu, Chunlai; Liu, Hongyu; Chen, Jun

    2016-09-20

    Suppressor of cytokine signaling (SOCS) family proteins are a group of negative regulatory factors that plays important roles in the negative regulation of cytokine responses by terminating the activation of the JAK-STAT and other signaling pathways. The family is composed of eight structurally related proteins. mainly through the inhibition of the activation of JAK-STAT signaling pathway and regulates cell proliferation, differentiation and apoptosis. In the process of tumor progression, the promoter CG island hypermethylation, gene mutation, gene deletion and inactivation lead to the abnormal expression of SOCS protein make JAK-STAT continuous activation, resulting in the development and metastasis of tumor. Here, we review the SOCS family members found, composition and molecular structure, the domain of the function, and the latest progress of development in tumor. Based on the important role of SOCS in tumor development, SOCS as a negative regulator factor represent a kind of tumor suppressor genes, has become a new target for tumor therapy. PMID:27666555

  3. Solitary Fibrous Tumor of the Kidney Developing Local Recurrence.

    PubMed

    Usuba, Wataru; Sasaki, Hideo; Yoshie, Hidekazu; Kitajima, Kazuki; Kudo, Hiroya; Nakazawa, Ryuto; Sato, Yuichi; Takagi, Masayuki; Chikaraishi, Tatsuya

    2016-01-01

    Solitary fibrous tumor (SFT) of the kidney is a rare entity and usually displays a favorable prognosis. We herein report a second case of renal SFT developing local recurrence. A 50-year-old man was referred to our hospital because of a left renal mass. An abdominal CT detected a large renal tumor and radical nephrectomy was performed with a possible diagnosis of renal cell carcinoma. The resected tumor size was measured at 17 × 11 × 8 cm. Grossly, necrosis was observed in central lesion of the tumor but hemorrhage was not observed. Microscopically, the tumor consisted of spindle-shaped cells with scant cytoplasm accompanied by hyalinized collagenous tissue, which displayed hemangiopericytomatous patterns. The cellularity was normal and nuclear pleomorphism was not observed. Ki-67 labeling index was less than 3%. The pathological diagnosis of SFT was made without obvious malignant findings. Three years after the surgery, a follow-up CT scan detected a mass lesion in the tumor bed. Surgical resection was performed and the resected tumor was compatible with local recurrence of the SFT without obvious malignant findings. Renal SFT should be carefully monitored even in the absence of obvious malignant findings. PMID:27239363

  4. Solitary Fibrous Tumor of the Kidney Developing Local Recurrence

    PubMed Central

    Usuba, Wataru; Sasaki, Hideo; Yoshie, Hidekazu; Kitajima, Kazuki; Kudo, Hiroya; Nakazawa, Ryuto; Sato, Yuichi; Takagi, Masayuki; Chikaraishi, Tatsuya

    2016-01-01

    Solitary fibrous tumor (SFT) of the kidney is a rare entity and usually displays a favorable prognosis. We herein report a second case of renal SFT developing local recurrence. A 50-year-old man was referred to our hospital because of a left renal mass. An abdominal CT detected a large renal tumor and radical nephrectomy was performed with a possible diagnosis of renal cell carcinoma. The resected tumor size was measured at 17 × 11 × 8 cm. Grossly, necrosis was observed in central lesion of the tumor but hemorrhage was not observed. Microscopically, the tumor consisted of spindle-shaped cells with scant cytoplasm accompanied by hyalinized collagenous tissue, which displayed hemangiopericytomatous patterns. The cellularity was normal and nuclear pleomorphism was not observed. Ki-67 labeling index was less than 3%. The pathological diagnosis of SFT was made without obvious malignant findings. Three years after the surgery, a follow-up CT scan detected a mass lesion in the tumor bed. Surgical resection was performed and the resected tumor was compatible with local recurrence of the SFT without obvious malignant findings. Renal SFT should be carefully monitored even in the absence of obvious malignant findings. PMID:27239363

  5. Solitary Fibrous Tumor of the Kidney Developing Local Recurrence.

    PubMed

    Usuba, Wataru; Sasaki, Hideo; Yoshie, Hidekazu; Kitajima, Kazuki; Kudo, Hiroya; Nakazawa, Ryuto; Sato, Yuichi; Takagi, Masayuki; Chikaraishi, Tatsuya

    2016-01-01

    Solitary fibrous tumor (SFT) of the kidney is a rare entity and usually displays a favorable prognosis. We herein report a second case of renal SFT developing local recurrence. A 50-year-old man was referred to our hospital because of a left renal mass. An abdominal CT detected a large renal tumor and radical nephrectomy was performed with a possible diagnosis of renal cell carcinoma. The resected tumor size was measured at 17 × 11 × 8 cm. Grossly, necrosis was observed in central lesion of the tumor but hemorrhage was not observed. Microscopically, the tumor consisted of spindle-shaped cells with scant cytoplasm accompanied by hyalinized collagenous tissue, which displayed hemangiopericytomatous patterns. The cellularity was normal and nuclear pleomorphism was not observed. Ki-67 labeling index was less than 3%. The pathological diagnosis of SFT was made without obvious malignant findings. Three years after the surgery, a follow-up CT scan detected a mass lesion in the tumor bed. Surgical resection was performed and the resected tumor was compatible with local recurrence of the SFT without obvious malignant findings. Renal SFT should be carefully monitored even in the absence of obvious malignant findings.

  6. Development of Hypoxia in a Preclinical Model of Tumor Micrometastases

    SciTech Connect

    Simonsen, Trude G.; Gaustad, Jon-Vidar; Rofstad, Einar K.

    2010-03-01

    Purpose: Hypoxic regions have been shown to be a characteristic feature of a wide variety of human primary tumors, whereas the oxygenation status of subclinical micrometastases is in general unknown. The development of hypoxia in a xenograft model of microscopic metastases was investigated in this study. Methods and Materials: U-25-GFP human melanomas growing in dorsal window chamber preparations in BALB/c nu/nu mice were used as a preclinical model of micrometastases. Tumor blood supply time and morphologic parameters of the vascular network were determined from first-pass imaging movies and vascular maps recorded by use of 155-kDa tetramethylrhodamine isothiocyanate-labeled dextran as a vascular tracer. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by use of pimonidazole as a hypoxia marker. Results: Nearly half of the tumors had developed hypoxic regions when they reached a diameter of 2 to 3 mm. Tumors with multiple hypoxic foci showed a low growth rate, low blood flow velocity, high vessel tortuosity, high vessel segment length, and high vascular density, whereas tumors with a single hypoxic region showed a high growth rate, high blood flow velocity, low vessel tortuosity, low vessel segment length, and low vascular density. The tumors with hypoxic regions did not differ from those without hypoxia in any single parameter. Conclusions: U-25-GFP xenograft models of vascularized human tumor micrometastases may develop hypoxic regions as a consequence of two distinctly different morphologic abnormalities in the vascular network: high resistance against blood flow (i.e., high vessel tortuosity and high vessel segment length) or low vascular density.

  7. Development of natural anti-tumor drugs by microorganisms.

    PubMed

    Chang, Chia-Che; Chen, Wei-Chuan; Ho, Tsing-Fen; Wu, Ho-Shing; Wei, Yu-Hong

    2011-05-01

    Discoveries of tumor-resistant pharmacological drugs have mainly resulted from screening of natural products and their analogs. Some are also discovered incidentally when studying organisms. The great biodiversity of microorganisms raises the possibility of producing secondary metabolites (e.g., mevastatin, lovastatin, epothilone, salinosporamide A) to cope with adverse environments. Recently, natural plant pigments with anti-tumor activities such as β-carotene, lycopene, curcumin and anthocyanins have been proposed. However, many plants have a long life cycle. Therefore, pigments from microorganisms represent another option for the development of novel anti-tumor drugs. Prodigiosin (PG) is a natural red pigment produced by microorganisms, i.e., Serratia marcescens and other gram-negative bacteria. The anti-tumor potential of PG has been widely demonstrated. The families of PG (PGs), which share a common pyrrolylpyrromethene (PPM) skeleton, are produced by various bacteria. PGs are bioactive pigments and are known to exert immunosuppressive properties, in vitro apoptotic effects, and in vivo anti-tumor activities. Currently the most common strain used for producing PGs is S. marcescens. However, few reports have discussed PGs production. This review therefore describes the development of an anti-tumor drug, PG, that can be naturally produced by microorganisms, and evaluates the microbial production system, fermentation strategies, purification and identification processes. The application potential of PGs is also discussed. PMID:21277252

  8. Development of natural anti-tumor drugs by microorganisms.

    PubMed

    Chang, Chia-Che; Chen, Wei-Chuan; Ho, Tsing-Fen; Wu, Ho-Shing; Wei, Yu-Hong

    2011-05-01

    Discoveries of tumor-resistant pharmacological drugs have mainly resulted from screening of natural products and their analogs. Some are also discovered incidentally when studying organisms. The great biodiversity of microorganisms raises the possibility of producing secondary metabolites (e.g., mevastatin, lovastatin, epothilone, salinosporamide A) to cope with adverse environments. Recently, natural plant pigments with anti-tumor activities such as β-carotene, lycopene, curcumin and anthocyanins have been proposed. However, many plants have a long life cycle. Therefore, pigments from microorganisms represent another option for the development of novel anti-tumor drugs. Prodigiosin (PG) is a natural red pigment produced by microorganisms, i.e., Serratia marcescens and other gram-negative bacteria. The anti-tumor potential of PG has been widely demonstrated. The families of PG (PGs), which share a common pyrrolylpyrromethene (PPM) skeleton, are produced by various bacteria. PGs are bioactive pigments and are known to exert immunosuppressive properties, in vitro apoptotic effects, and in vivo anti-tumor activities. Currently the most common strain used for producing PGs is S. marcescens. However, few reports have discussed PGs production. This review therefore describes the development of an anti-tumor drug, PG, that can be naturally produced by microorganisms, and evaluates the microbial production system, fermentation strategies, purification and identification processes. The application potential of PGs is also discussed.

  9. Compartmentalized Epidermal Activation of β-Catenin Differentially Affects Lineage Reprogramming and Underlies Tumor Heterogeneity.

    PubMed

    Kretzschmar, Kai; Weber, Christine; Driskell, Ryan R; Calonje, Eduardo; Watt, Fiona M

    2016-01-12

    Wnt/β-catenin activation in adult epidermis can induce new hair follicle formation and tumor development. We used lineage tracing to uncover the relative contribution of different stem cell populations. LGR6(+) and LRIG1(+) stem cells contributed to ectopic hair follicles formed in the sebaceous gland upon β-catenin activation, whereas LGR5(+) cells did not. Lgr6, but not Lrig1 or Lgr5, was expressed in a subpopulation of interfollicular epidermal cells that were competent to form new hair follicles. Oncogenic β-catenin expression in LGR5(+) cells led to formation of pilomatricomas, while LRIG1(+) cells formed trichoadenomas and LGR6(+) cells formed dermatofibromas. Tumor formation was always accompanied by a local increase in dermal fibroblast density and transient extracellular matrix remodeling. However, each tumor had a distinct stromal signature in terms of immune cell infiltrate and expression of CD26 and CD44. We conclude that compartmentalization of epidermal stem cells underlies different responses to β-catenin and skin tumor heterogeneity. PMID:26771241

  10. The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia.

    PubMed

    Villares Fragoso, Maria Candida Barisson; Wanichi, Ingrid Quevedo; Cavalcante, Isadora Pontes; Mariani, Beatriz Marinho de Paula

    2016-01-01

    Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune-Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1-3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia. PMID:27512387

  11. The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia

    PubMed Central

    Villares Fragoso, Maria Candida Barisson; Wanichi, Ingrid Quevedo; Cavalcante, Isadora Pontes; Mariani, Beatriz Marinho de Paula

    2016-01-01

    Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune–Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1–3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia. PMID:27512387

  12. Gene Therapy for Brain Tumors: Basic Developments and Clinical Implementation

    PubMed Central

    Assi, Hikmat; Candolfi, Marianela; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro R; Castro, Maria G

    2012-01-01

    Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM. PMID:22906921

  13. Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo−/− mice

    PubMed Central

    Campbell, Elizabeth J; Vissers, Margreet CM; Dachs, Gabi U

    2016-01-01

    In solid tumors, HIF1 upregulates the expression of hundreds of genes involved in cell survival, tumor growth, and adaptation to the hypoxic microenvironment. HIF1 stabilization and activity are suppressed by prolyl and asparagine hydroxylases, which require oxygen as a substrate and ascorbate as a cofactor. This has led us to hypothesize that intracellular ascorbate availability could modify the hypoxic HIF1 response and influence tumor growth. In this study, we investigated the effect of variable intracellular ascorbate levels on HIF1 induction in cancer cells in vitro, and on tumor-take rate and growth in the Gulo−/− mouse. These mice depend on dietary ascorbate, and were supplemented with 3,300 mg/L, 330 mg/L, or 33 mg/L ascorbate in their drinking water, resulting in saturating, medium, or low plasma and tissue ascorbate levels, respectively. In Lewis lung carcinoma cells (LL/2) in culture, optimal ascorbate supplementation reduced HIF1 accumulation under physiological but not pathological hypoxia. LL/2, B16-F10 melanoma, or CMT-93 colorectal cancer cells were implanted subcutaneously into Gulo−/− mice at a range of cell inocula. Establishment of B16-F10 tumors in mice supplemented with 3,300 mg/L ascorbate required an increased number of cancer cells to initiate tumor growth compared with the number of cells required in mice on suboptimal ascorbate intake. Elevated ascorbate intake was also associated with decreased tumor ascorbate levels and a reduction in HIF1α expression and transcriptional activity. Following initial growth, all CMT-93 tumors regressed spontaneously, but mice supplemented with 33 mg/L ascorbate had lower plasma ascorbate levels and grew larger tumors than optimally supplemented mice. The data from this study indicate that improved ascorbate intake is consistent with increased intracellular ascorbate levels, reduced HIF1 activity and reduced tumor initiation and growth, and this may be advantageous in the management of cancer

  14. Developing vascular and hypoxia based theranostics in solid tumors

    NASA Astrophysics Data System (ADS)

    Koonce, Nathan A.

    Tissue hypoxia was recognized for its biological attenuating effects on ionizing radiation over a century ago and is a characteristic feature of many solid tumors. Clinical and experimental evidence indicates tumor hypoxia plays diverse and key roles in tumor progression, angiogenesis, and resistance to chemotherapy/radiotherapy. Hypoxia has known effects on progression and resistance to several standard treatment approaches and the significant history of study might suggest diagnostic imaging and therapeutic interventions would be routine in oncological practice. Curiously, this is not the case and the research results involved in this report will attempt to better understand and contribute to why this gap in knowledge exists and a rationale for harnessing the potential of detecting and targeting hypoxia. Despite the addition of oxygen and reversal of hypoxia being known as the best radiosensitizer, hypoxia remains unexploited in clinical cancer therapy. The studies reported herein detail development of a novel imaging technique to detect a subtype of tumor hypoxia, vascular hypoxia or hypoxemia, with a 17-fold increase (p<0.05) in uptake of pimonidazole targeted microbubbles observed compared to controls. This technique creates the potential to study the role of hypoxemia in progression and therapeutic response. Additionally, description of a nanoparticle-based therapy that targets tumor areas associated with tumor hypoxia and the tumor microenvironment in general is reported. TNF-loaded nanoparticles combined with radiotherapy resulted in a 5.25-fold growth delay that was found to be synergistic (p<0.05) and suggests clinical evaluation is warranted. An additional study to evaluate an approach to use thermal ablation of intratumoral hypoxia by an image-guided technique developed in our group is described along with a sequence dependence of radiation preceding ablation. A final study on the use of galectin-1 antagonist to significantly decrease (p<0.05) hypoxia

  15. Development, Selection, and Validation of Tumor Growth Models

    NASA Astrophysics Data System (ADS)

    Shahmoradi, Amir; Lima, Ernesto; Oden, J. Tinsley

    In recent years, a multitude of different mathematical approaches have been taken to develop multiscale models of solid tumor growth. Prime successful examples include the lattice-based, agent-based (off-lattice), and phase-field approaches, or a hybrid of these models applied to multiple scales of tumor, from subcellular to tissue level. Of overriding importance is the predictive power of these models, particularly in the presence of uncertainties. This presentation describes our attempt at developing lattice-based, agent-based and phase-field models of tumor growth and assessing their predictive power through new adaptive algorithms for model selection and model validation embodied in the Occam Plausibility Algorithm (OPAL), that brings together model calibration, determination of sensitivities of outputs to parameter variances, and calculation of model plausibilities for model selection. Institute for Computational Engineering and Sciences.

  16. Development of multifunctional nanoparticles for brain tumor diagnosis and therapy

    NASA Astrophysics Data System (ADS)

    Veiseh, Omid

    Magnetic nanoparticles (MNPs) represent a class of non-invasive imaging agents developed for magnetic resonance (MR) imaging and drug delivery. MNPs have traditionally been developed for disease imaging via passive targeting, but recent advances in nanotechnology have enabled cellular-specific targeting, drug delivery and multi-modal imaging using these nanoparticles. Opportunities now exist to engineer MNP with designated features (e.g., size, coatings, and molecular functionalizations) for specific biomedical applications. The goal of this interdisciplinary research project is to develop targeting multifunctional nanoparticles, serving as both contrast agents and drug carriers that can effectively pass biological barriers, for diagnosis, staging and treatment of brain tumors. The developed nanoparticle system consists of a superparamagnetic iron oxide nanoparticle core (NP) and a shell comprised of biodegradable polymers such as polyethylene glycol (PEG) and chitosan. Additionally, near-infrared fluorescing (NIRF) molecules were integrated onto the NP shell to enable optical detection. Tumor targeting was achieved by the addition of chlorotoxin, a peptide with that has high affinity to 74 out of the 79 classifications of primary brain tumors and ability to illicit a therapeutic effect. This novel NP system was tested both in vitro and in vivo and was shown to specifically target gliomas in tissue culture and medulloblastomas in transgenic mice with an intact blood brain barriers (BBB), and delineate tumor boundaries in both MR and optical imaging. Additionally, the therapeutic potential of this NP system was explored in vitro, which revealed a unique nanoparticle-enabled pathway that enhances the therapeutic potential of bound peptides by promoting the internalization of membrane bound cell surface receptors. This NP system was further modified with siRNA and evaluated as a carrier for brain tumor targeted gene therapy. Most significantly, the evaluation of

  17. Variables Affecting Economic Development of Wind Energy

    SciTech Connect

    Lantz, E.; Tegen, S.

    2008-07-01

    NREL's JEDI Wind model performed an analysis of wind-power-related economic development drivers. Economic development benefits for wind and coal were estimated using NREL's JEDI Wind and JEDI Coal models.

  18. Canine tumor development and crude incidence of tumors by breed based on domestic dogs in Gifu prefecture

    PubMed Central

    KOMAZAWA, Satoshi; SAKAI, Hiroki; ITOH, Yusuke; KAWABE, Mifumi; MURAKAMI, Mami; MORI, Takashi; MARUO, Kohji

    2016-01-01

    We analyzed the status of tumor development in dogs by breed based on tumor cases that presented to the Department of Veterinary Pathology of the Gifu University for diagnostic examinations over eight years (2005–2012). We also calculated the crude incidence of tumors in dogs by breed based on the results of a survey conducted in 2011 in Gifu Prefecture. The most common sites of tumor development included the skin, digestive organs and mammary glands. Smaller dogs showed a tendency to have a higher incidence of breast tumors. We thus identified dog breeds with a higher crude incidence of tumors (Bernese mountain dog, golden retriever, corgi, etc.) and those with a lower crude incidence of tumors (Pomeranian, poodle, Chihuahua, etc.). Unlike the current trends for domestic dogs in the US and Europe, Japan has a higher number of small dogs as pets; it is therefore necessary to develop a policy for canine cancer specific to Japan. PMID:27150207

  19. Critical role of PTEN for development and progression of nerve sheath tumors in neurofibromatosis type 1.

    PubMed

    Mawrin, Christian

    2010-04-01

    Evaluation of: Gregorian C, Nakashima J, Dry SM et al.: PTEN dosage is essential for neurofibroma development and malignant transformation. Proc. Natl Acad. Sci. USA 106(46), 19479-19484 (2009). Neurofibromatosis type 1 (NF1) is among the most common inherited tumor-predisposing syndromes in humans. Development of malignant peripheral nerve sheath tumors (MPNSTs) from neurofibroma significantly affects the morbidity and mortality of NF1 patients. The authors demonstrate, using different genetically engineered mouse models, that loss of the tumor suppressor Pten in combination with overexpression of the K-ras oncogene is an important step in MPNST development. In both mouse and human tumors, the transition from low-grade neurofibromas to MPNST is associated with reduced Pten expression, deregulated mTOR signaling activity and increased proliferation. This tumor transition can be monitored by (18)F-fluoro-D-glucose-PET, offering close clinical monitoring of NF1 patients and thus early detection of MPNST development in the future. PMID:20373864

  20. Critical role of PTEN for development and progression of nerve sheath tumors in neurofibromatosis type 1.

    PubMed

    Mawrin, Christian

    2010-04-01

    Evaluation of: Gregorian C, Nakashima J, Dry SM et al.: PTEN dosage is essential for neurofibroma development and malignant transformation. Proc. Natl Acad. Sci. USA 106(46), 19479-19484 (2009). Neurofibromatosis type 1 (NF1) is among the most common inherited tumor-predisposing syndromes in humans. Development of malignant peripheral nerve sheath tumors (MPNSTs) from neurofibroma significantly affects the morbidity and mortality of NF1 patients. The authors demonstrate, using different genetically engineered mouse models, that loss of the tumor suppressor Pten in combination with overexpression of the K-ras oncogene is an important step in MPNST development. In both mouse and human tumors, the transition from low-grade neurofibromas to MPNST is associated with reduced Pten expression, deregulated mTOR signaling activity and increased proliferation. This tumor transition can be monitored by (18)F-fluoro-D-glucose-PET, offering close clinical monitoring of NF1 patients and thus early detection of MPNST development in the future.

  1. Advances in the biology of bone metastasis: how the skeleton affects tumor behavior.

    PubMed

    Sterling, Julie A; Edwards, James R; Martin, T John; Mundy, Gregory R

    2011-01-01

    It is increasingly evident that the microenvironment of bone can influence the cancer phenotype in many ways that favor growth in bone. The ability of cancer cells to adhere to bone matrix and to promote osteoclast formation are key requirements for the establishment and growth of bone metastases. Several cytokine products of breast cancers (e.g. PTHrP, IL-11, IL-8) have been shown to act upon host cells of the bone microenvironment to promote osteoclast formation, allowing for excessive bone resorption. The increased release of matrix-derived growth factors, especially TGF-β, acts back upon the tumor to facilitate further tumor expansion and enhance cytokine production, and also upon osteoblasts to suppress bone formation. This provides a self-perpetuating cycle of bone loss and tumor growth within the skeleton. Other contributing factors favoring tumor metastasis and colonization in bone include the unique structure and stiffness of skeletal tissue, along with the diverse cellular composition of the marrow environment (e.g. bone cells, stromal fibroblasts, immune cells), any of which can contribute to the phenotypic changes that can take place in metastatic deposits that favor their survival. Additionally, it is also apparent that breast cancer cells begin to express different bone specific proteins as well as proteins important for normal breast development and lactation that allow them to grow in bone and stimulate bone destruction. Taken together, these continually emerging areas of study suggest new potential pathways important in the pathogenesis of bone metastasis and potential areas for targeting therapeutics.

  2. Input and output constraints affecting irrigation development

    NASA Astrophysics Data System (ADS)

    Schramm, G.

    1981-05-01

    In many of the developing countries the expansion of irrigated agriculture is used as a major development tool for bringing about increases in agricultural output, rural economic growth and income distribution. Apart from constraints imposed by water availability, the major limitations considered to any acceleration of such programs are usually thought to be those of costs and financial resources. However, as is shown on the basis of empirical data drawn from Mexico, in reality the feasibility and effectiveness of such development programs is even more constrained by the lack of specialized physical and human factors on the input and market limitations on the output side. On the input side, the limited availability of complementary factors such as, for example, truly functioning credit systems for small-scale farmers or effective agricultural extension services impose long-term constraints on development. On the output side the limited availability, high risk, and relatively slow growth of markets for high-value crops sharply reduce the usually hoped-for and projected profitable crop mix that would warrant the frequently high costs of irrigation investments. Three conclusions are drawn: (1) Factors in limited supply have to be shadow-priced to reflect their high opportunity costs in alternative uses. (2) Re-allocation of financial resources from immediate construction of projects to longer-term increase in the supply of scarce, highly-trained manpower resources are necessary in order to optimize development over time. (3) Inclusion of high-value, high-income producing crops in the benefit-cost analysis of new projects is inappropriate if these crops could potentially be grown in already existing projects.

  3. Conditional ablation of Ikkb inhibits melanoma tumor development in mice.

    PubMed

    Yang, Jinming; Splittgerber, Ryan; Yull, Fiona E; Kantrow, Sara; Ayers, Gregory D; Karin, Michael; Richmond, Ann

    2010-07-01

    Several lines of evidence suggest that tumor cells show elevated activity of the NF-kappaB transcription factor, a phenomenon often resulting from constitutive activity of IkappaB kinase beta (IKKbeta). However, others have found that loss of NF-kappaB activity or IKKbeta is tumor promoting. The role of NF-kappaB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKbeta in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby HRasV12 is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/Arf-/- mice with melanocyte-specific deletion of Ikkb were protected from HRasV12-initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkbeta-mediated NF-kappaB activity. PMID:20530876

  4. Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis

    PubMed Central

    Habibi, Mehran; Kmieciak, Maciej; Graham, Laura; Morales, Johanna K; Bear, Harry D; Manjili, Masoud H

    2008-01-01

    Tumor development or recurrence is always a matter of concern following radiofrequency thermal ablation (RFA) of tumors. To determine whether combining RFA with immunologically active cytokines might induce tumor-specific immune responses against mammary carcinoma and inhibit tumor development or metastasis, we evaluated intralesional injection of IL-7 and IL-15 in RFA-treated murine tumors. We used two different breast carcinoma models: neu-overexpressing mouse mammary carcinoma (MMC) in FVBN202 transgenic mouse and 4T1 tumors in Balb/c mouse. MMC tend to relapse even in the presence of neu-specific immune responses, and 4T1 is a weakly immunogenic, aggressive and highly metastatic transplantable tumor. In vivo growth of both of these tumors is also associated with increased numbers of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC). We showed for the first time that unlike RFA alone, RFA combined with the administration of intralesional IL-7 and IL-15 (after RFA), induced immune responses to tumors, inhibited tumor development and lung metastasis, and reduced MDSC. PMID:18425677

  5. The 5p12 breast cancer susceptibility locus affects MRPS30 expression in estrogen-receptor positive tumors

    PubMed Central

    Quigley, David A.; Fiorito, Elisa; Nord, Silje; Van Loo, Peter; Alnæs, Grethe Grenaker; Fleischer, Thomas; Tost, Jorg; Vollan, Hans Kristian Moen; Tramm, Trine; Overgaard, Jens; Bukholm, Ida R; Hurtado, Antoni; Balmain, Allan; Børresen-Dale, Anne-Lise; Kristensen, Vessela

    2014-01-01

    Genome-wide association studies have identified numerous loci linked to breast cancer susceptibility, but the mechanism by which variations at these loci influence susceptibility is usually unknown. Some variants are only associated with particular clinical subtypes of breast cancer. Understanding how and why these variants influence subtype-specific cancer risk contributes to our understanding of cancer etiology. We conducted a genome-wide expression Quantitative Trait Locus (eQTL) study in a discovery set of 287 breast tumors and 97 normal mammary tissue samples and a replication set of 235 breast tumors. We found that the risk-associated allele of rs7716600 in the 5p12 estrogen receptor-positive (ER-positive) susceptibility locus was associated with elevated expression of the nearby gene MRPS30 exclusively in ER-positive tumors. We replicated this finding in 235 independent tumors. Further, we showed the rs7716600 risk genotype was associated with decreased MRPS30 promoter methylation exclusively in ER-positive breast tumors. In vitro studies in MCF-7 cells carrying the protective genotype showed that estrogen stimulation decreased MRPS30 promoter chromatin availability and mRNA levels. In contrast, in 600MPE cells carrying the risk genotype, estrogen increased MRPS30 expression and did not affect promoter availability. Our data suggest the 5p12 risk allele affects MRPS30 expression in estrogen-responsive tumor cells after tumor initiation by a mechanism affecting chromatin availability. These studies emphasize that the genetic architecture of breast cancer is context-specific, and integrated analysis of gene expression and chromatin remodeling in normal and tumor tissues will be required to explain the mechanisms of risk alleles. PMID:24388359

  6. GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers.

    PubMed

    Lee, Jandee; Jeong, Seonhyang; Lee, Cho Rok; Ku, Cheol Ryong; Kang, Sang-Wook; Jeong, Jong Ju; Nam, Kee-Hyun; Shin, Dong Yeob; Chung, Woong Youn; Lee, Eun Jig; Jo, Young Suk

    2015-06-01

    A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414-13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674-18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292-13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097-14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects.GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers

  7. GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers

    PubMed Central

    Lee, Jandee; Jeong, Seonhyang; Lee, Cho Rok; Ku, Cheol Ryong; Kang, Sang-Wook; Jeong, Jong Ju; Nam, Kee-Hyun; Shin, Dong Yeob; Chung, Woong Youn; Lee, Eun Jig; Jo, Young Suk

    2015-01-01

    Abstract A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414–13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674–18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292–13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097–14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects. GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new

  8. GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers.

    PubMed

    Lee, Jandee; Jeong, Seonhyang; Lee, Cho Rok; Ku, Cheol Ryong; Kang, Sang-Wook; Jeong, Jong Ju; Nam, Kee-Hyun; Shin, Dong Yeob; Chung, Woong Youn; Lee, Eun Jig; Jo, Young Suk

    2015-06-01

    A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414-13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674-18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292-13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097-14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects.GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers

  9. Factors affecting proximal tubular reabsorption during development

    SciTech Connect

    Kaskel, F.J.; Kumar, A.M.; Lockhart, E.A.; Evan, A.; Spitzer, A.

    1987-01-01

    Studies performed in several animal species have demonstrated that glomerulotubular balance is maintained throughout development despite the many changes that occur in the factors known to control it. In an attempt to understand the nature of this phenomenon the authors quantified the magnitude and described the profile of these changes in guinea pigs. The changes in physical forces were assessed from measurements of hydrostatic and oncotic pressures, whereas those in the permeability characteristics of the proximal tubule epithelium were estimated from permanence to radioactivity-labelled macromolecules of graded radii, histologic measurements of the intercellular channels, and measurements of end-proximal ratio of tubular fluid-to-plasma osmolality (TF/P/sub osm/). Between 1 and 50 days of age the net pressure for reabsorption increased from 15.0 to 30.9 mmHg with the major change occurring during the first 2-3 wk of postnatal life. The urinary recovery of (/sup 3/H)inulin, (/sup 14/C)sucrose, and (/sup 14/C)creatinine, injected in the early segment of proximal tubules did not vary with age. The urinary recovery of (/sup 14/C)mannitol increased from 92% at birth to 100% at 49 days of age. The length of the zonulae occludens and the width of the intercellular channels did not change during this period. The findings support the hypothesis that during early postnatal life glomerulotubular balance is made possible by a high permeability of the proximal tubule, which compensates for the low net reabsorptive pressure. As the animal matures and the proximal tubule epithelium becomes tighter, for glomerulotubular balance to be maintained, an increase in the number of intercellular channels and in the active transport of sodium need to be postulated.

  10. Pre-selective and selective phase in tumor development

    NASA Astrophysics Data System (ADS)

    Kimmel, Marek; Wojdyla, Tomasz

    2016-06-01

    This contribution presents a brief study of conditions for fixation of a cancer driver mutation if selective pressures change during individual's lifetime. A branching process model is used to represent the pre-selection stage, which leads to creation of highly heterogeneous subclones of transformed cells. A Moran model with selection is used to represent the second phase, which leads to development of a primary tumor. Computations and simulations allow determining feasibility of the mechanisms proposed.

  11. Transcriptional mutagenesis: causes and involvement in tumor development

    PubMed Central

    Brégeon, Damien; Doetsch, Paul W.

    2013-01-01

    The majority of normal cells in a human do not multiply continuously but are quiescent and devote most of their energy to gene transcription. When DNA damages in the transcribed strand of an active gene are bypassed by an RNA polymerase, they can miscode at the damaged site and produce mutant transcripts. This process known as transcriptional mutagenesis can lead to the production of mutant proteins that could be important in tumor development. PMID:21346784

  12. Are preoperative sex-related differences of affective symptoms in primary brain tumor patients associated with postoperative histopathological grading?

    PubMed

    Richter, Andre; Jenewein, J; Krayenbühl, N; Woernle, C; Bellut, D

    2016-01-01

    Our objective was to explore the impact of the histopathological tumor type on affective symptoms before surgery among male and female patients with supratentorial primary brain tumors. A total of 44 adult patients were included in the study. Depression and anxiety were measured using the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory. Additionally, clinical interviews, including the Hamilton Depression Rating Scale (HDRS), were conducted. The general function of patients was measured with the Karnofsky Performance Status scale (KPS). All measures were obtained before surgery and therefore before the final histopathological diagnosis. All self-rating questionnaires but not the HDRS, showed significantly higher scores in female patients. The functional status assessed with the KPS was lower in female patients and correlated to the somatic part of the BDI. We further found a tendency for higher HDRS scores in male patients with a WHO grade 4 tumor stage compared to female patients. This finding was supported by positive correlations between HDRS scores and WHO grade in male and negative correlations between HDRS scores and WHO grade in female patients. In conclusion the preoperative evaluation of affective symptoms with self-rating questionnaires in patients with brain tumors may be invalidated by the patient’s functional status. Depression should be explored with clinical interviews in these patients. Sex differences of affective symptoms in this patient group may also be related to the malignancy of the tumor, but further studies are needed to disentangle this relationship. PMID:26468140

  13. Are preoperative sex-related differences of affective symptoms in primary brain tumor patients associated with postoperative histopathological grading?

    PubMed

    Richter, Andre; Jenewein, J; Krayenbühl, N; Woernle, C; Bellut, D

    2016-01-01

    Our objective was to explore the impact of the histopathological tumor type on affective symptoms before surgery among male and female patients with supratentorial primary brain tumors. A total of 44 adult patients were included in the study. Depression and anxiety were measured using the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory. Additionally, clinical interviews, including the Hamilton Depression Rating Scale (HDRS), were conducted. The general function of patients was measured with the Karnofsky Performance Status scale (KPS). All measures were obtained before surgery and therefore before the final histopathological diagnosis. All self-rating questionnaires but not the HDRS, showed significantly higher scores in female patients. The functional status assessed with the KPS was lower in female patients and correlated to the somatic part of the BDI. We further found a tendency for higher HDRS scores in male patients with a WHO grade 4 tumor stage compared to female patients. This finding was supported by positive correlations between HDRS scores and WHO grade in male and negative correlations between HDRS scores and WHO grade in female patients. In conclusion the preoperative evaluation of affective symptoms with self-rating questionnaires in patients with brain tumors may be invalidated by the patient’s functional status. Depression should be explored with clinical interviews in these patients. Sex differences of affective symptoms in this patient group may also be related to the malignancy of the tumor, but further studies are needed to disentangle this relationship.

  14. GATA transcription factors in adrenal development and tumors.

    PubMed

    Parviainen, Helka; Kiiveri, Sanne; Bielinska, Malgorzata; Rahman, Nafis; Huhtaniemi, Ilpo T; Wilson, David B; Heikinheimo, Markku

    2007-02-01

    Of the six GATA transcription factors, GATA-4 and GATA-6 are expressed in the mouse and human adrenal with distinct developmental profiles. GATA-4 is confined to the fetal cortex, i.e. to the less differentiated proliferating cells, while GATA-6 is expressed both in the fetal and adult adrenal. In vitro, GATA-4 regulates inhibin-alpha and steroidogenic factor-1 implicated in normal adrenal function. GATA-6 probably has roles in the development and differentiation of adrenocortical cells, and in the regulation of steroidogenesis. GATA-4 expression is dramatically upregulated and GATA-6 downregulated in gonadotropin dependent mouse adrenocortical tumors. This is accompanied by the appearance of luteinizing hormone receptor (LHR). In vitro, GATA-4 transactivates LHR promoter, and gonadotropins upregulate GATA-4 levels. Human adrenal tumors occasionally express GATA-4, whereas GATA-6 levels are usually lower than normal.

  15. Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma.

    PubMed

    Hung, Noelyn A; Eiholzer, Ramona A; Kirs, Stenar; Zhou, Jean; Ward-Hartstonge, Kirsten; Wiles, Anna K; Frampton, Chris M; Taha, Ahmad; Royds, Janice A; Slatter, Tania L

    2016-03-01

    Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor-associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumor-associated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P=0.0004, and telomerase with and without macrophages P=0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1-3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs >76% for all other subtypes

  16. Affective Development in Advanced Old Age: Analyses of Terminal Change in Positive and Negative Affect

    ERIC Educational Resources Information Center

    Schilling, Oliver K.; Wahl, Hans-Werner; Wiegering, Sarah

    2013-01-01

    Late-life development of affect may unfold terminal changes that are driven more by end-of-life processes and not so much by time since birth. This study aimed to explore time-to-death-related effects in measures of affect in a sample of the very old. We used longitudinal data (2 measurement occasions: 2002 and 2003) from 140 deceased…

  17. Cathepsin S-mediated autophagic flux in tumor-associated macrophages accelerate tumor development by promoting M2 polarization

    PubMed Central

    2014-01-01

    Background Tumor-associated macrophages (TAMs) are the major component of tumor-infiltrating leukocytes. TAMs are heterogeneous, with distinct phenotypes influenced by the microenvironment surrounding tumor tissues, but relatively little is known about the key molecular in these cells that contribute to malignant phenotypes. Autophagic activity is a critical factor in tumor development that contributes to enhancing cellular fitness and survival in the hostile tumor microenvironment. However, the molecular basis and relations between autophagy and TAMs polarization remain unclear. Methods Cathepsin S (Cat S) expression was analyzed in human colon carcinoma and normal colon tissues. In vivo effects were evaluated using PancO2 subcutaneous tumor model and SL4 hepatic metastasis model. Immunofluorescence staining, flow cytometry and real-time PCR were done to examine TAMs polarization. Western blotting assay, transmission electron microscopy, mCherry-GFP-LC3 transfection and DQ-BSA degradation assays were carried out to determine its role in regulating autophagy. Results In the present study, we showed that the enhanced expression of Cat S correlated with the severity of histologic grade as well as clinical stage, metastasis, and recurrence, which are known indicators of a relatively poor prognosis of human colon carcinoma. Cat S knockout led to decreased tumor growth and metastasis. Moreover, Cat S knockout inhibited M2 macrophage polarization during tumor development. We further demonstrated that Cat S was required for not only autophagic flux but also the fusion processes of autophagosomes and lysosomes in TAMs. Importantly, we found that Cat S contributed to tumor development by regulating the M2 phenotype of TAMs through the activation of autophagy. Conclusions These results indicated that Cat S-mediated autophagic flux is an important mechanism for inducing M2-type polarization of TAMs, which leads to tumor development. These data provide strong evidence for a

  18. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by viruses are: Cervical cancer (human papillomavirus) Hepatocellular carcinoma (hepatitis B and hepatitis C ...

  19. Apoptin T108 phosphorylation is not required for its tumor-specific nuclear localization but partially affects its apoptotic activity

    SciTech Connect

    Lee, Y.-H.; Cheng, C.-M.; Chang, Y.-F.; Wang, T.-Y.; Yuo, C.-Y.; E-mail: m815006@kmu.edu.tw

    2007-03-09

    Apoptin, a chicken anemia virus-encoded protein, induces apoptosis in human tumor cells but not in normal cells. In addition, Apoptin also exhibits tumor-specific nuclear localization and tumor-specific phosphorylation on threonine 108 (T108). Here, we studied the effects of T108 phosphorylation on the tumor-specific nuclear localization and apoptotic activity of Apoptin. We first showed that a hemagglutinin (HA)-tagged Apoptin, but not the green fluorescent protein-fused Apoptin used in many previous studies, exhibited the same intracellular distribution pattern as native Apoptin. We then made and analyzed an HA-Apoptin mutant with its T108 phosphorylation site abolished. We found that Apoptin T108 phosphorylation is not required for its tumor-specific nuclear localization and abolishing the T108 phosphorylation of Apoptin does affect its apoptotic activity in tumor cells but only partially. Our results support the previous finding that Apoptin contains two distinct apoptosis domains located separately at the N- and C-terminal regions and suggest that the T108 phosphorylation may only be required for the apoptotic activity mediated through the C-terminal apoptosis domain.

  20. Ongoing neural development of affective theory of mind in adolescence

    PubMed Central

    Weigelt, Sarah; Döhnel, Katrin; Smolka, Michael N.; Kliegel, Matthias

    2014-01-01

    Affective Theory of Mind (ToM), an important aspect of ToM, involves the understanding of affective mental states. This ability is critical in the developmental phase of adolescence, which is often related with socio-emotional problems. Using a developmentally sensitive behavioral task in combination with functional magnetic resonance imaging, the present study investigated the neural development of affective ToM throughout adolescence. Eighteen adolescent (ages 12–14 years) and 18 young adult women (aged 19–25 years) were scanned while evaluating complex affective mental states depicted by actors in video clips. The ventromedial prefrontal cortex (vmPFC) showed significantly stronger activation in adolescents in comparison to adults in the affective ToM condition. Current results indicate that the vmPFC might be involved in the development of affective ToM processing in adolescence. PMID:23716712

  1. Solitary fibrous tumor of the liver from development to resection.

    PubMed

    Makino, Yuki; Miyazaki, Masanori; Shigekawa, Minoru; Ezaki, Hisao; Sakamori, Ryotaro; Yakushijin, Takayuki; Ohkawa, Kazuyoshi; Kato, Motohiko; Akasaka, Tomofumi; Shinzaki, Shinichiro; Nishida, Tsutomu; Miyake, Yuichiro; Hama, Naoki; Nagano, Hiroaki; Honma, Keiichiro; Morii, Eiichi; Wakasa, Kenichi; Hikita, Hayato; Tatsumi, Tomohide; Iijima, Hideki; Hiramatsu, Naoki; Tsujii, Masahiko; Takehara, Tetsuo

    2015-01-01

    A 55-year-old man was annually followed up for a large hepatic cyst. In 2006, a 20-mm nodule was detected in contact with the cyst that gradually grew thereafter. By 2013, the mass had expanded to 90 mm, and a percutaneous biopsy revealed a solitary fibrous tumor (SFT). Surgical resection was subsequently performed, and the patient has since been doing well for 11 months, without recurrence. SFT of the liver is a rare neoplasm; only 44 cases have been reported to date. This is the first report to describe the long-term progression of hepatic SFT from the time of its development.

  2. Solitary fibrous tumor of the liver from development to resection.

    PubMed

    Makino, Yuki; Miyazaki, Masanori; Shigekawa, Minoru; Ezaki, Hisao; Sakamori, Ryotaro; Yakushijin, Takayuki; Ohkawa, Kazuyoshi; Kato, Motohiko; Akasaka, Tomofumi; Shinzaki, Shinichiro; Nishida, Tsutomu; Miyake, Yuichiro; Hama, Naoki; Nagano, Hiroaki; Honma, Keiichiro; Morii, Eiichi; Wakasa, Kenichi; Hikita, Hayato; Tatsumi, Tomohide; Iijima, Hideki; Hiramatsu, Naoki; Tsujii, Masahiko; Takehara, Tetsuo

    2015-01-01

    A 55-year-old man was annually followed up for a large hepatic cyst. In 2006, a 20-mm nodule was detected in contact with the cyst that gradually grew thereafter. By 2013, the mass had expanded to 90 mm, and a percutaneous biopsy revealed a solitary fibrous tumor (SFT). Surgical resection was subsequently performed, and the patient has since been doing well for 11 months, without recurrence. SFT of the liver is a rare neoplasm; only 44 cases have been reported to date. This is the first report to describe the long-term progression of hepatic SFT from the time of its development. PMID:25832939

  3. Role of ribosomal protein mutations in tumor development (Review).

    PubMed

    Goudarzi, Kaveh M; Lindström, Mikael S

    2016-04-01

    Ribosomes are cellular machines essential for protein synthesis. The biogenesis of ribosomes is a highly complex and energy consuming process that initiates in the nucleolus. Recently, a series of studies applying whole-exome or whole-genome sequencing techniques have led to the discovery of ribosomal protein gene mutations in different cancer types. Mutations in ribosomal protein genes have for example been found in endometrial cancer (RPL22), T-cell acute lymphoblastic leukemia (RPL10, RPL5 and RPL11), chronic lymphocytic leukemia (RPS15), colorectal cancer (RPS20), and glioma (RPL5). Moreover, patients suffering from Diamond-Blackfan anemia, a bone marrow failure syndrome caused by mutant ribosomal proteins are also at higher risk for developing leukemia, or solid tumors. Different experimental models indicate potential mechanisms whereby ribosomal proteins may initiate cancer development. In particular, deregulation of the p53 tumor suppressor network and altered mRNA translation are mechanisms likely to be involved. We envisage that changes in expression and the occurrence of ribosomal protein gene mutations play important roles in cancer development. Ribosome biology constitutes a re-emerging vital area of basic and translational cancer research.

  4. Role of ribosomal protein mutations in tumor development (Review)

    PubMed Central

    GOUDARZI, KAVEH M.; LINDSTRÖM, MIKAEL S.

    2016-01-01

    Ribosomes are cellular machines essential for protein synthesis. The biogenesis of ribosomes is a highly complex and energy consuming process that initiates in the nucleolus. Recently, a series of studies applying whole-exome or whole-genome sequencing techniques have led to the discovery of ribosomal protein gene mutations in different cancer types. Mutations in ribosomal protein genes have for example been found in endometrial cancer (RPL22), T-cell acute lymphoblastic leukemia (RPL10, RPL5 and RPL11), chronic lymphocytic leukemia (RPS15), colorectal cancer (RPS20), and glioma (RPL5). Moreover, patients suffering from Diamond-Blackfan anemia, a bone marrow failure syndrome caused by mutant ribosomal proteins are also at higher risk for developing leukemia, or solid tumors. Different experimental models indicate potential mechanisms whereby ribosomal proteins may initiate cancer development. In particular, deregulation of the p53 tumor suppressor network and altered mRNA translation are mechanisms likely to be involved. We envisage that changes in expression and the occurrence of ribosomal protein gene mutations play important roles in cancer development. Ribosome biology constitutes a re-emerging vital area of basic and translational cancer research. PMID:26892688

  5. The Development of the Meta-Affective Trait Scale

    ERIC Educational Resources Information Center

    Uzuntiryaki-Kondakci, Esen; Kirbulut, Zubeyde Demet

    2016-01-01

    The purpose of this study was to develop a Meta-Affective Trait Scale (MATS) to measure the meta-affective inclinations related to emotions that students have while they are studying for their classes. First, a pilot study was performed with 380 10th-grade students. Results of the exploratory factor analysis supported a two-factor structure of the…

  6. Character Development. Does Sport Affect Character Development in Athletes?

    ERIC Educational Resources Information Center

    Sage, George

    1998-01-01

    Examines the impact of sport on character development, noting that historically British and American schools have valued sports for helping develop social character and citizenship. The paper discusses research on sport as a character builder, suggesting that the effect of sport on character depends on the positive or negative social contextual…

  7. Factors Affecting the Development and Use of Learning Objects

    ERIC Educational Resources Information Center

    Moisey, Susan D.; Ally, Mohamed; Spencer, Bob

    2006-01-01

    This study explored barriers and facilitating factors affecting the development and use of learning objects in developing instructional materials and their use in supporting individualized learning. Over a two-month period, students in a graduate-level instructional design course developed instructional materials incorporating learning objects or…

  8. SU-E-J-175: Comparison of the Treatment Reproducibility of Tumors Affected by Breathing Motion

    SciTech Connect

    Adamczyk, M; Piotrowski, T; Adamczyk, S

    2015-06-15

    Purpose: The aim of the dose distribution simulations was to form a global idea of intensity-modulated radiation therapy (IMRT) realization, by its comparison to three-dimensional conformal radiation therapy (3DCRT) delivery for tumors affected by respiratory motion. Methods: In the group of 10patients both 3DCRT and IMRT plans were prepared.For each field the motion kernel was generated with the largest movement amplitude of 4;6 and 8mm.Additionally,the sets of reference measurements were made in no motion conditions(0 mm).The evaluation of plan delivery,using a diode array placed on moving platform,was based on the Gamma Index analysis with distance to agreement of 3mm and dose difference of 3%. Results: IMRT plans tended to spare doses delivered to lungs compared to 3DCRT.Nonetheless,analyzed volumes showed no significant difference between the static and dynamic techniques,except for the volumes of both lungs receiving 10 and 15Gy.After adding the components associated with the respiratory movement,all IMRT lung parameters evaluated for the ipsilateral,contralateral and both lungs together,revealed considerable differences between the 0vs.6, 0vs.8 and 4vs.8-mm amplitudes.Similar results were obtained for the 3DCRT lung measurements,but without significance between the 0vs.6-mm amplitude.Taking into account the CTV score parameter in 3DCRT and IMRT plans,there was no statistically significant difference between the motion patterns with the smallest amplitudes.The differences were found for the 8-mm amplitude when it was compared both with static conditions and 4-mm amplitude (for 3DCRT) and between 0vs.6, 0vs.8 and 4vs.8-mm amplitudes (for IMRT).All accepted and measured 3DCRT and IMRT doses to spinal cord,esophagus and heart were always below the QUANTEC limits. Conclusion: The application of IMRT technique in lung radiotherapy affords possibilities for reducing the lung doses.For maximal amplitudes of breathing trajectory below 4mm,the disagreement between CTV

  9. Ramucirumab Clinical Development: an Emerging Role in Gastrointestinal Tumors.

    PubMed

    Sanchez-Gastaldo, Amparo; Gonzalez-Exposito, Reyes; Garcia-Carbonero, Rocío

    2016-08-01

    Ramucirumab (IMC-1121B, LY3009806) is a fully human G1 monoclonal antibody that specifically targets vascular endotelial growth factor receptor 2 (VEGFR-2) with a substantially greater binding affinity than that of its natural ligands. Early clinical trials in patients with advanced solid tumors demonstrated that biologically relevant blood target concentrations are achievable with tolerable doses, and also showed some preliminary evidence of clinical activity. Several pivotal phase III trials have now been concluded and have led regulatory agencies to grant marketing authorization to ramucirumab for use as second line therapy in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (as single agent or in combination with paclitaxel), in patients with advanced colorectal carcinoma (CRC) (in combination with infusional fluorouracil and irinotecan (FOLFIRI regimen)) and in patients with advanced non-small cell lung cancer (NSCLC) (in combination with docetaxel). In contrast, ramucirumab failed to significantly improve survival versus placebo as second line therapy in patients with advanced hepatocellular carcinoma (HCC). The aim of this review is to summarize the clinical development and emerging role of ramucirumab in gastrointestinal (GI) tumors, including relevant aspects of its mechanism of action, pharmacology, safety profile, and antitumor activity in gastric, HCC, and CRC carcinomas.

  10. Ramucirumab Clinical Development: an Emerging Role in Gastrointestinal Tumors.

    PubMed

    Sanchez-Gastaldo, Amparo; Gonzalez-Exposito, Reyes; Garcia-Carbonero, Rocío

    2016-08-01

    Ramucirumab (IMC-1121B, LY3009806) is a fully human G1 monoclonal antibody that specifically targets vascular endotelial growth factor receptor 2 (VEGFR-2) with a substantially greater binding affinity than that of its natural ligands. Early clinical trials in patients with advanced solid tumors demonstrated that biologically relevant blood target concentrations are achievable with tolerable doses, and also showed some preliminary evidence of clinical activity. Several pivotal phase III trials have now been concluded and have led regulatory agencies to grant marketing authorization to ramucirumab for use as second line therapy in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (as single agent or in combination with paclitaxel), in patients with advanced colorectal carcinoma (CRC) (in combination with infusional fluorouracil and irinotecan (FOLFIRI regimen)) and in patients with advanced non-small cell lung cancer (NSCLC) (in combination with docetaxel). In contrast, ramucirumab failed to significantly improve survival versus placebo as second line therapy in patients with advanced hepatocellular carcinoma (HCC). The aim of this review is to summarize the clinical development and emerging role of ramucirumab in gastrointestinal (GI) tumors, including relevant aspects of its mechanism of action, pharmacology, safety profile, and antitumor activity in gastric, HCC, and CRC carcinomas. PMID:26887374

  11. Luciferase expression and bioluminescence does not affect tumor cell growth in vitro or in vivo.

    PubMed

    Tiffen, Jessamy C; Bailey, Charles G; Ng, Cynthia; Rasko, John E J; Holst, Jeff

    2010-01-01

    Live animal imaging is becoming an increasingly common technique for accurate and quantitative assessment of tumor burden over time. Bioluminescence imaging systems rely on a bioluminescent signal from tumor cells, typically generated from expression of the firefly luciferase gene. However, previous reports have suggested that either a high level of luciferase or the resultant light reaction produced upon addition of D-luciferin substrate can have a negative influence on tumor cell growth. To address this issue, we designed an expression vector that allows simultaneous fluorescence and luminescence imaging. Using fluorescence activated cell sorting (FACS), we generated clonal cell populations from a human breast cancer (MCF-7) and a mouse melanoma (B16-F10) cell line that stably expressed different levels of luciferase. We then compared the growth capabilities of these clones in vitro by MTT proliferation assay and in vivo by bioluminescence imaging of tumor growth in live mice. Surprisingly, we found that neither the amount of luciferase nor biophotonic activity was sufficient to inhibit tumor cell growth, in vitro or in vivo. These results suggest that luciferase toxicity is not a necessary consideration when designing bioluminescence experiments, and therefore our approach can be used to rapidly generate high levels of luciferase expression for sensitive imaging experiments. PMID:21092230

  12. Stress and morphine affect survival of rats challenged with a mammary ascites tumor (MAT 13762B).

    PubMed

    Lewis, J W; Shavit, Y; Terman, G W; Gale, R P; Liebeskind, J C

    We have previously shown that exposure to inescapable footshock stress decreases survival of rats injected with a mammary ascites tumor (MAT 13762B). This increased vulnerability to the tumor challenge was prevented by an opiate antagonist, naltrexone, suggesting mediation by opioid peptides. Supporting this hypothesis, we now report that a high dose of an opiate agonist, morphine, also reduces survival of rats given the same tumor. This effect shows tolerance after 14 daily injections. The adverse effect of stress, however, did not show other signs of opioid involvement: it manifested neither tolerance with repeated stress exposures nor cross-tolerance in morphine-tolerant rats. Our recent findings that stress and morphine reduce natural killer cell cytotoxicity in a similar fashion suggest an immune mechanism that may explain the present results.

  13. Affect on survival per increase in each millimeter of tumor depth in tongue cancer.

    PubMed

    Gokavarapu, Sandhya; Ahmed, Murtaza; Parvataneni, Nagendra; Raju, K V V N; Chander, Ravi; Chandrasekhara Rao S, L M

    2015-03-01

    The critical tumor depth at which the risk of occult metastasis increases in tongue cancer has been demonstrated as ≥4-5 mm. Conventional T staging might not be an accurate predictor for survival in situations wherein infiltrative growth pattern is easily overlooked. Thus risk of death associated with increase in tumor depth per millimeter might be useful to understand patient's disease status during follow up. Historical cohorts of patients with pT1N0 and pT2N0 primary squamous cell carcinoma of tongue treated between January 2010 and December 2011 were selected and analyzed in univariate and multivariate cox-regression model to indicate the risk of death associated with an increase in each millimeter of tumor depth. The median period of follow up was 34 months. Total 67 patients fulfilled the above mentioned criteria, among them 11 patients died by the end of study period. The mean (SD) age of the patients studied was 49.7 (12.7) years and their age ranged from 21 to 74 years. Among these 66 % (n = 44) were males. In the univariate log-rank test, margin status (p = 0.016), t-stage (p = 0.018) and increased tumor depth (p < 0.0001) were risk factors for occurrence of death. When adjusted for other risk factors in the multivariate cox-regression model, per one unit increase of tumor depth (mm) there was 1.07 (95 % CI 0.95, 1.21) units increased risk of death. Depth of tumor with increase in each millimeter in tongue cancer appears to be associated with risk of death irrespective of regional lymphatic spread.

  14. ENaC/DEG in Tumor Development and Progression

    PubMed Central

    Liu, Cui; Zhu, Li-Li; Xu, Si-Guang; Ji, Hong-Long; Li, Xiu-Min

    2016-01-01

    The epithelial Na+ channel/degenerin (ENaC/DEG) superfamily, including the acid-sensing ion channels (ASICs), is characterized by a high degree of similarity in structure but highly diverse in physiological functions. These ion channels have been shown to be important in several physiological functions of normal epithelial cells, including salt homeostasis, fluid transportation and cell mobility. There is increasing evidence suggesting that ENaC/DEG channels are critically engaged in cancer cell biology, such as proliferation, migration, invasion and apoptosis, playing a role in tumor development and progression. In this review, we will discuss recent studies showing the role of ENaC and ASIC channels in epithelial cells and its relationship to the oncogenesis. PMID:27698929

  15. ENaC/DEG in Tumor Development and Progression

    PubMed Central

    Liu, Cui; Zhu, Li-Li; Xu, Si-Guang; Ji, Hong-Long; Li, Xiu-Min

    2016-01-01

    The epithelial Na+ channel/degenerin (ENaC/DEG) superfamily, including the acid-sensing ion channels (ASICs), is characterized by a high degree of similarity in structure but highly diverse in physiological functions. These ion channels have been shown to be important in several physiological functions of normal epithelial cells, including salt homeostasis, fluid transportation and cell mobility. There is increasing evidence suggesting that ENaC/DEG channels are critically engaged in cancer cell biology, such as proliferation, migration, invasion and apoptosis, playing a role in tumor development and progression. In this review, we will discuss recent studies showing the role of ENaC and ASIC channels in epithelial cells and its relationship to the oncogenesis.

  16. Gonadal development and germ cell tumors in mouse and humans.

    PubMed

    Dolci, Susanna; Campolo, Federica; De Felici, Massimo

    2015-09-01

    In multicellular organisms, proper development of gonads and germ cells is essential for the transmission of genetic information to the next generations and eventually for the survival of the species. For this reason, germline development is finely regulated to control germ cell proliferation, survival and differentiation. Disruption of such controls can lead to infertility or germ cell tumors (GCTs). GCTs are particularly hideous pathologies since they occur mainly in neonates, infants, and children, rarely in the adults. They arise primarily in the testes and ovaries, though they can also develop in extragonadal sites along the midline of the body and the brain. Many similarities exist between most types of GCTs of the ovary and testis, including a morphological resemblance (often constituting a caricature of normal embryogenesis) and a similar pattern of chromosomal alterations. Furthermore, families with both ovarian and testicular GCTs have been reported, suggesting a possible common genetic etiology. This review focuses on the cellular processes, differentiation events and molecular mechanisms occurring during gonad development in mice and humans whose disturbance can be implicated in GCT formation.

  17. Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice

    SciTech Connect

    Li, Guodong; Kong, Bo; Zhu, Yan; Zhan, Le; Williams, Jessica A.; Tawfik, Ossama; Kassel, Karen M.; Luyendyk, James P.; Wang, Li; Guo, Grace L.

    2013-10-15

    Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR{sup −/−} and SHP{sup −/−} mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR{sup −/−} mice and therefore, increased SHP expression in FXR{sup −/−} mice reduces liver tumorigenesis. To test this hypothesis, we generated FXR{sup −/−} mice with overexpression of SHP in hepatocytes (FXR{sup −/−}/SHP{sup Tg}) and determined the contribution of SHP in HCC development in FXR{sup −/−} mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR{sup −/−} mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR{sup −/−} mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXR deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver. - Highlights: • SHP does not prevent HCC incidence nor size in FXR KO mice but reduces malignancy. • Increased SHP promotes apoptosis. • Bile acids and inflammation maybe critical for HCC formation with FXR deficiency.

  18. Development and psychometric validation of the verbal affective memory test.

    PubMed

    Jensen, Christian G; Hjordt, Liv V; Stenbæk, Dea S; Andersen, Emil; Back, Silja K; Lansner, Jon; Hageman, Ida; Dam, Henrik; Nielsen, Anna P; Knudsen, Gitte M; Frokjaer, Vibe G; Hasselbalch, Steen G

    2016-10-01

    We here present the development and validation of the Verbal Affective Memory Test-24 (VAMT-24). First, we ensured face validity by selecting 24 words reliably perceived as positive, negative or neutral, respectively, according to healthy Danish adults' valence ratings of 210 common and non-taboo words. Second, we studied the test's psychometric properties in healthy adults. Finally, we investigated whether individuals diagnosed with Seasonal Affective Disorder (SAD) differed from healthy controls on seasonal changes in affective recall. Recall rates were internally consistent and reliable and converged satisfactorily with established non-affective verbal tests. Immediate recall (IMR) for positive words exceeded IMR for negative words in the healthy sample. Relatedly, individuals with SAD showed a significantly larger decrease in positive recall from summer to winter than healthy controls. Furthermore, larger seasonal decreases in positive recall significantly predicted larger increases in depressive symptoms. Retest reliability was satisfactory, rs ≥ .77. In conclusion, VAMT-24 is more thoroughly developed and validated than existing verbal affective memory tests and showed satisfactory psychometric properties. VAMT-24 seems especially sensitive to measuring positive verbal recall bias, perhaps due to the application of common, non-taboo words. Based on the psychometric and clinical results, we recommend VAMT-24 for international translations and studies of affective memory.

  19. Developing Worksheet Based on Science Process Skills: Factors Affecting Solubility

    ERIC Educational Resources Information Center

    Karsli, Fethiye; Sahin, Cigdem

    2009-01-01

    The purpose of this study is to develop a worksheet about the factors affecting solubility, which could be useful for the prospective science teachers (PST) to remind and regain their science process skills (SPS). The pilot study of the WS was carried out with 32 first grade PST during the 2007-2008 academic year in the education department at…

  20. Modeling Breast Tumor Development with a Humanized Mouse Model.

    PubMed

    Arendt, Lisa M

    2016-01-01

    The tumor microenvironment plays a critical role in breast cancer growth and progression to metastasis. Here, we describe a method to examine stromal-epithelial interactions during tumor formation and progression utilizing human-derived mammary epithelial cells and breast stromal cells. This method outlines the isolation of each cell type from reduction mammoplasty tissue, the culture and genetic modification of both epithelial and stromal cells using lentiviral technology, and the method of humanizing and implantation of transformed epithelial cells into the cleared mammary fat pads of immunocompromised mice. This model system may be a useful tool to dissect signaling interactions that contribute to invasive tumor behavior and therapeutic resistance. PMID:27581027

  1. The Immunogenicity of Colorectal Cancer in Relation to Tumor Development and Treatment

    PubMed Central

    de Vries, Natasja L.; Swets, Marloes; Vahrmeijer, Alexander L.; Hokland, Marianne; Kuppen, Peter J. K.

    2016-01-01

    Although most cancer types have been viewed as immunologically silent until recently, it has become increasingly clear that the immune system plays key roles in the course of tumor development. Remarkable progress towards understanding cancer immunogenicity and tumor-immune system interactions has revealed important implications for the design of novel immune-based therapies. Natural immune responses, but also therapeutic interventions, can modulate the tumor phenotype due to selective outgrowth of resistant subtypes. This is the result of heterogeneity of tumors, with genetic instability as a driving force, and obviously changes the immunogenicity of tumors. In this review, we discuss the immunogenicity of colorectal cancer (CRC) in relation to tumor development and treatment. As most tumors, CRC activates the immune system in various ways, and is also capable of escaping recognition and elimination by the immune system. Tumor-immune system interactions underlie the balance between immune control and immune escape, and may differ in primary tumors, in the circulation, and in liver metastases of CRC. Since CRC immunogenicity varies between tumors and individuals, novel immune-based therapeutic strategies should not only anticipate the molecular profile, but also the immunological profile of a specific tumor. PMID:27367680

  2. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development.

    PubMed

    Dong, Dezheng; Ni, Min; Li, Jianze; Xiong, Shigang; Ye, Wei; Virrey, Jenilyn J; Mao, Changhui; Ye, Risheng; Wang, Miao; Pen, Ligaya; Dubeau, Louis; Groshen, Susan; Hofman, Florence M; Lee, Amy S

    2008-01-15

    The unfolded protein response (UPR) is an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to endoplasmic reticulum (ER) stress. Although the UPR has been implicated in tumorigenesis, its precise role in endogenous cancer remains unclear. A major UPR protective response is the induction of the ER chaperone GRP78/BiP, which is expressed at high levels in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells. To determine the physiologic role of GRP78 in in situ-generated tumor and the consequence of its suppression on normal organs, we used a genetic model of breast cancer in the Grp78 heterozygous mice where GRP78 expression level was reduced by about half, mimicking anti-GRP78 agents that achieve partial suppression of GRP78 expression. Here, we report that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth. Our results reveal three major mechanisms mediated by GRP78 for cancer progression: enhancement of tumor cell proliferation, protection against apoptosis, and promotion of tumor angiogenesis. Importantly, although partial reduction of GRP78 in the Grp78 heterozygous mice substantially reduces the tumor microvessel density, it has no effect on vasculature of normal organs. Our findings establish that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis, underscoring its potential value as a novel therapeutic target for dual antitumor and antiangiogenesis activity.

  3. Development of Anti-EGF Receptor Peptidomimetics (AERP) as Tumor Imaging Agent

    PubMed Central

    Ponde, Datta E.; Su, ZiFen; Berezov, Alan; Zhang, Hongtao; Alavi, Abbas; Greene, Mark I.; Murali, Ramachandran

    2011-01-01

    EGFR is over-expressed in several solid tumors including breast, prostate, pancreas and lung cancers and is correlated to the metastasic potential of the tumor. Anti-EGFR receptor-binding peptidomimetics (AERP) were examined to assess the small molecule's potential use as tumor-specific imaging agents. The aim of this work was to design and characterize the binding specificity of the radiolabeled peptidomimetics to EGFR over-expressing cell lysate and to A431 xenograft tumors. Our newly designed peptidomimetic, AERP, was conjugated to DTPA and labeled with 99mTc. The in vivo tumor accumulation of [99mTc] DTPA-AERP-2 was 1.6 ± 0.1 %ID/g and tumor to muscle ratio was 5.5. Our studies suggest that this novel peptidomimetic, AERP-2, warrants further development as an EGFR-specific tumor-imaging agent. PMID:21392985

  4. Beneficial Microbes Affect Endogenous Mechanisms Controlling Root Development.

    PubMed

    Verbon, Eline H; Liberman, Louisa M

    2016-03-01

    Plants have incredible developmental plasticity, enabling them to respond to a wide range of environmental conditions. Among these conditions is the presence of plant growth-promoting rhizobacteria (PGPR) in the soil. Recent studies show that PGPR affect Arabidopsis thaliana root growth and development by modulating cell division and differentiation in the primary root and influencing lateral root development. These effects lead to dramatic changes in root system architecture that significantly impact aboveground plant growth. Thus, PGPR may promote shoot growth via their effect on root developmental programs. This review focuses on contextualizing root developmental changes elicited by PGPR in light of our understanding of plant-microbe interactions and root developmental biology.

  5. Enhanced tumor development by butylated hydroxytoluene (BHT) in liver, lung and gastrointestinal tract

    SciTech Connect

    Witschi, H.P.

    1986-04-03

    Continuous feeding of 0.5% or 0.05% of butylated hydroxytoluene (BHT) enhances the development of spontaneously occurring liver tumors in C3H mice, but not in BALB/c mice. In mouse lung, the tumor-enhancing effects of BHT vary with the carcinogen used and in the gastrointestinal tract of mice and rats BHT enhances development of dimethylhydrazine-induced tumors but is without effect on tumors produced by methylnitrosourea. Strain differences, effect upon various carcinogens, paradoxical dose-responses and mechanisms of action remain major questions in the toxicology of BHT. 14 refs., 2 tabs.

  6. New technique identifies first events in tumor development

    Cancer.gov

    A novel technique that enables scientists to measure and document tumor-inducing changes in DNA is providing new insight into the earliest events involved in the formation of leukemias, lymphomas and sarcomas, and could potentially lead to the discovery o

  7. Training affects the development of postural adjustments in sitting infants.

    PubMed Central

    Hadders-Algra, M; Brogren, E; Forssberg, H

    1996-01-01

    1. The present study addressed the question of whether daily balance training can affect the development of postural adjustments in sitting infants. 2. Postural responses during sitting on a moveable platform were assessed in twenty healthy infants at 5-6, 7-8 and 9-10 months of age. Multiple surface EMGs and kinematics were recorded while the infants were exposed to slow and fast horizontal forward (Fw) and backward (Bw) displacements of the platform. After the first session the parents of nine infants trained their child's sitting balance daily. 3. At the youngest age, when none of the infants could sit independently, the muscle activation patterns were direction specific and showed a large variation. This variation decreased with increasing age, resulting in selection of the most complete responses. Training facilitated response selection both during Fw and Bw translations. This suggests a training effect on the first level of the central pattern generator (CPG) model of postural control. 4. Training also affected the development of response modulation during Fw translations. It accelerated the development of: (1) the ability to modulate EMG amplitude with respect to platform velocity and initial sitting position, (2) antagonist activity and (3) a distal onset of the response. These findings point to a training effect on the second level of the CPG model of postural adjustments. Images Figure 1 Figure 4 PMID:8735713

  8. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice.

    PubMed

    Vila-Leahey, Ava; Oldford, Sharon A; Marignani, Paola A; Wang, Jun; Haidl, Ian D; Marshall, Jean S

    2016-07-01

    Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1(-/-)/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression. PMID:27622015

  9. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice

    PubMed Central

    Vila-Leahey, Ava; Oldford, Sharon A.; Marignani, Paola A.; Wang, Jun; Haidl, Ian D.; Marshall, Jean S.

    2016-01-01

    ABSTRACT Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1−/−/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression. PMID:27622015

  10. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice

    PubMed Central

    Vila-Leahey, Ava; Oldford, Sharon A.; Marignani, Paola A.; Wang, Jun; Haidl, Ian D.; Marshall, Jean S.

    2016-01-01

    ABSTRACT Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1−/−/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression.

  11. FTIR spectro-imaging of collagen scaffold formation during glioma tumor development.

    PubMed

    Noreen, Razia; Chien, Chia-Chi; Chen, Hsiang-Hsin; Bobroff, Vladimir; Moenner, Michel; Javerzat, Sophie; Hwu, Yeukuang; Petibois, Cyril

    2013-11-01

    Evidence has recently emerged that solid and diffuse tumors produce a specific extracellular matrix (ECM) for division and diffusion, also developing a specific interface with microvasculature. This ECM is mainly composed of collagens and their scaffolding appears to drive tumor growth. Although collagens are not easily analyzable by UV-fluorescence means, FTIR imaging has appeared as a valuable tool to characterize collagen contents in tissues, specially the brain, where ECM is normally devoid of collagen proteins. Here, we used FTIR imaging to characterize collagen content changes in growing glioma tumors. We could determine that C6-derived solid tumors presented high content of triple helix after 8-11 days of growth (typical of collagen fibrils formation; 8/8 tumor samples; 91 % of total variance), and further turned to larger α-helix (days 12-15; 9/10 of tumors; 94 % of variance) and β-turns (day 18-21; 7/8 tumors; 97 % of variance) contents, which suggest the incorporation of non-fibrillar collagen types in ECM, a sign of more and more organized collagen scaffold along tumor progression. The growth of tumors was also associated to the level of collagen produced (P < 0.05). This study thus confirms that collagen scaffolding is a major event accompanying the angiogenic shift and faster tumor growth in solid glioma phenotypes. PMID:24068168

  12. Myeloid cell TRAF3 regulates immune responses and inhibits inflammation and tumor development in mice1

    PubMed Central

    Lalani, Almin I.; Moore, Carissa R.; Luo, Chang; Kreider, Benjamin Z.; Liu, Yan; Morse, Herbert C.; Xie, Ping

    2014-01-01

    Myeloid cells, including granulocytes, monocytes, macrophages and dendritic cells, are crucial players in innate immunity and inflammation. These cells constitutively or inducibly express a number of receptors of the TNF receptor and Toll-like receptor (TLR) families, whose signals are transduced by TRAF molecules. In vitro studies showed that TRAF3 is required for TLR-induced type I interferon production, but the in vivo function of TRAF3 in myeloid cells remains unknown. Here we report the generation and characterization of myeloid cell-specific TRAF3-deficient (M-TRAF3−/−) mice, which allowed us to gain insights into the in vivo functions of TRAF3 in myeloid cells. We found that TRAF3 ablation did not affect the maturation or homeostasis of myeloid cells in young adult mice, even though TRAF3-deficient macrophages and neutrophils exhibited constitutive NF-κB2 activation. However, in response to injections with LPS (a bacterial mimic) or polyI:C (a viral mimic), M-TRAF3−/− mice exhibited an altered profile of cytokine production. M-TRAF3−/− mice immunized with T cell-independent (TI) and -dependent (TD) antigens displayed elevated TI IgG3 as well as TD IgG2b responses. Interestingly, 15–22 month old M-TRAF3−/− mice spontaneously developed chronic inflammation or tumors, often affecting multiple organs. Taken together, our findings indicate that TRAF3 expressed in myeloid cells regulates immune responses in myeloid cells and acts to inhibit inflammation and tumor development in mice. PMID:25422508

  13. Rearing environment affects development of the immune system in neonates.

    PubMed

    Inman, C F; Haverson, K; Konstantinov, S R; Jones, P H; Harris, C; Smidt, H; Miller, B; Bailey, M; Stokes, C

    2010-06-01

    Early-life exposure to appropriate microbial flora drives expansion and development of an efficient immune system. Aberrant development results in increased likelihood of allergic disease or increased susceptibility to infection. Thus, factors affecting microbial colonization may also affect the direction of immune responses in later life. There is a need for a manipulable animal model of environmental influences on the development of microbiota and the immune system during early life. We assessed the effects of rearing under low- (farm, sow) and high-hygiene (isolator, milk formula) conditions on intestinal microbiota and immune development in neonatal piglets, because they can be removed from the mother in the first 24 h for rearing under controlled conditions and, due to placental structure, neither antibody nor antigen is transferred in utero. Microbiota in both groups was similar between 2 and 5 days. However, by 12-28 days, piglets reared on the mother had more diverse flora than siblings reared in isolators. Dendritic cells accumulated in the intestinal mucosa in both groups, but more rapidly in isolator piglets. Importantly, the minority of 2-5-day-old farm piglets whose microbiota resembled that of an older (12-28-day-old) pig also accumulated dendritic cells earlier than the other farm-reared piglets. Consistent with dendritic cell control of T cell function, the effects on T cells occurred at later time-points, and mucosal T cells from high-hygiene, isolator pigs made less interleukin (IL)-4 while systemic T cells made more IL-2. Neonatal piglets may be a valuable model for studies of the effects of interaction between microbiota and immune development on allergy.

  14. Aire-dependent thymic development of tumor-associated regulatory T cells.

    PubMed

    Malchow, Sven; Leventhal, Daniel S; Nishi, Saki; Fischer, Benjamin I; Shen, Lynn; Paner, Gladell P; Amit, Ayelet S; Kang, Chulho; Geddes, Jenna E; Allison, James P; Socci, Nicholas D; Savage, Peter A

    2013-03-01

    Despite considerable interest in the modulation of tumor-associated Foxp3(+) regulatory T cells (T(regs)) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. We identified an endogenous population of antigen-specific T(regs) (termed MJ23 T(regs)) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 T(regs) were not reactive to a tumor-specific antigen but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 T(regs) underwent autoimmune regulator (Aire)-dependent thymic development in both male and female mice. Thus, Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific T(regs), which are likely coopted by tumors developing within the associated organ.

  15. Aire-dependent thymic development of tumor-associated regulatory T cells*

    PubMed Central

    Malchow, Sven; Leventhal, Daniel S.; Nishi, Saki; Fischer, Benjamin I.; Shen, Lynn; Paner, Gladell P.; Amit, Ayelet S.; Kang, Chulho; Geddes, Jenna E.; Allison, James P.; Socci, Nicholas D.; Savage, Peter A.

    2013-01-01

    Despite considerable interest in the modulation of tumor-associated Foxp3+ regulatory T cells (Tregs) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. Here, we identified an endogenous population of antigen-specific Tregs (termed “MJ23” Tregs) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 Tregs were not reactive to a tumor-specific antigen, but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 Tregs underwent Aire-dependent thymic development in both male and female mice. Thus Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific Tregs, which are likely co-opted by tumors developing within the associated organ. PMID:23471412

  16. CD34 EXPRESSION BY HAIR FOLLICLE STEM CELLS IS REQUIRED FOR SKIN TUMOR DEVELOPMENT IN MICE

    EPA Science Inventory

    We used knockout mice to show that a cell surface protein called CD34 is required for skin tumor formation in mice. Wild type mice treated with 7-12-Dimethylbenz(a)anthracene (DMBA) and a tumor promoter developed papillomas. When we treated CD34 knockout (KO) mice the same way, n...

  17. The Development and Evaluation of a Correspondence Training Program for Tumor Registrars.

    ERIC Educational Resources Information Center

    Fink, C. Dennis; Ryan, Robert F.

    A program designed to teach the medical vocabulary required of tumor registrars was developed and administered to 33 persons, 31 of whom were employed at 25 Louisiana hospitals. The training program was administered as a correspondence course covering such topics as the purposes of a tumor registry and how the registry is established; how to code…

  18. Bone development in black ducks as affected by dietary toxaphene

    USGS Publications Warehouse

    Mehrle, P.M.; Finley, M.T.; Ludke, J.L.; Mayer, F.L.; Kaiser, T.E.

    1979-01-01

    Black ducks, Anas rubripes, were exposed to dietary toxaphene concentrations of 0, 10, or 50 μg/g of food for 90 days prior to laying and through the reproductive season. Toxaphene did not affect reproduction or survival, but reduced growth and impaired backbone development in ducklings. Collagen, the organic matrix of bone, was decreased significantly in cervical vertebrae of ducklings fed 50 μg/g, and calcium conentrations increased in vertebrae of ducklings fed 10 or 50 μg/g. The effects of toxaphene were observed only in female ducklings. In contrast to effects on vertebrae, toxaphene exposure did not alter tibia development. Toxaphene residues in carcasses of these ducklings averaged slightly less than the dietary levels.

  19. Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments.

    PubMed

    Papathomas, Thomas G; de Krijger, Ronald R; Tischler, Arthur S

    2013-08-01

    Recent developments in molecular genetics have expanded the spectrum of disorders associated with pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGLs) and have increased the roles of pathologists in helping to guide patient care. At least 30% of these tumors are now known to be hereditary, and germline mutations of at least 10 genes are known to cause the tumors to develop. Genotype-phenotype correlations have been identified, including differences in tumor distribution, catecholamine production, and risk of metastasis, and types of tumors not previously associated with PCC/PGL are now considered in the spectrum of hereditary disease. Important new findings are that mutations of succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 (collectively "SDHx") are responsible for a large percentage of hereditary PCC/PGL and that SDHB mutations are strongly correlated with extra-adrenal tumor location, metastasis, and poor prognosis. Further, gastrointestinal stromal tumors and renal tumors are now associated with SDHx mutations. A PCC or PGL caused by any of the hereditary susceptibility genes can present as a solitary, apparently sporadic, tumor, and substantial numbers of patients presenting with apparently sporadic tumors harbor occult germline mutations of susceptibility genes. Current roles of pathologists are differential diagnosis of primary tumors and metastases, identification of clues to occult hereditary disease, and triaging of patients for optimal genetic testing by immunohistochemical staining of tumor tissue for the loss of SDHB and SDHA protein. Diagnostic pitfalls are posed by morphological variants of PCC/PGL, unusual anatomic sites of occurrence, and coexisting neuroendocrine tumors of other types in some hereditary syndromes. These pitfalls can be avoided by judicious use of appropriate immunohistochemical stains. Aside from loss of staining for SDHB, criteria for predicting risk of metastasis are still controversial, and

  20. Drosophila neural stem cells in brain development and tumor formation.

    PubMed

    Jiang, Yanrui; Reichert, Heinrich

    2014-01-01

    Neuroblasts, the neural stem cells in Drosophila, generate the complex neural structure of the central nervous system. Significant progress has been made in understanding the mechanisms regulating the self-renewal, proliferation, and differentiation in Drosophila neuroblast lineages. Deregulation of these mechanisms can lead to severe developmental defects and the formation of malignant brain tumors. Here, the authors review the molecular genetics of Drosophila neuroblasts and discuss some recent advances in stem cell and cancer biology using this model system.

  1. Measurement of changes in blood oxygenation using Multispectral Optoacoustic Tomography (MSOT) allows assessment of tumor development

    NASA Astrophysics Data System (ADS)

    Tomaszewski, Michal R.; Quiros-Gonzalez, Isabel; Joseph, James; Bohndiek, Sarah E.

    2016-03-01

    The ability to evaluate tumor oxygenation in the clinic could indicate prognosis and enable treatment monitoring, since oxygen deficient cancer cells are more resistant to chemotherapy and radiotherapy. MultiSpectral Optoacoustic Tomography (MSOT) is a hybrid technique combining the high contrast of optical imaging with the spatial resolution and penetration depth similar to ultrasound. We aim to demonstrate that MSOT can be used to monitor the development of tumor vasculature. To establish the relationship between MSOT derived imaging biomarkers and biological changes during tumor development, we performed MSOT on nude mice (n=10) bearing subcutaneous xenograft U87 glioblastoma tumors using a small animal optoacoustic tomography system. The mice were maintained under inhalation anesthesia during imaging and respired oxygen content was modified between 21% and 100%. The measurements from early (week 4) and late (week 7) stages of tumor development were compared. To further explore the functionality of the blood vessels, we examined the evolution of changes in the abundance of oxy- and deoxyhemoglobin in the tumors in response to a gas challenge. We found that the kinetics of the change in oxygen saturation (SO2) were significantly different between small tumors and the healthy blood vessels in nearby normal tissue (p=0.0054). Furthermore, we showed that there was a significant difference in the kinetics of the gas challenge between small and large tumors (p=0.0015). We also found that the tumor SO2 was significantly correlated (p=0.0057) with the tumor necrotic fraction as assessed by H&E staining in histology. In the future, this approach may be of use in the clinic as a method for tumor staging and assessment of treatment response.

  2. Development of Membrane-Bound GM-CSF and IL-18 as an Effective Tumor Vaccine

    PubMed Central

    Cheng, Ta-Chun; Chuang, Chih-Hung; Kao, Chien-Han; Hsieh, Yuan-Chin; Cheng, Kuang-Hung; Wang, Jaw-Yuan; Cheng, Chiu-Min; Chen, Chien-Shu; Cheng, Tian-Lu

    2015-01-01

    The development of effective adjuvant is the key factor to boost the immunogenicity of tumor cells as a tumor vaccine. In this study, we expressed membrane-bound granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-18 (IL-18) as adjuvants in tumor cells to stimulate immune response. B7 transmembrane domain fused GM-CSF and IL-18 was successfully expressed in the cell membrane and stimulated mouse splenocyte proliferation. Co-expression of GM-CSF and IL-18 reduced tumorigenesis (P<0.05) and enhanced tumor protective efficacy (P<0.05) significantly in comparison with GM-CSF alone. These results indicated that the combination of GM-CSF andIL-18 will enhance the immunogenicity of a cell-based anti-tumor vaccine. This membrane-bound approach can be applied to other cytokines for the development of novel vaccine strategies. PMID:26186692

  3. Development of brain mechanisms for processing affective touch

    PubMed Central

    Björnsdotter, Malin; Gordon, Ilanit; Pelphrey, Kevin A.; Olausson, Håkan; Kaiser, Martha D.

    2014-01-01

    Affective tactile stimulation plays a key role in the maturation of neural circuits, but the development of brain mechanisms processing touch is poorly understood. We therefore used functional magnetic resonance imaging (fMRI) to study brain responses to soft brush stroking of both glabrous (palm) and hairy (forearm) skin in healthy children (5–13 years), adolescents (14–17 years), and adults (25–35 years). Adult-defined regions-of-interests in the primary somatosensory cortex (SI), secondary somatosensory cortex (SII), insular cortex and right posterior superior temporal sulcus (pSTS) were significantly and similarly activated in all age groups. Whole-brain analyses revealed that responses in the ipsilateral SII were positively correlated with age in both genders, and that responses in bilateral regions near the pSTS correlated significantly and strongly with age in females but not in males. These results suggest that brain mechanisms associated with both sensory-discriminative and affective-motivational aspects of touch are largely established in school-aged children, and that there is a general continuing maturation of SII and a female-specific increase in pSTS sensitivity with age. Our work establishes a groundwork for future comparative studies of tactile processing in developmental disorders characterized by disrupted social perception such as autism. PMID:24550800

  4. Failure of ozone and nitrogen dioxide to enhance lung tumor development in hamsters

    SciTech Connect

    Witschi, H.; Breider, M.A.; Schuller, H.M. )

    1993-09-01

    We tested the hypothesis that the two common oxidant air pollutants, ozone and nitrogen dioxide, modulate the development of respiratory tract tumors in Syrian golden hamsters. The animals received subcutaneous injections of the carcinogen diethylnitrosamine (20 mg/kg) twice a week while being exposed continuously to an atmosphere of 0.8 parts per million (ppm)* of ozone or 15 ppm of nitrogen dioxide. Animals were killed 16 weeks or 24 to 32 weeks after the beginning of the treatment. Ozone delayed the appearance of tracheal tumors and reduced the incidence of tumors in the lung periphery. A suspected neuroendocrine differentiation of those lung tumors could not be established by immunocytochemistry due to overfixation of tissues. On the other hand, ozone seemed to mitigate development of hepatotoxic lesions mediated by diethylnitrosamine. In animals treated with diethylnitrosamine and exposed to nitrogen dioxide, fewer tracheal tumors and no lung tumors were found. Only a few lung tumors were produced in animals treated with diethylnitrosamine and kept in an atmosphere of 65% oxygen. The previously observed neuroendocrine nature of tumors induced by simultaneous exposure to diethylnitrosamine and hyperoxia could not be established because the long fixation of tissues precluded immunocytochemical stains. Animals treated with diethylnitrosamine and kept in filtered air while being housed in wire-mesh cages developed fewer lung tumors than animals given the same treatment and kept on conventional bedding in shoebox cages. Although all inhalants tested are known to produce substantial cell proliferation in the respiratory tract, it was not possible to document whether this would enhance lung tumor development. The role of the two common air pollutants, ozone and nitrogen dioxide, as possible additional risks in the pathogenesis of lung cancer in animals continues to remain uncertain.

  5. Methodological issues associated with tumor marker development. Biostatistical aspects.

    PubMed

    Faraggi; Kramar

    2000-09-01

    The search for markers as potential prognostic factors for different stages of disease is becoming a major task in clinical research. Enormous amounts of information on the effectiveness of tumor markers are being published, and many of these results are conflicting and thus adding confusion to the area. In this paper we discuss the problem of multiplicity that we believe is one of the major statistical reasons for the conflicting results. We further review the ROC curve and the area under it as a popular statistical tool for evaluating the ability of a marker to distinguish between two populations. Finally we provide an extension to the ROC analysis when several markers are available.

  6. Development and validation of a microRNA based diagnostic assay for primary tumor site classification of liver core biopsies.

    PubMed

    Perell, Katharina; Vincent, Martin; Vainer, Ben; Petersen, Bodil Laub; Federspiel, Birgitte; Møller, Anne Kirstine; Madsen, Mette; Hansen, Niels Richard; Friis-Hansen, Lennart; Nielsen, Finn Cilius; Daugaard, Gedske

    2015-01-01

    Identification of the primary tumor site in patients with metastatic cancer is clinically important, but remains a challenge. Hence, efforts have been made towards establishing new diagnostic tools. Molecular profiling is a promising diagnostic approach, but tissue heterogeneity and inadequacy may negatively affect the accuracy and usability of molecular classifiers. We have developed and validated a microRNA-based classifier, which predicts the primary tumor site of liver biopsies, containing a limited number of tumor cells. Concurrently we explored the influence of surrounding normal tissue on classification. MicroRNA profiling was performed using quantitative Real-Time PCR on formalin-fixed paraffin-embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust for normal liver tissue contamination. Performance was estimated by cross-validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74.5% upon independent validation. Two-thirds of the samples were classified with high-confidence, with an accuracy of 92% on high-confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding normal tissue from the biopsy site may critically influence molecular classification. A significant improvement in classification accuracy was obtained when the influence of normal tissue was limited by application of a statistical contamination model. PMID:25131495

  7. Development of a Biomimetic Chondroitin Sulfate-modified Hydrogel to Enhance the Metastasis of Tumor Cells

    PubMed Central

    Liu, Yang; Wang, Shujun; Sun, Dongsheng; Liu, Yongdong; Liu, Yang; Wang, Yang; Liu, Chang; Wu, Hao; Lv, Yan; Ren, Ying; Guo, Xin; Sun, Guangwei; Ma, Xiaojun

    2016-01-01

    Tumor metastasis with resistance to anticancer therapies is the main cause of death in cancer patients. It is necessary to develop reliable tumor metastasis models that can closely recapitulate the pathophysiological features of the native tumor tissue. In this study, chondroitin sulfate (CS)-modified alginate hydrogel beads (ALG-CS) are developed to mimic the in vivo tumor microenvironment with an abnormally increased expression of CS for the promotion of tumor cell metastasis. The modification mechanism of CS on alginate hydrogel is due to the cross-linking between CS and alginate molecules via coordination of calcium ions, which enables ALG-CS to possess significantly different physical characteristics than the traditional alginate beads (ALG). And quantum chemistry calculations show that in addition to the traditional egg-box structure, novel asymmetric egg-box-like structures based on the interaction between these two kinds of polymers are also formed within ALG-CS. Moreover, tumor cell metastasis is significantly enhanced in ALG-CS compared with that in ALG, as confirmed by the increased expression of MMP genes and proteins and greater in vitro invasion ability. Therefore, ALG-CS could be a convenient and effective 3D biomimetic scaffold that would be used to construct standardized tumor metastasis models for tumor research and anticancer drug screening. PMID:27432752

  8. Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development

    PubMed Central

    Liu, Yueyong; Huang, Yurong; Wang, Zeran; Huang, Yong; Li, Xiaohua; Louie, Alexander; Wei, Guangwei; Mao, Jian-Hua

    2013-01-01

    FBXW7 acts as a tumor suppressor in numerous types of human cancers through ubiquitination of different oncoproteins including mTOR. However, how the mutation/loss of Fbxw7 results in tumor development remains largely unknown. Here we report that downregulation of mTOR by radiation is Fbxw7-dependent, and short-term mTOR inhibition by rapamycin after exposure to radiation significantly postpones tumor development in Fbxw7/p53 double heterozygous (Fbxw7+/−p53+/−) mice but not in p53 single heterozygous (p53+/−) mice. Tumor latency of rapamycin treated Fbxw7+/−p53+/− mice is remarkably similar to those of p53+/− mice while placebo treated Fbxw7+/−p53+/− mice develop tumor significantly earlier than placebo treated p53+/− mice. Furthermore, we surprisingly find that, although temporal treatment of rapamycin is given at a young age, the inhibition of mTOR activity sustainably remains in tumors. These results indicate that inhibition of mTOR signaling pathway suppresses the contribution of Fbxw7 loss toward tumor development. PMID:23454868

  9. Development of Lymantria dispar affected by manganese in food.

    PubMed

    Kula, Emanuel; Martinek, Petr; Chromcová, Lucie; Hedbávný, Josef

    2014-10-01

    We studied the response of gypsy moth (Lymantria dispar (Linnaeus) (Lepidoptera: Lymantriidae)) to the content of manganese in food in the laboratory breeding of caterpillars. The food of the caterpillars {Betula pendula Roth (Fagales: Betulaceae) leaves} was contaminated by dipping in the solution of MnCl2 · 4H2O with manganese concentrations of 0, 0.5, 5 and 10 mg ml(-1), by which differentiated manganese contents (307; 632; 4,087 and 8,124 mg kg(-1)) were reached. Parameters recorded during the rearing were as follows: effect of manganese on food consumption, mortality and length of the development of caterpillars, pupation and hatching of imagoes. At the same time, manganese concentrations were determined in the offered and unconsumed food, excrements, and exuviae of the caterpillars, pupal cases and imagoes by using the AAS method. As compared with the control, high manganese contents in the food of gypsy moth caterpillars affected the process of development particularly by increased mortality of the first instar caterpillars (8 % mortality for caterpillars with no Mn contamination (T0) and 62 % mortality for subjects with the highest contamination by manganese (T3)), by prolonged development of the first-third instar (18.7 days (T0) and 27.8 days (T3)) and by increased food consumption of the first-third instar {0.185 g of leaf dry matter (T0) and 0.483 g of leaf dry matter (T3)}. The main defence strategy of the caterpillars to prevent contamination by the increased manganese content in food is the translocation of manganese into frass and exuviae castoff in the process of ecdysis. In the process of development, the content of manganese was reduced by excretion in imagoes to 0.5 % of the intake level even at its maximum inputs in food.

  10. Development of Lymantria dispar affected by manganese in food.

    PubMed

    Kula, Emanuel; Martinek, Petr; Chromcová, Lucie; Hedbávný, Josef

    2014-10-01

    We studied the response of gypsy moth (Lymantria dispar (Linnaeus) (Lepidoptera: Lymantriidae)) to the content of manganese in food in the laboratory breeding of caterpillars. The food of the caterpillars {Betula pendula Roth (Fagales: Betulaceae) leaves} was contaminated by dipping in the solution of MnCl2 · 4H2O with manganese concentrations of 0, 0.5, 5 and 10 mg ml(-1), by which differentiated manganese contents (307; 632; 4,087 and 8,124 mg kg(-1)) were reached. Parameters recorded during the rearing were as follows: effect of manganese on food consumption, mortality and length of the development of caterpillars, pupation and hatching of imagoes. At the same time, manganese concentrations were determined in the offered and unconsumed food, excrements, and exuviae of the caterpillars, pupal cases and imagoes by using the AAS method. As compared with the control, high manganese contents in the food of gypsy moth caterpillars affected the process of development particularly by increased mortality of the first instar caterpillars (8 % mortality for caterpillars with no Mn contamination (T0) and 62 % mortality for subjects with the highest contamination by manganese (T3)), by prolonged development of the first-third instar (18.7 days (T0) and 27.8 days (T3)) and by increased food consumption of the first-third instar {0.185 g of leaf dry matter (T0) and 0.483 g of leaf dry matter (T3)}. The main defence strategy of the caterpillars to prevent contamination by the increased manganese content in food is the translocation of manganese into frass and exuviae castoff in the process of ecdysis. In the process of development, the content of manganese was reduced by excretion in imagoes to 0.5 % of the intake level even at its maximum inputs in food. PMID:25028315

  11. Maternal Photoperiodic History Affects Offspring Development in Syrian Hamsters

    PubMed Central

    Beery, Annaliese K.; Paul, Matthew J.; Routman, David M.; Zucker, Irving

    2009-01-01

    During the first 7 weeks of postnatal life, short day lengths inhibit the onset of puberty in many photoperiodic rodents, but not in Syrian hamsters. In this species, timing of puberty and fecundity are independent of the early postnatal photoperiod. Gestational day length affects postnatal reproductive development in several rodents; its role in Syrian hamsters has not been assessed. We tested the hypothesis that cumulative effects of pre- and postnatal short day lengths would restrain gonadal development in male Syrian hamsters. Males with prenatal short day exposure were generated by dams transferred to short day lengths 6 weeks, 3 weeks, and 0 weeks prior to mating. Additional groups were gestated in long day lengths and transferred to short days at birth, at 4 weeks of age, or not transferred (control hamsters). In pups of dams exposed to short day treatment throughout gestation, decreased testis growth was apparent by 3 weeks and persisted through 9 weeks of age, at which time maximum testis size was attained. A subset of males (14%), whose dams had been in short days for 3 to 6 weeks prior to mating displayed pronounced delays in testicular development, similar to those of other photoperiodic rodents. This treatment also increased the percentage of male offspring that underwent little or no gonadal regression postnatally (39%). By 19 weeks of age, males housed in short days completed spontaneous gonadal development. After prolonged long day treatment to break refractoriness, hamsters that initially were classified as nonregressors underwent testicular regression in response to a 2nd sequence of short day lengths. The combined action of prenatal and early postnatal short day lengths diminishes testicular growth of prepubertal Syrian hamsters no later than the 3rd week of postnatal life, albeit to a lesser extent than in other photoperiodic rodents. PMID:18838610

  12. Spaceflight affects postnatal development of the aortic wall in rats.

    PubMed

    Katsuda, Shin-ichiro; Yamasaki, Masao; Waki, Hidefumi; Miyake, Masao; O-ishi, Hirotaka; Katahira, Kiyoaki; Nagayama, Tadanori; Miyamoto, Yukako; Hasegawa, Masamitsu; Wago, Haruyuki; Okouchi, Toshiyasu; Shimizu, Tsuyoshi

    2014-01-01

    We investigated effect of microgravity environment during spaceflight on postnatal development of the rheological properties of the aorta in rats. The neonate rats were randomly divided at 7 days of age into the spaceflight, asynchronous ground control, and vivarium control groups (8 pups for one dam). The spaceflight group rats at 9 days of age were exposed to microgravity environment for 16 days. A longitudinal wall strip of the proximal descending thoracic aorta was subjected to stress-strain and stress-relaxation tests. Wall tensile force was significantly smaller in the spaceflight group than in the two control groups, whereas there were no significant differences in wall stress or incremental elastic modulus at each strain among the three groups. Wall thickness and number of smooth muscle fibers were significantly smaller in the spaceflight group than in the two control groups, but there were no significant differences in amounts of either the elastin or collagen fibers among the three groups. The decreased thickness was mainly caused by the decreased number of smooth muscle cells. Plastic deformation was observed only in the spaceflight group in the stress-strain test. A microgravity environment during spaceflight could affect postnatal development of the morphological and rheological properties of the aorta. PMID:25210713

  13. Spaceflight Affects Postnatal Development of the Aortic Wall in Rats

    PubMed Central

    Yamasaki, Masao; Waki, Hidefumi; Miyake, Masao; Nagayama, Tadanori; Miyamoto, Yukako; Wago, Haruyuki; Okouchi, Toshiyasu; Shimizu, Tsuyoshi

    2014-01-01

    We investigated effect of microgravity environment during spaceflight on postnatal development of the rheological properties of the aorta in rats. The neonate rats were randomly divided at 7 days of age into the spaceflight, asynchronous ground control, and vivarium control groups (8 pups for one dam). The spaceflight group rats at 9 days of age were exposed to microgravity environment for 16 days. A longitudinal wall strip of the proximal descending thoracic aorta was subjected to stress-strain and stress-relaxation tests. Wall tensile force was significantly smaller in the spaceflight group than in the two control groups, whereas there were no significant differences in wall stress or incremental elastic modulus at each strain among the three groups. Wall thickness and number of smooth muscle fibers were significantly smaller in the spaceflight group than in the two control groups, but there were no significant differences in amounts of either the elastin or collagen fibers among the three groups. The decreased thickness was mainly caused by the decreased number of smooth muscle cells. Plastic deformation was observed only in the spaceflight group in the stress-strain test. A microgravity environment during spaceflight could affect postnatal development of the morphological and rheological properties of the aorta. PMID:25210713

  14. Oligosaccharides Affect Performance and Gut Development of Broiler Chickens

    PubMed Central

    Ao, Z.; Choct, M.

    2013-01-01

    The effects of oligosaccharide supplementation on the growth performance, flock uniformity and GIT development of broiler chickens were investigated. Four diets, one negative control, one positive control supplemented with zinc-bacitracin, and two test diets supplemented with mannoligosaccharide (MOS) and fructooligosaccharide (FOS), were used for the experiment. Birds given MOS or FOS had improved body weight (BW) and feed efficiency (FCR), compared to those fed the negative control diet during the 35-d trial period. The effect on FCR became less apparent when the birds got older. FOS and MOS supplementation reduced the pancreas weight as a percentage of BW, with an effect similar to that of the antibiotic, at 35 d of age. Birds given MOS tended to have a heavier bursa (p = 0.164) and lower spleen/bursa weight ratio (p = 0.102) at 35 d of age. MOS and Zn-bacitracin showed a clear improvement on flock uniformity, compared to FOS. The mortality rate was not affected by FOS or MOS. PMID:25049713

  15. Large-scale mapping of mutations affecting zebrafish development

    PubMed Central

    Geisler, Robert; Rauch, Gerd-Jörg; Geiger-Rudolph, Silke; Albrecht, Andrea; van Bebber, Frauke; Berger, Andrea; Busch-Nentwich, Elisabeth; Dahm, Ralf; Dekens, Marcus PS; Dooley, Christopher; Elli, Alexandra F; Gehring, Ines; Geiger, Horst; Geisler, Maria; Glaser, Stefanie; Holley, Scott; Huber, Matthias; Kerr, Andy; Kirn, Anette; Knirsch, Martina; Konantz, Martina; Küchler, Axel M; Maderspacher, Florian; Neuhauss, Stephan C; Nicolson, Teresa; Ober, Elke A; Praeg, Elke; Ray, Russell; Rentzsch, Brit; Rick, Jens M; Rief, Eva; Schauerte, Heike E; Schepp, Carsten P; Schönberger, Ulrike; Schonthaler, Helia B; Seiler, Christoph; Sidi, Samuel; Söllner, Christian; Wehner, Anja; Weiler, Christian; Nüsslein-Volhard, Christiane

    2007-01-01

    Background Large-scale mutagenesis screens in the zebrafish employing the mutagen ENU have isolated several hundred mutant loci that represent putative developmental control genes. In order to realize the potential of such screens, systematic genetic mapping of the mutations is necessary. Here we report on a large-scale effort to map the mutations generated in mutagenesis screening at the Max Planck Institute for Developmental Biology by genome scanning with microsatellite markers. Results We have selected a set of microsatellite markers and developed methods and scoring criteria suitable for efficient, high-throughput genome scanning. We have used these methods to successfully obtain a rough map position for 319 mutant loci from the Tübingen I mutagenesis screen and subsequent screening of the mutant collection. For 277 of these the corresponding gene is not yet identified. Mapping was successful for 80 % of the tested loci. By comparing 21 mutation and gene positions of cloned mutations we have validated the correctness of our linkage group assignments and estimated the standard error of our map positions to be approximately 6 cM. Conclusion By obtaining rough map positions for over 300 zebrafish loci with developmental phenotypes, we have generated a dataset that will be useful not only for cloning of the affected genes, but also to suggest allelism of mutations with similar phenotypes that will be identified in future screens. Furthermore this work validates the usefulness of our methodology for rapid, systematic and inexpensive microsatellite mapping of zebrafish mutations. PMID:17212827

  16. Neonatal Handling Affects Durably Bonding and Social Development

    PubMed Central

    Henry, Séverine; Richard-Yris, Marie-Annick; Tordjman, Sylvie; Hausberger, Martine

    2009-01-01

    The neonatal period in humans and in most mammals is characterized by intense mother-young interactions favoring pair bonding and the adaptation of neonates to their new environment. However, in many post-delivery procedures, human babies commonly experience combined maternal separation and intense handling for about one hour post-birth. Currently, the effects of such disturbances on later attachment and on the development of newborns are still debated: clearly, further investigations are required. As animals present good models for controlled experimentation, we chose domestic horses to investigate this issue. Horses, like humans, are characterized by single births, long lactating periods and selective mother-infant bonds. Routine postnatal procedures for foals, as for human babies, also involve intense handling and maternal separation. In the present study, we monitored the behavior of foals from early stages of development to “adolescence”, in a normal ecological context (social groups with adults and peers). Experimental foals, separated from their mothers and handled for only 1 hour post-birth, were compared to control foals, left undisturbed after birth. Our results revealed short- and long-term effects of this unique neonatal experience on attachment and subsequent social competences. Thus, experimental foals presented patterns of insecure attachment to their mothers (strong dependence on their mothers, little play) and impaired social competences (social withdrawal, aggressiveness) at all ages. We discuss these results in terms of mother-young interactions, timing of interactions and relationships between bonding and subsequent social competences. Our results indicate that this ungulate species could become an interesting animal model. To our knowledge, this is the first clear demonstration that intervention just after birth affects bonding and subsequent social competences (at least until “adolescence”). It opens new research directions for studies

  17. Development of 99mTc-N4-NIM for Molecular Imaging of Tumor Hypoxia

    PubMed Central

    Ali, Mohammad S.; Kong, Fan-Lin; Rollo, Alex; Mendez, Richard; Kohanim, Saady; Smith, Daniel Lee; Yang, David J.

    2012-01-01

    The nitro group of 2-nitroimidazole (NIM) enters the tumor cells and is bioreductively activated and fixed in the hypoxia cells. 1,4,8,11-tetraazacyclotetradecane (N4) has shown to be a stable chelator for 99mTc. The present study was aimed to develop 99mTc-cyclam-2-nitroimidazole (99mTc-N4-NIM) for tumor hypoxia imaging. N4-NIM precursor was synthesized by reacting N4-oxalate and 1,3-dibromopropane-NIM, yielded 14% (total synthesis). Cell uptake of 99mTc-N4-NIM and 99mTc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of 99mTc-N4-NIM was evaluated in breast-tumor-bearing rats at 0.5–4 hrs. Tumor oxygen tension was measured using an oxygen probe. Planar imaging was performed in the tumor-bearing rat and rabbit models. Radiochemical purity of 99mTc-N4-NIM was >96% by HPLC. Cell uptake of 99mTc-N4-NIM was higher than 99mTc-N4 in both cell lines. Biodistribution of 99mTc-N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Oxygen tension in tumor tissue was 6–10 mmHg compared to 40–50 mmHg in normal muscle tissue. Planar imaging studies confirmed that the tumors could be visualized clearly with 99mTc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. 99mTc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy. PMID:22719210

  18. Development of cell-cycle checkpoint therapy for solid tumors.

    PubMed

    Tamura, Kenji

    2015-12-01

    Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available. For instance, palbociclib (PD0332991) is a first-in-class, oral, highly selective inhibitor of CDK4/6 and, in combination with letrozole (Phase II; PALOMA-1) or with fulvestrant (Phase III; PALOMA-3), it has significantly prolonged progression-free survival, in patients with metastatic estrogen receptor-positive, HER2-negative breast cancer, in comparison with that observed in patients using letrozole, or fulvestrant alone, respectively. In this review, we provide an overview of the current compounds available for cell-cycle checkpoint protein-directed therapy for solid tumors. PMID:26486823

  19. [Specific features of mammographic visualization of "small" breast tumors developing on the background of fibrocystic disease].

    PubMed

    Bukharin, D G; Velichko, S A; Slonimskaia, E M; Frolova, I G; Luneva, S V; Garbukov, E Iu; Doroshenko, A V

    2011-01-01

    All complications diagnosed at early stages of breast cancer were associated with small tumors, especially with those arising in the aftermath of fibrocystic disease. Hence, our task was to study the XR-semiotics of lesions of less than 15 mm in diameter and of the same origin. 100 mammograms of breast cancer patients with benign disease of the breast were studied. The presence of moderate-to-severe fibrocystic disease significantly affected the visualization of lesions of less than 10 mm in diameter. Since the XR-semiotics of small tumors failed to reveal malignancy features, all lesions visualized by mammography required additional diagnostic procedures using ultrasound and invasive radiology.

  20. Conditional Knockout of Tumor Overexpressed Gene in Mouse Neurons Affects RNA Granule Assembly, Granule Translation, LTP and Short Term Habituation

    PubMed Central

    Barbarese, Elisa; Ifrim, Marius F.; Hsieh, Lawrence; Guo, Caiying; Tatavarty, Vedakumar; Maggipinto, Michael J.; Korza, George; Tutolo, Jessica W.; Giampetruzzi, Anthony; Le, Hien; Ma, Xin-Ming; Levine, Eric; Bishop, Brian; Kim, Duck O.; Kuwada, Shigeyuki; Carson, John H.

    2013-01-01

    In neurons, specific RNAs are assembled into granules, which are translated in dendrites, however the functional consequences of granule assembly are not known. Tumor overexpressed gene (TOG) is a granule-associated protein containing multiple binding sites for heterogeneous nuclear ribonucleoprotein (hnRNP) A2, another granule component that recognizes cis-acting sequences called hnRNP A2 response elements (A2REs) present in several granule RNAs. Translation in granules is sporadic, which is believed to reflect monosomal translation, with occasional bursts, which are believed to reflect polysomal translation. In this study, TOG expression was conditionally knocked out (TOG cKO) in mouse hippocampal neurons using cre/lox technology. In TOG cKO cultured neurons granule assembly and bursty translation of activity-regulated cytoskeletal associated (ARC) mRNA, an A2RE RNA, are disrupted. In TOG cKO brain slices synaptic sensitivity and long term potentiation (LTP) are reduced. TOG cKO mice exhibit hyperactivity, perseveration and impaired short term habituation. These results suggest that in hippocampal neurons TOG is required for granule assembly, granule translation and synaptic plasticity, and affects behavior. PMID:23936366

  1. Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway.

    PubMed

    Yan, Ping; Gong, Hui; Zhai, Xiaoyan; Feng, Yi; Wu, Jun; He, Sheng; Guo, Jian; Wang, Xiaoxia; Guo, Rui; Xie, Jun; Li, Ren-Ke

    2016-04-01

    Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator. PMID:26835537

  2. A Multimodal Imaging Approach for Longitudinal Evaluation of Bladder Tumor Development in an Orthotopic Murine Model.

    PubMed

    Scheepbouwer, Chantal; Meyer, Sandra; Burggraaf, Maroeska J; Jose, Jithin; Molthoff, Carla F M

    2016-01-01

    Bladder cancer is the fourth most common malignancy amongst men in Western industrialized countries with an initial response rate of 70% for the non-muscle invasive type, and improving therapy efficacy is highly needed. For this, an appropriate, reliable animal model is essential to gain insight into mechanisms of tumor growth for use in response monitoring of (new) agents. Several animal models have been described in previous studies, but so far success has been hampered due to the absence of imaging methods to follow tumor growth non-invasively over time. Recent developments of multimodal imaging methods for use in animal research have substantially strengthened these options of in vivo visualization of tumor growth. In the present study, a multimodal imaging approach was addressed to investigate bladder tumor proliferation longitudinally. The complementary abilities of Bioluminescence, High Resolution Ultrasound and Photo-acoustic Imaging permit a better understanding of bladder tumor development. Hybrid imaging modalities allow the integration of individual strengths to enable sensitive and improved quantification and understanding of tumor biology, and ultimately, can aid in the discovery and development of new therapeutics. PMID:27533303

  3. A Multimodal Imaging Approach for Longitudinal Evaluation of Bladder Tumor Development in an Orthotopic Murine Model

    PubMed Central

    Meyer, Sandra; Burggraaf, Maroeska J.; Jose, Jithin; Molthoff, Carla F. M.

    2016-01-01

    Bladder cancer is the fourth most common malignancy amongst men in Western industrialized countries with an initial response rate of 70% for the non-muscle invasive type, and improving therapy efficacy is highly needed. For this, an appropriate, reliable animal model is essential to gain insight into mechanisms of tumor growth for use in response monitoring of (new) agents. Several animal models have been described in previous studies, but so far success has been hampered due to the absence of imaging methods to follow tumor growth non-invasively over time. Recent developments of multimodal imaging methods for use in animal research have substantially strengthened these options of in vivo visualization of tumor growth. In the present study, a multimodal imaging approach was addressed to investigate bladder tumor proliferation longitudinally. The complementary abilities of Bioluminescence, High Resolution Ultrasound and Photo-acoustic Imaging permit a better understanding of bladder tumor development. Hybrid imaging modalities allow the integration of individual strengths to enable sensitive and improved quantification and understanding of tumor biology, and ultimately, can aid in the discovery and development of new therapeutics. PMID:27533303

  4. Evaluation of Elephantopus scaber on the inhibition of chemical carcinogenesis and tumor development in mice.

    PubMed

    Geetha, B S; Latha, P G; Remani, P

    2010-03-01

    The effect of the active fraction of Elephantopus scaber L. (Asteraceae) (ES) on skin papillomas induced by 7,12-dimethylbenz(a)anthracene (DMBA) as an initiator and croton oil as promoter was studied in mice. The active fraction of E. scaber (100 mg/kg) on topical application delayed the onset of papilloma formation and reduced the mean number of papillomas and the mean weight of papillomas per mouse. The intraperitoneal administration of the active fraction of E. scaber also had a significant effect on subcutaneous injection of 20-methylcholanthrene (20-MCA)-induced soft tissue sarcomas in mice. It inhibited the incidence of sarcomas and reduced the tumor diameter compared to MCA-treated control animals. The subcutaneous administration of the active fraction of E. scaber significantly inhibited the growth of subcutaneously transplanted DLA and EAC solid tumors, delayed the onset of tumor formation, and increased the life span of tumor bearing mice. The present study thus indicates the tumor inhibitory activity of the active fraction of E. scaber against chemically induced tumors and its ability to inhibit the development of solid tumors. PMID:20645824

  5. A Look at Recent Legal Developments Affecting Residential Living.

    ERIC Educational Resources Information Center

    Miller, Thomas E.; And Others

    1979-01-01

    Reviews court decisions concerning search and seizure, intervisitation between sexes, canvassing and solicitation, and damage assessments. College administrators must rely on fairness, ethics and sound educational philosophies in the design of policies affecting residence halls. (JAC)

  6. Development of photostabilized asymmetrical cyanine dyes for in vivo photoacoustic imaging of tumors.

    PubMed

    Onoe, Satoru; Temma, Takashi; Kanazaki, Kengo; Ono, Masahiro; Saji, Hideo

    2015-09-01

    Photoacoustic imaging (PAI) contributes to tumor diagnosis through the use of PAI probes that effectively accumulate in tumors. Previously, we developed a symmetrical cyanine dye, IC7-1-Bu, which showed high potential as a PAI probe because of its high tumor targeting ability and sufficient in vivo PA signal. However, IC7-1-Bu lacks photostability for multiple laser irradiations, so we developed stabilized PAI probes using IC7-1-Bu as a lead compound. We focused on the effect of singlet oxygen (1O2) generated by excited PAI probes on probe degeneration. We introduced a triplet-state quencher (TSQ) moiety into IC7-1-Bu to quench 1O2 generation and designed three IC-n-T derivatives with different linker lengths (n indicates linker length). The IC-n-T derivatives emitted in vitro PA signals that were comparable to IC7-1-Bu and significantly reduced 1O2 generation while showing improved photostability against multiple irradiations. Of the three derivatives evaluated, IC-5-T accumulated in tumors effectively to allow clear PAI of tumors in vivo. Furthermore, the photostability of IC-5-T was 1.5-fold higher than that of IC7-1-Bu in in vivo sequential PAI. These results suggest that IC-5-T is a potential PAI probe for in vivo sequential tumor imaging.

  7. Student Cognitive and Affective Development in the Context of Classroom-Level Curriculum Development

    ERIC Educational Resources Information Center

    Shawer, Saad Fathy; Gilmore, Deanna; Banks-Joseph, Susan Rae

    2008-01-01

    This qualitative study examined the impact of teacher curriculum approaches (curriculum-transmitter/curriculum-developer/curriculum-maker) on student cognitive change (reading, writing, speaking, and listening abilities) and their affective change (motivation and interests). This study's conceptual framework was grounded in teacher curriculum…

  8. Akkermansia muciniphila and Helicobacter typhlonius modulate intestinal tumor development in mice.

    PubMed

    Dingemanse, Celia; Belzer, Clara; van Hijum, Sacha A F T; Günthel, Marie; Salvatori, Daniela; den Dunnen, Johan T; Kuijper, Ed J; Devilee, Peter; de Vos, Willem M; van Ommen, GertJan B; Robanus-Maandag, Els C

    2015-11-01

    Gastrointestinal tumor growth is thought to be promoted by gastrointestinal bacteria and their inflammatory products. We observed that intestine-specific conditional Apc mutant mice (FabplCre;Apc (15lox/+)) developed many more colorectal tumors under conventional than under pathogen-low housing conditions. Shotgun metagenomic sequencing plus quantitative PCR analysis of feces DNA revealed the presence of two bacterial species in conventional mice, absent from pathogen-low mice. One, Helicobacter typhlonius, has not been associated with cancer in man, nor in immune-competent mice. The other species, mucin-degrading Akkermansia muciniphila, is abundantly present in healthy humans, but reduced in patients with inflammatory gastrointestinal diseases and in obese and type 2 diabetic mice. Eradication of H.typhlonius in young conventional mice by antibiotics decreased the number of intestinal tumors. Additional presence of A.muciniphila prior to the antibiotic treatment reduced the tumor number even further. Colonization of pathogen-low FabplCre;Apc (15lox/+) mice with H.typhlonius or A.muciniphila increased the number of intestinal tumors, the thickness of the intestinal mucus layer and A.muciniphila colonization without H.typhlonius increased the density of mucin-producing goblet cells. However, dual colonization with H.typhlonius and A.muciniphila significantly reduced the number of intestinal tumors, the mucus layer thickness and goblet cell density to that of control mice. By global microbiota composition analysis, we found a positive association of A.muciniphila, and of H.typhlonius, and a negative association of unclassified Clostridiales with increased tumor burden. We conclude that A.muciniphila and H.typhlonius can modulate gut microbiota composition and intestinal tumor development in mice. PMID:26320104

  9. Toward the development of intrafraction tumor deformation tracking using a dynamic multi-leaf collimator

    SciTech Connect

    Ge, Yuanyuan; O’Brien, Ricky T.; Shieh, Chun-Chien; Keall, Paul J.; Booth, Jeremy T.

    2014-06-15

    Purpose: Intrafraction deformation limits targeting accuracy in radiotherapy. Studies show tumor deformation of over 10 mm for both single tumor deformation and system deformation (due to differential motion between primary tumors and involved lymph nodes). Such deformation cannot be adapted to with current radiotherapy methods. The objective of this study was to develop and experimentally investigate the ability of a dynamic multi-leaf collimator (DMLC) tracking system to account for tumor deformation. Methods: To compensate for tumor deformation, the DMLC tracking strategy is to warp the planned beam aperture directly to conform to the new tumor shape based on real time tumor deformation input. Two deformable phantoms that correspond to a single tumor and a tumor system were developed. The planar deformations derived from the phantom images in beam's eye view were used to guide the aperture warping. An in-house deformable image registration software was developed to automatically trigger the registration once new target image was acquired and send the computed deformation to the DMLC tracking software. Because the registration speed is not fast enough to implement the experiment in real-time manner, the phantom deformation only proceeded to the next position until registration of the current deformation position was completed. The deformation tracking accuracy was evaluated by a geometric target coverage metric defined as the sum of the area incorrectly outside and inside the ideal aperture. The individual contributions from the deformable registration algorithm and the finite leaf width to the tracking uncertainty were analyzed. Clinical proof-of-principle experiment of deformation tracking using previously acquired MR images of a lung cancer patient was implemented to represent the MRI-Linac environment. Intensity-modulated radiation therapy (IMRT) treatment delivered with enabled deformation tracking was simulated and demonstrated. Results: The first

  10. Development and Validation of the Temperament and Affectivity Inventory (TAI).

    PubMed

    Watson, David; Stasik, Sara M; Chmielewski, Michael; Naragon-Gainey, Kristin

    2015-10-01

    Trait affect scales have been a mainstay of the assessment literature for more than 50 years. These scales have demonstrated impressive construct validity, including substantial relations with personality, satisfaction, and psychopathology. However, the accumulating evidence has exposed several limitations, including (a) problems associated with retrospective biases, (b) lower temporal stability because of enhanced susceptibility to transient error, and (c) reduced self-other agreement. These limitations motivated the creation of the Temperament and Affectivity Inventory (TAI), which uses a traditional personality format (i.e., full sentences rather than single words or short phrases). The 12 TAI scales were created based on factor analyses in two samples and validated in four additional samples. The scales are internally consistent, highly stable over time, and show strong convergent, discriminant, and incremental validity in relation to self-report and interview-based measures of personality and psychopathology. Thus, the TAI provides a promising new approach to assessing trait affectivity.

  11. Brain tumors.

    PubMed Central

    Black, K. L.; Mazziotta, J. C.; Becker, D. P.

    1991-01-01

    Recent advances in experimental tumor biology are being applied to critical clinical problems of primary brain tumors. The expression of peripheral benzodiazepine receptors, which are sparse in normal brain, is increased as much as 20-fold in brain tumors. Experimental studies show promise in using labeled ligands to these receptors to identify the outer margins of malignant brain tumors. Whereas positron emission tomography has improved the dynamic understanding of tumors, the labeled selective tumor receptors with positron emitters will enhance the ability to specifically diagnose and greatly aid in the pretreatment planning for tumors. Modulation of these receptors will also affect tumor growth and metabolism. Novel methods to deliver antitumor agents to the brain and new approaches using biologic response modifiers also hold promise to further improve the management of brain tumors. Images PMID:1848735

  12. Factors affecting mammary tumor incidence in chlorotriazine-treated female rats: hormonal properties, dosage, and animal strain.

    PubMed Central

    Eldridge, J C; Tennant, M K; Wetzel, L T; Breckenridge, C B; Stevens, J T

    1994-01-01

    Chlorotriazines are widely used in agriculture as broadleaf herbicides. The compounds specifically inhibit photosynthesis, and, as such, display little interaction with animal systems. However, a 24-month feeding study with atrazine (ATR) revealed a significant dose-related increase of mammary tumors in female Sprague-Dawley (SD) rats. Because numerous studies indicated that ATR had a low mutagenic and oncogenic potential, it was decided to test a hypothesis that the herbicide possessed endocrine activity. Among tests for estrogenic action, oral dosing of ATR up to 300 mg/kg did not stimulate uterine weight of ovariectomized rats. However, ATR administration did reduce estrogen-stimulated uterine weight gain. Further evidence of inhibition came from measures of [3H]-thymidine incorporation into uterine DNA of ATR-treated immature rats. Again, no intrinsic estrogenic activity was observed up to a 300-mg/kg dose. In vitro, ATR competed poorly against estradiol binding to cytosolic receptors, with an approximate IC50 of 10(-5) M. Atrazine administration to SD and Fischer-344 (F-344) rats for 12 months, up to 400 ppm in food, was correlated with significant alterations of estrous cycling activity; but there was a divergent strain response. SD rats showed an increased number of days in vaginal estrus, increased plasma estradiol, and decreased plasma progesterone by 9 to 12 months of treatment. F-344 rats did not demonstrate treatment-related affects. A study of ultrastructure in the hypothalamic arcuate nucleus of female SD rats that were fed diaminochlorotriazine (DACT), an ATR metabolite, suggested that age-associated glial pathology was enhanced by treatment.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 8. PMID:7737039

  13. Maternal Stress and Affect Influence Fetal Neurobehavioral Development.

    ERIC Educational Resources Information Center

    DiPietro, Janet A.; Hilton, Sterling C.; Hawkins, Melissa; Costigan, Kathleen A.; Pressman, Eva K.

    2002-01-01

    Investigated associations between maternal psychological and fetal neurobehavioral functioning with data provided at 24, 30, and 36 weeks gestation. Found that fetuses of women who were more affectively intense, appraised their lives as more stressful, and reported more pregnancy-specific hassles were more active across gestation. Fetuses of women…

  14. Affect regulation training (ART) for alcohol use disorders: development of a novel intervention for negative affect drinkers.

    PubMed

    Stasiewicz, Paul R; Bradizza, Clara M; Schlauch, Robert C; Coffey, Scott F; Gulliver, Suzy B; Gudleski, Gregory D; Bole, Christopher W

    2013-01-01

    Although negative affect is a common precipitant of alcohol relapse, there are few interventions for alcohol dependence that specifically target negative affect. In this stage 1a/1b treatment development study, several affect regulation strategies (e.g., mindfulness, prolonged exposure, distress tolerance) were combined to create a new treatment supplement called affect regulation training (ART), which could be added to enhance cognitive-behavioral therapy (CBT) for alcohol dependence. A draft therapy manual was given to therapists and treatment experts before being administered to several patients who also provided input. After two rounds of manual development (stage 1a), a pilot randomized clinical trial (N=77) of alcohol-dependent outpatients who reported drinking often in negative affect situations was conducted (stage 1b). Participants received 12-weekly, 90-minute sessions of either CBT for alcohol dependence plus ART (CBT+ART) or CBT plus a healthy lifestyles control condition (CBT+HLS). Baseline, end-of-treatment, and 3- and 6-month posttreatment interviews were conducted. For both treatment conditions, participant ratings of treatment satisfaction were high, with CBT+ART rated significantly higher. Drinking outcome results indicated greater reductions in alcohol use for CBT+ART when compared to CBT+HLS, with moderate effect sizes for percent days abstinent, drinks per day, drinks per drinking day, and percent heavy drinking days. Overall, findings support further research on affect regulation interventions for negative affect drinkers.

  15. Affect Regulation Training (ART) for Alcohol Use Disorders: Development of a Novel Intervention for Negative Affect Drinkers

    PubMed Central

    Stasiewicz, Paul R.; Bradizza, Clara M.; Schlauch, Robert C.; Coffey, Scott F.; Gulliver, Suzy B.; Gudleski, Gregory; Bole, Christopher W.

    2013-01-01

    Although negative affect is a common precipitant of alcohol relapse, there are few interventions for alcohol dependence that specifically target negative affect. In this Stage 1a/1b treatment development study, several affect regulation strategies (e.g., mindfulness, prolonged exposure, distress tolerance) were combined to create a new treatment supplement called Affect Regulation Training (ART), which could be added to enhance Cognitive-Behavioral Therapy (CBT) for alcohol dependence. A draft therapy manual was given to therapists and treatment experts before being administered to several patients who also provided input. After two rounds of manual development (Stage 1a), a pilot randomized clinical trial (N = 77) of alcohol-dependent outpatients who reported drinking often in negative affect situations was conducted (Stage 1b). Participants received 12-weekly, 90-minute sessions of either CBT for alcohol dependence plus ART (CBT + ART) or CBT plus a healthy lifestyles control condition (CBT + HLS). Baseline, end-of-treatment, and 3- and 6-month posttreatment interviews were conducted. For both treatment conditions, participant ratings of treatment satisfaction were high, with CBT + ART rated significantly higher. Drinking outcome results indicated greater reductions in alcohol use for CBT + ART when compared to CBT + HLS, with moderate effect sizes for percent days abstinent, drinks per day, drinks per drinking day, and percent heavy drinking days. Overall, findings support further research on affect regulation interventions for negative affect drinkers. PMID:23876455

  16. Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.

    PubMed

    Inagaki-Ohara, K; Mayuzumi, H; Kato, S; Minokoshi, Y; Otsubo, T; Kawamura, Y I; Dohi, T; Matsuzaki, G; Yoshimura, A

    2014-01-01

    Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

  17. CAPS1 Negatively Regulates Hepatocellular Carcinoma Development through Alteration of Exocytosis-Associated Tumor Microenvironment

    PubMed Central

    Xue, Ruyi; Tang, Wenqing; Dong, Pingping; Weng, Shuqiang; Ma, Lijie; Chen, She; Liu, Taotao; Shen, Xizhong; Huang, Xiaowu; Zhang, Si; Dong, Ling

    2016-01-01

    The calcium-dependent activator protein for secretion 1 (CAPS1) regulates exocytosis of dense-core vesicles (DCVs) in neurons and neuroendocrine cells. The role of CAPS1 in cancer biology remains unknown. The purpose of this study was to investigate the role of CAPS1 in hepatocellular carcinoma (HCC). We determined the levels of CAPS1 in eight hepatoma cell lines and 141 HCC specimens. We evaluated the prognostic value of CAPS1 expression and its association with clinical parameters. We investigated the biological consequences of CAPS1 overexpression in two hepatoma cell lines in vitro and in vivo. The results showed that loss of CAPS1 expression in HCC tissues was markedly correlated with aggressive tumor phenotypes, such as high-grade tumor node metastasis (TNM) stage (p = 0.003) and absence of tumor encapsulation (p = 0.016), and was associated with poor overall survival (p = 0.008) and high recurrence (p = 0.015). CAPS1 overexpression inhibited cell proliferation and migration by changing the exocytosis-associated tumor microenvironment in hepatoma cells in vitro. The in vivo study showed that CAPS1 overexpression inhibited xenograft tumor growth. Together, these results identified a previously unrecognized tumor suppressor role for CAPS1 in HCC development. PMID:27689999

  18. Impaired Lymphocytes Development and Xenotransplantation of Gastrointestinal Tumor Cells in Prkdc-Null SCID Zebrafish Model.

    PubMed

    Jung, In Hye; Chung, Yong-Yoon; Jung, Dawoon E; Kim, Young Jin; Kim, Do Hee; Kim, Kyung-Sik; Park, Seung Woo

    2016-08-01

    Severe combined immunodeficiency (SCID) mice have widely been used as hosts for human tumor cell xenograft study. This animal model, however, is labor intensive. As zebrafish is largely emerging as a promising model system for studying human diseases including cancer, developing efficient immunocompromised strains for tumor xenograft study are also demanded in zebrafish. Here, we have created the Prkdc-null SCID zebrafish model which provides the stable immune-deficient background required for xenotransplantation of tumor cell. In this study, the two transcription activator-like effector nucleases that specifically target the exon3 of the zebrafish Prkdc gene were used to induce a frame shift mutation, causing a complete knockout of the gene function. The SCID zebrafish showed susceptibility to spontaneous infection, a well-known phenotype found in the SCID mutation. Further characterization revealed that the SCID zebrafish contained no functional T and B lymphocytes which reflected the phenotypes identified in the mice SCID model. Intraperitoneal injection of human cancer cells into the adult SCID zebrafish clearly showed tumor cell growth forming into a solid mass. Our present data show the suitability of using the SCID zebrafish strain for xenotransplantation experiments, and in vivo monitoring of the tumor cell growth in the zebrafish demonstrates use of the animal model as a new platform of tumor xenograft study.

  19. Impaired Lymphocytes Development and Xenotransplantation of Gastrointestinal Tumor Cells in Prkdc-Null SCID Zebrafish Model.

    PubMed

    Jung, In Hye; Chung, Yong-Yoon; Jung, Dawoon E; Kim, Young Jin; Kim, Do Hee; Kim, Kyung-Sik; Park, Seung Woo

    2016-08-01

    Severe combined immunodeficiency (SCID) mice have widely been used as hosts for human tumor cell xenograft study. This animal model, however, is labor intensive. As zebrafish is largely emerging as a promising model system for studying human diseases including cancer, developing efficient immunocompromised strains for tumor xenograft study are also demanded in zebrafish. Here, we have created the Prkdc-null SCID zebrafish model which provides the stable immune-deficient background required for xenotransplantation of tumor cell. In this study, the two transcription activator-like effector nucleases that specifically target the exon3 of the zebrafish Prkdc gene were used to induce a frame shift mutation, causing a complete knockout of the gene function. The SCID zebrafish showed susceptibility to spontaneous infection, a well-known phenotype found in the SCID mutation. Further characterization revealed that the SCID zebrafish contained no functional T and B lymphocytes which reflected the phenotypes identified in the mice SCID model. Intraperitoneal injection of human cancer cells into the adult SCID zebrafish clearly showed tumor cell growth forming into a solid mass. Our present data show the suitability of using the SCID zebrafish strain for xenotransplantation experiments, and in vivo monitoring of the tumor cell growth in the zebrafish demonstrates use of the animal model as a new platform of tumor xenograft study. PMID:27566103

  20. Flor-Essence? Herbal Tonic Promotes Mammary Tumor Development in Sprague Dawley Rats

    SciTech Connect

    Bennett, L; Montgomery, J; Steinberg, S; Kulp, K

    2004-01-28

    Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} Tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague Dawley rats were given water or exposed to 3% or 6% Flor-Essence{reg_sign} beginning at one day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethylbenz(a)anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0% and 59.4% for the 3% and 6% Flor-Essence{reg_sign} groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0% and 97.3% for rats consuming 3% and 6% Flor-Essence{reg_sign}, respectively. Mean mammary tumor multiplicity ({+-}SES) for the controls was 2.8 ({+-} 0.5) and statistically different from the 3% or 6% Flor- Essence{reg_sign} groups with 5.2 ({+-} 0.7), and 4.8 ({+-} 0.6), respectively (p{<=}0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence{reg_sign} can promote mammary tumor development in the Sprague Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

  1. Amifostine Induces Antioxidant Enzymatic Activities in Normal Tissues and a Transplantable Tumor That Can Affect Radiation Response

    SciTech Connect

    Grdina, David J. Murley, Jeffrey S.; Kataoka, Yasushi; Baker, Kenneth L.; Kunnavakkam, Rangesh; Coleman, Mitchell C.; Spitz, Douglas R.

    2009-03-01

    Purpose: To determine whether amifostine can induce elevated manganese superoxide dismutase (SOD2) in murine tissues and a transplantable SA-NH tumor, resulting in a delayed tumor cell radioprotective effect. Methods and Materials: SA-NH tumor-bearing C3H mice were treated with a single 400 mg/kg or three daily 50 mg/kg doses of amifostine administered intraperitoneally. At selected time intervals after the last injection, the heart, liver, lung, pancreas, small intestine, spleen, and SA-NH tumor were removed and analyzed for SOD2, catalase, and glutathione peroxidase (GPx) enzymatic activity. The effect of elevated SOD2 enzymatic activity on the radiation response of SA-NH cells was determined. Results: SOD2 activity was significantly elevated in selected tissues and a tumor 24 h after amifostine treatment. Catalase and GPx activities remained unchanged except for significant elevations in the spleen. GPx was also elevated in the pancreas. SA-NH tumor cells exhibited a twofold elevation in SOD2 activity and a 27% elevation in radiation resistance. Amifostine administered in three daily fractions of 50 mg/kg each also resulted in significant elevations of these antioxidant enzymes. Conclusions: Amifostine can induce a delayed radioprotective effect that correlates with elevated levels of SOD2 activity in SA-NH tumor. If limited to normal tissues, this delayed radioprotective effect offers an additional potential for overall radiation protection. However, amifostine-induced elevation of SOD2 activity in tumors could have an unanticipated deleterious effect on tumor responses to fractionated radiation therapy, given that the radioprotector is administered daily just before each 2-Gy fractionated dose.

  2. Butylated hydroxyanisole and lung tumor development in A/J mice

    SciTech Connect

    Witschi, H.R.; Doherty, D.G.

    1984-01-01

    A diet containing 0.75% butylated hydroxyanisole (BHA) did not enhance the development of lung tumors in A/J mice if fed for 8 weeks after administration of urethane, benzo(a)pyrene (B(a)P), or dimethylnitrosamine (DMN). Prefeeding animals with BHA partially protected animals against the tumorigenic effect of urethane and B(a)P. Partial protection was also seen in animals given B(a)P and then exposed to BHA in the diet. The two isomers of BHA 3-tert.-butyl-4-hydroxyanisole and 2-tert.-butyl-4-hydroxyanisole) were synthesized and injected ip. They failed to enhance lung tumor development. It is concluded that BHA is not a promoting agent as is butylated hydroxytoluene (BHT) for lung tumors in mice. One possible explanation is that BHA in the diet does not produce the extensive cell proliferation seen in the lungs of mice fed BHT. 19 references, 5 tables.

  3. Anti-Gb3 monoclonal antibody inhibits angiogenesis and tumor development.

    PubMed

    Desselle, Ariane; Chaumette, Tanguy; Gaugler, Marie-Hélène; Cochonneau, Denis; Fleurence, Julien; Dubois, Nolwenn; Hulin, Philippe; Aubry, Jacques; Birklé, Stéphane; Paris, François

    2012-01-01

    Inhibiting the growth of tumor vasculature represents one of the relevant strategies against tumor progression. Between all the different pro-angiogenic molecular targets, plasma membrane glycosphingolipids have been under-investigated. In this present study, we explore the anti-angiogenic therapeutic advantage of a tumor immunotherapy targeting the globotriaosylceramide Gb3. In this purpose, a monoclonal antibody against Gb3, named 3E2 was developed and characterized. We first demonstrate that Gb3 is over-expressed in proliferative endothelial cells relative to quiescent cells. Then, we demonstrate that 3E2 inhibits endothelial cell proliferation in vitro by slowing endothelial cell proliferation and by increasing mitosis duration. Antibody 3E2 is further effective in inhibiting ex vivo angiogenesis in aorta ring assays. Moreover, 3E2 treatment inhibits NXS2 neuroblastoma development and liver metastases spreading in A/J mice. Immunohistology examination of the NXS2 metastases shows that only endothelial cells, but not cancer cells express Gb3. Finally, 3E2 treatment diminishes tumor vessels density, proving a specific therapeutic action of our monoclonal antibody to tumor vasculature. Our study demonstrates that Gb3 is a viable alternative target for immunotherapy and angiogenesis inhibition.

  4. Anti-Gb3 Monoclonal Antibody Inhibits Angiogenesis and Tumor Development

    PubMed Central

    Gaugler, Marie-Hélène; Cochonneau, Denis; Fleurence, Julien; Dubois, Nolwenn; Hulin, Philippe; Aubry, Jacques; Birklé, Stéphane; Paris, François

    2012-01-01

    Inhibiting the growth of tumor vasculature represents one of the relevant strategies against tumor progression. Between all the different pro-angiogenic molecular targets, plasma membrane glycosphingolipids have been under-investigated. In this present study, we explore the anti-angiogenic therapeutic advantage of a tumor immunotherapy targeting the globotriaosylceramide Gb3. In this purpose, a monoclonal antibody against Gb3, named 3E2 was developed and characterized. We first demonstrate that Gb3 is over-expressed in proliferative endothelial cells relative to quiescent cells. Then, we demonstrate that 3E2 inhibits endothelial cell proliferation in vitro by slowing endothelial cell proliferation and by increasing mitosis duration. Antibody 3E2 is further effective in inhibiting ex vivo angiogenesis in aorta ring assays. Moreover, 3E2 treatment inhibits NXS2 neuroblastoma development and liver metastases spreading in A/J mice. Immunohistology examination of the NXS2 metastases shows that only endothelial cells, but not cancer cells express Gb3. Finally, 3E2 treatment diminishes tumor vessels density, proving a specific therapeutic action of our monoclonal antibody to tumor vasculature. Our study demonstrates that Gb3 is a viable alternative target for immunotherapy and angiogenesis inhibition. PMID:23189121

  5. Early Tumor Development Captured Through Nondestructive, High Resolution Differential Phase Contrast X-ray Imaging

    PubMed Central

    Beheshti, A.; Pinzer, B. R.; McDonald, J. T.; Stampanoni, M.; Hlatky, L.

    2014-01-01

    Although a considerable amount is known about molecular dysregulations in later stages of tumor progression, much less is known about the regulated processes supporting initial tumor growth. Insight into such processes can provide a fuller understanding of carcinogenesis, with implications for cancer treatment and risk assessment. Work from our laboratory suggests that organized substructure emerges during tumor formation. The goal here was to examine the feasibility of using state-of-the-art differential phase contrast X-ray imaging to investigate density differentials that evolve during early tumor development. To this end the beamline for TOmographic Microscopy and Coherent rAdiology experimenTs (TOMCAT) at the Swiss Light Source was used to examine the time-dependent assembly of substructure in developing tumors. Differential phase contrast (DPC) imaging based on grating interferometry as implemented with TOMCAT, offers sensitivity to density differentials within soft tissues and a unique combination of high resolution coupled with a large field of view that permits the accommodation of larger tissue sizes (1 cm in diameter), difficult with other imaging modalities. PMID:24125488

  6. Brain tumors and synchrotron radiation: Methodological developments in quantitative brain perfusion imaging and radiation therapy

    SciTech Connect

    Adam, Jean-Francois

    2005-04-01

    High-grade gliomas are the most frequent type of primary brain tumors in adults. Unfortunately, the management of glioblastomas is still mainly palliative and remains a difficult challenge, despite advances in brain tumor molecular biology and in some emerging therapies. Synchrotron radiation opens fields for medical imaging and radiation therapy by using monochromatic intense x-ray beams. It is now well known that angiogenesis plays a critical role in the tumor growth process and that brain perfusion is representative of the tumor mitotic activity. Synchrotron radiation quantitative computed tomography (SRCT) is one of the most accurate techniques for measuring in vivo contrast agent concentration and thus computing precise and accurate absolute values of the brain perfusion key parameters. The methodological developments of SRCT absolute brain perfusion measurements as well as their preclinical validation are detailed in this thesis. In particular, absolute cerebral volume and blood brain barrier permeability high-resolution (pixel size <50x50 {mu}m{sup 2}) parametric maps were reported. In conventional radiotherapy, the treatment of these tumors remains a delicate challenge, because the damages to the surrounding normal brain tissue limit the amount of radiation that can be delivered. One strategy to overcome this limitation is to infuse an iodinated contrast agent to the patient during the irradiation. The contrast agent accumulates in the tumor, through the broken blood brain barrier, and the irradiation is performed with kilovoltage x rays, in tomography mode, the tumor being located at the center of rotation and the beam size adjusted to the tumor dimensions. The dose enhancement results from the photoelectric effect on the heavy element and from the irradiation geometry. Synchrotron beams, providing high intensity, tunable monochromatic x rays, are ideal for this treatment. The beam properties allow the selection of monochromatic irradiation, at the optimal

  7. The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.

    PubMed

    Yoshii, J; Yoshiji, H; Kuriyama, S; Ikenaka, Y; Noguchi, R; Okuda, H; Tsujinoue, H; Nakatani, T; Kishida, H; Nakae, D; Gomez, D E; De Lorenzo, M S; Tejera, A M; Fukui, H

    2001-12-15

    Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.

  8. Development and characterization of non-resonant multiphoton photoacoustic spectroscopy (NMPPAS) for brain tumor margining

    NASA Astrophysics Data System (ADS)

    Dahal, Sudhir

    During tumor removal surgery, due to the problems associated with obtaining high-resolution, real-time chemical images of where exactly the tumor ends and healthy tissue begins (tumor margining), it is often necessary to remove a much larger volume of tissue than the tumor itself. In the case of brain tumor surgery, however, it is extremely unsafe to remove excess tissue. Therefore, without an accurate image of the tumor margins, some of the tumor's finger-like projections are inevitably left behind in the surrounding parenchyma to grow again. For this reason, the development of techniques capable of providing high-resolution real-time images of tumor margins up to centimeters below the surface of a tissue is ideal for the diagnosis and treatment of tumors, as well as surgical guidance during brain tumor excision. A novel spectroscopic technique, non-resonant multiphoton photoacoustic spectroscopy (NMPPAS), is being developed with the capabilities of obtaining high-resolution subsurface chemical-based images of underlying tumors. This novel technique combines the strengths of multiphoton tissue spectroscopy and photoacoustic spectroscopy into a diagnostic methodology that will, ultimately, provide unparalleled chemical information and images to provide the state of sub-surface tissues. The NMPPAS technique employs near-infrared light (in the diagnostic window) to excite ultraviolet and/or visible light absorbing species deep below the tissue's surface. Once a multiphoton absorption event occurs, non-radiative relaxation processes generates a localized thermal expansion and subsequent acoustic wave that can be detected using a piezoelectric transducer. Since NMPPAS employs an acoustic detection modality, much deeper diagnoses can be performed than that is possible using current state of the art high-resolution chemical imaging techniques such as multiphoton fluorescence spectroscopy. NMPPAS was employed to differentiate between excised brain tumors (astrocytoma III

  9. MicroRNA-320 family is downregulated in colorectal adenoma and affects tumor proliferation by targeting CDK6

    PubMed Central

    Tadano, Toshihiro; Kakuta, Yoichi; Hamada, Shin; Shimodaira, Yosuke; Kuroha, Masatake; Kawakami, Yoko; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Masamune, Atsushi; Takahashi, Seiichi; Kinouchi, Yoshitaka; Shimosegawa, Tooru

    2016-01-01

    AIM: To investigate the microRNA (miRNA) expression during histological progression from colorectal normal mucosa through adenoma to carcinoma within a lesion. METHODS: Using microarray, the sequential changes in miRNA expression profiles were compared in colonic lesions from matched samples; histologically, non-neoplastic mucosa, adenoma, and submucosal invasive carcinoma were microdissected from a tissue sample. Cell proliferation assay was performed to observe the effect of miRNA, and its target genes were predicted using bioinformatics approaches and the expression profile of SW480 transfected with the miRNA mimics. mRNA and protein levels of the target gene in colon cancer cell lines with a mimic control or miRNA mimics were measured using qRT-PCR and Western blotting. The expression levels of miRNA and target gene in colorectal tissue samples were also measured. RESULTS: Microarray analysis identified that the miR-320 family, including miR-320a, miR-320b, miR-320c, miR-320d and miR-320e, were differentially expressed in adenoma and submucosal invasive carcinoma. The miR-320 family, which inhibits cell proliferation, is frequently downregulated in colorectal adenoma and submucosal invasive carcinoma tissues. Seven genes including CDK6 were identified to be common in the results of gene expression array and bioinformatics analyses performed to find the target gene of the miR-320 family. We confirmed that mRNA and protein levels of CDK6 were significantly suppressed in colon cancer cell lines with miR-320 family mimics. CDK6 expression was found to increase from non-neoplastic mucosa through adenoma to submucosal invasive carcinoma tissues and showed an inverse correlation with miR-320 family expression. CONCLUSION: MiR-320 family affects colorectal tumor proliferation by targeting CDK6, plays important role in its growth, and is considered to be a biomarker for its early detection. PMID:27559432

  10. Collaborative Development: A New Culture Affects an Old Organization

    ERIC Educational Resources Information Center

    Phelps, Jim; Ruzicka, Terry

    2008-01-01

    At the University of Wisconsin (UW)-Madison, the Registrar's Office and the Division of Information Technology (DoIT) apply a collaborative development process to joint projects. This model differs from a "waterfall" model in that technical and functional staff work closely to develop requirements, prototypes, and the product throughout its life…

  11. How does Low Impact Development affect Urban Base Flow?

    NASA Astrophysics Data System (ADS)

    Bhaskar, A.; Hogan, D. M.; Archfield, S. A.

    2015-12-01

    A novel form of urban development, Low Impact Development (LID), aims to engineer systems that replicate natural hydrologic functioning. LID includes the preservation of near-natural groundwater recharge via infiltration close to impervious surfaces where stormwater is generated. Our study watershed in Clarksburg, Maryland is an instrumented 1.11 km2 watershed developed between 2004 and 2010 with 73 infiltration-focused stormwater facilities, including bioretention facilities, dry wells, and dry swales. We examined changes to annual and monthly streamflow during and after urban development (2004—2014) and compared alterations to nearby forested and urban control watersheds. We show that total flow and base flow increased in the study watershed during development as compared to control watersheds. We also found that the study watershed had slower storm recessions after development and less seasonality in base flow. These changes may be due to a combination of urban processes occurring during development, including reduction in evapotranspiration and the increase in point sources of recharge. Precipitation that may have infiltrated a forested landscape pre-development, been stored in soil moisture, and eventually been transpired by plants may now be recharged to groundwater and become base flow. A transfer of evapotranspiration to base flow is an unintended alteration to the urban water budget, here observed in a watershed using LID.

  12. Development of a Behavioral Affective Relationship Scale for Encounter Research.

    ERIC Educational Resources Information Center

    Shadish, William R., Jr.; Zarle, Thomas

    The paper outlines several studies over a two-year period to develop a self-report and observer-rating measure of sensitivity/encounter group outcome. The initial form of the scale was taken from McMillan (1971) who developed a measure of 16 categories of group outcome; McMillan's work indicated the scale had high reliability. Subsequent study…

  13. Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels

    SciTech Connect

    Mertins, Philipp; Yang, Feng; Liu, Tao; Mani, DR; Petyuk, Vladislav A.; Gillette, Michael; Clauser, Karl; Qiao, Jana; Gritsenko, Marina A.; Moore, Ronald J.; Levine, Douglas; Townsend, Reid; Erdmann-Gilmore, Petra; Snider, Jacqueline E.; Davies, Sherri; Ruggles, Kelly; Fenyo, David; Kitchens, R. T.; Li, Shunqiang; Olvera, Narcisco; Dao, Fanny; Rodriguez, Henry; Chan, Daniel W.; Liebler, Daniel; White, Forest; Rodland, Karin D.; Mills, Gordon; Smith, Richard D.; Paulovich, Amanda G.; Ellis, Matthew; Carr, Steven A.

    2014-07-01

    Advances in quantitative mass spectrometry (MS)-based proteomics have sparked efforts to characterize the proteomes of tumor samples to provide complementary and unique information inaccessible by genomics. Tumor samples are usually not accrued with proteomic characterization in mind, raising concerns regarding effects of undocumented sample ischemia on protein abundance and phosphosite stoichiometry. Here we report the effects of cold ischemia time on clinical ovarian cancer samples and patient-derived basal and luminal breast cancer xenografts. Tumor tissues were excised and collected prior to vascular ligation, subjected to accurately defined ischemia times up to 60 min, and analyzed by quantitative proteomics and phosphoproteomics using isobaric tags and high-performance, multidimensional LC-MS/MS. No significant changes were detected at the protein level in each tumor type after 60 minutes of ischemia, and the majority of the >25,000 phosphosites detected were also stable. However, large, reproducible increases and decreases in protein phosphorylation at specific sites were observed in up to 24% of the phosphoproteome starting as early as 5 minutes post-excision. Early and sustained activation of stress response, transcriptional regulation and cell death pathways were observed in common across tumor types. Tissue-specific changes in phosphosite stability were also observed suggesting idiosyncratic effects of ischemia in particular lineages. Our study provides insights into the information that may be obtained by proteomic characterization of tumor samples after undocumented periods of ischemia, and suggests caution especially in interpreting activation of stress pathways in such samples as they may reflect sample handling rather than tumor physiology.

  14. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T-cells

    PubMed Central

    Hudecek, Michael; Lupo-Stanghellini, Maria-Teresa; Kosasih, Paula L.; Sommermeyer, Daniel; Jensen, Michael C.; Rader, Christoph; Riddell, Stanley R.

    2013-01-01

    Purpose The adoptive transfer of T-cells modified to express a chimeric antigen receptor (CAR) comprised of an extracellular single chain antibody (scFV) fragment specific for a tumor cell surface molecule, and linked to an intracellular signaling module has activity in advanced malignancies. ROR1 is a tumor-associated molecule expressed on prevalent B-lymphoid and epithelial cancers, and is absent on normal mature B-cells and vital tissues, making it a candidate for CAR T-cell therapy. Experimental Design We constructed ROR1-CARs from scFVs with different affinities and containing extracellular IgG4-Fc spacer domains of different lengths, and evaluated the ability of T-cells expressing each CAR to recognize ROR1+ hematopoietic and epithelial tumors in vitro, and to eliminate human mantle cell lymphoma engrafted into immunodeficient mice. Results ROR1-CARs containing a short ‘Hinge-only’ extracellular spacer conferred superior lysis of ROR1+ tumor cells and induction of T-cell effector functions compared to CARs with long ‘Hinge-CH2-CH3’ spacers. CARs derived from a higher affinity scFV conferred maximum T-cell effector function against primary CLL and ROR1+ epithelial cancer lines in vitro without inducing activation induced T-cell death. T-cells modified with an optimal ROR1-CAR were equivalently effective as CD19-CAR modified T-cells in mediating regression of JeKo-1 mantle cell lymphoma in immunodeficient mice. Conclusions Our results demonstrate that customizing spacer design and increasing affinity of ROR1-CARs enhances T-cell effector function and recognition of ROR1+ tumors. T-cells modified with an optimized ROR1-CAR have significant anti-tumor efficacy in a preclinical model in vivo, suggesting they may be useful to treat ROR1+ tumors in clinical applications. PMID:23620405

  15. Development of apoptosis in irradiated murine tumors as a function of time and dose.

    PubMed

    Stephens, L C; Hunter, N R; Ang, K K; Milas, L; Meyn, R E

    1993-07-01

    In a previous paper (Radiat. Res. 127, 308-316, 1991), we reported that a moderately radiosensitive, transplantable murine ovarian carcinoma (OCaI) displayed apoptosis after irradiation whereas a radioresistant hepatocellular carcinoma (HCaI) did not. These initial observations have been followed up in this detailed analysis of the development of apoptosis in these two tumors as a function of time and dose. Histological sections of OCaI and HCaI carcinomas were scored at various times between 0.5 and 24 h after single doses of 2.5 or 25 Gy gamma radiation for the incidence of apoptosis. The percentage of nuclei undergoing apoptosis in untreated tumors was 5% in OCaI and 0.6% in HCaI. The peak in the number of apoptotic bodies occurred in the OCaI tumors 3-5 h after either dose. After 2.5 Gy, the peak incidence was about 20% and after 25 Gy it was about 30%. Irrespective of dose, HCaI tumors had an incidence of apoptosis of less than 3%. Based on the results of this time course, 4 h after irradiation was chosen for the determination of the dose response, over doses ranging from 2.5 to 25 Gy. The dose response for the OCaI tumors reached a plateau at 25-30% apoptotic nuclei after doses of about 7.5 Gy and above. Autoradiographic analysis of histological sections from mice injected with [3H]thymidine showed that some apoptotic bodies in the OCaI tumors arose from cycling cells. These results confirm that the apoptotic mode of cell death may represent an important response in some irradiated tumors.

  16. Development of apoptosis in irradiated murine tumors as a function of time and dose.

    PubMed

    Stephens, L C; Hunter, N R; Ang, K K; Milas, L; Meyn, R E

    1993-07-01

    In a previous paper (Radiat. Res. 127, 308-316, 1991), we reported that a moderately radiosensitive, transplantable murine ovarian carcinoma (OCaI) displayed apoptosis after irradiation whereas a radioresistant hepatocellular carcinoma (HCaI) did not. These initial observations have been followed up in this detailed analysis of the development of apoptosis in these two tumors as a function of time and dose. Histological sections of OCaI and HCaI carcinomas were scored at various times between 0.5 and 24 h after single doses of 2.5 or 25 Gy gamma radiation for the incidence of apoptosis. The percentage of nuclei undergoing apoptosis in untreated tumors was 5% in OCaI and 0.6% in HCaI. The peak in the number of apoptotic bodies occurred in the OCaI tumors 3-5 h after either dose. After 2.5 Gy, the peak incidence was about 20% and after 25 Gy it was about 30%. Irrespective of dose, HCaI tumors had an incidence of apoptosis of less than 3%. Based on the results of this time course, 4 h after irradiation was chosen for the determination of the dose response, over doses ranging from 2.5 to 25 Gy. The dose response for the OCaI tumors reached a plateau at 25-30% apoptotic nuclei after doses of about 7.5 Gy and above. Autoradiographic analysis of histological sections from mice injected with [3H]thymidine showed that some apoptotic bodies in the OCaI tumors arose from cycling cells. These results confirm that the apoptotic mode of cell death may represent an important response in some irradiated tumors. PMID:8327664

  17. Disrupting circadian homeostatis of sympathetic signaling promotes tumor development in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Perio...

  18. [Development of a radiofrequency device for heating superficial and deep-seated tumors].

    PubMed

    Sugahara, T

    1988-12-01

    The author described the procedure of RF heating of tumors using a heating system Thermotron RF-8 (8 MHz), developed in Japan. The results of the treatment of 63 patients were reported. Limitations of the method and ways of their overcoming were shown.

  19. INFLUENCE OF ENDOCRINE DISRUPTING COMPOUNDS (EDCS) ON MAMMARY GLAND DEVELOPMENT AND TUMOR SUSCEPTIBILITY

    EPA Science Inventory

    Influence of Endocrine Disrupting Compounds (EDCs) on Mammary Gland Development and Tumor Susceptibility.

    Suzanne E. Fenton1, and Jennifer Rayner1,2

    1 Reproductive Toxicology Division, NHEERL/ORD, U.S. EPA, Research Triangle Park, NC, and 2 Department of Environmen...

  20. Identification of tumor-associated antigens on ultraviolet light-induced tumors using antitumor antibodies developed in ascites fluid

    SciTech Connect

    Fortner, G.W.; Takemoto, L.J.; Shehi, L.; Hansen, J.S.

    1982-06-01

    A method is described which leads to the production of large amounts of ascites containing antitumor antibody in small numbers of mice. The antibody was then used to identify and characterize tumor-associated antigens on an ultraviolet light-induced murine skin fibrosarcoma. The antibody showed specific complement-dependent cytotoxicity to the homologous tumor and to an allogeneic tumor line which displayed a glycoprotein viral determinant with a molecular weight of 70,000 on its surface. Absorption of the immune ascites with other tumor cell lines removed the cytotoxicity in relation to the presence of the glycoprotein. Isolation of the tumor cell surface components binding antibody revealed two components with molecular weights of approximately 70,000 and 60,000. The Mr 70,000 component was identified as viral gp70 by peptide mapping.

  1. Common mechanism of chromosome inversion in B- and T-cell tumors: relevance to lymphoid development.

    PubMed

    Denny, C T; Hollis, G F; Hecht, F; Morgan, R; Link, M P; Smith, S D; Kirsch, I R

    1986-10-10

    An inversion of chromosome 14 present in the tumor cells of a patient with childhood acute lymphoblastic leukemia of B-cell lineage was shown to be the result of a site-specific recombination event between an immunoglobulin heavy-chain variable gene and the joining segment of a T-cell receptor alpha chain. This rearrangement resulted in the formation of a hybrid gene, part immunoglobulin and part T-cell receptor. Furthermore, this hybrid gene was transcribed into messenger RNA with a completely open reading frame. Thus, two loci felt to be normally activated at distinct and disparate points in lymphocyte development were unified and expressed in this tumor.

  2. A review of recent developments affecting COBRA rights.

    PubMed

    Harris, J W

    1995-01-01

    Due to the high cost of health care claims and COBRA's status as remedial legislation, COBRA has generated a significant amount of litigation in recent years. While the early COBRA decisions tended to broaden the law in order to provide a remedy to an otherwise uninsured qualified beneficiary, the recent trend in the case law has been to limit the expansion of COBRA rights based on a narrower construction of the statute. Even so, COBRA still represents a legal minefield for employers. As a result, a careful employer will minimize its exposure by monitoring changes in the law and its interpretation and making appropriate modifications to its COBRA documentation and administration. This article discusses some of the more significant recent changes in the law affecting qualified beneficiaries' COBRA rights--and therefore, employers' exposure.

  3. Sexual dimorphism of liver metastasis by murine pancreatic neuroendocrine tumors is affected by expression of complement C5

    PubMed Central

    Contractor, Tanupriya; Kobayashi, Shinta; da Silva, Edaise; Clausen, Richard; Chan, Chang; Vosburgh, Evan; Tang, Laura H.; Levine, Arnold J.; Harris, Chris R.

    2016-01-01

    In a mouse model for neuroendocrine tumors of the pancreas (PanNETs), liver metastasis occurred at a higher frequency in males. Male mice also had higher serum and intratumoral levels of the innate immunity protein complement C5. In mice that lost the ability to express complement C5, there was a lower frequency of metastasis, and males no longer had a higher frequency of metastasis than females. Treatment with PMX53, a small molecule antagonist of C5aR1/CD88, the receptor for complement C5a, also reduced metastasis. Mice lacking a functional gene for complement C5 had smaller primary tumors, which were less invasive and lacked the CD68+ macrophages that have previously been associated with metastasis in this type of tumor. This is the first report of a gene that causes sexual dimorphism of metastasis in a mouse model. In the human disease, which also shows sexual dimorphism for metastasis, clinically advanced tumors expressed more complement C5 than less advanced tumors. PMID:27105526

  4. Rhizosphere microbiome assemblage is affected by plant development

    PubMed Central

    Chaparro, Jacqueline M; Badri, Dayakar V; Vivanco, Jorge M

    2014-01-01

    There is a concerted understanding of the ability of root exudates to influence the structure of rhizosphere microbial communities. However, our knowledge of the connection between plant development, root exudation and microbiome assemblage is limited. Here, we analyzed the structure of the rhizospheric bacterial community associated with Arabidopsis at four time points corresponding to distinct stages of plant development: seedling, vegetative, bolting and flowering. Overall, there were no significant differences in bacterial community structure, but we observed that the microbial community at the seedling stage was distinct from the other developmental time points. At a closer level, phylum such as Acidobacteria, Actinobacteria, Bacteroidetes, Cyanobacteria and specific genera within those phyla followed distinct patterns associated with plant development and root exudation. These results suggested that the plant can select a subset of microbes at different stages of development, presumably for specific functions. Accordingly, metatranscriptomics analysis of the rhizosphere microbiome revealed that 81 unique transcripts were significantly (P<0.05) expressed at different stages of plant development. For instance, genes involved in streptomycin synthesis were significantly induced at bolting and flowering stages, presumably for disease suppression. We surmise that plants secrete blends of compounds and specific phytochemicals in the root exudates that are differentially produced at distinct stages of development to help orchestrate rhizosphere microbiome assemblage. PMID:24196324

  5. Albumin-bound paclitaxel in solid tumors: clinical development and future directions.

    PubMed

    Kundranda, Madappa N; Niu, Jiaxin

    2015-01-01

    Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel's indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice.

  6. Hypoxia in Head and Neck Tumors: Characteristics and Development during Therapy

    PubMed Central

    Bittner, Martin-Immanuel; Grosu, Anca-Ligia

    2013-01-01

    Cancers of the head and neck are a malignancy causing a considerable health burden. In head and neck cancer patients, tumor hypoxia has been shown to be an important predictor of response to therapy and outcome. Several imaging modalities can be used to determine the amount and localization of tumor hypoxia. Especially PET has been used in a number of studies analyzing this phenomenon. However, only few studies have reported the characteristics and development during (chemoradio-) therapy. Yet, the characterization of tumor hypoxia in the course of treatment is of great clinical importance. Successful delineation of hypoxic subvolumes could make an inclusion into radiation treatment planning feasible, where dose painting is hypothesized to improve the tumor control probability. So far, hypoxic subvolumes have been shown to undergo changes during therapy; in most cases, a reduction in tumor hypoxia can be seen, but there are also differing observations. In addition, the hypoxic subvolumes have mostly been described as geographically rather stable. However, studies specifically addressing these issues are needed to provide more data regarding these initial findings and the hypotheses connected with them. PMID:24010122

  7. Albumin-bound paclitaxel in solid tumors: clinical development and future directions

    PubMed Central

    Kundranda, Madappa N; Niu, Jiaxin

    2015-01-01

    Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free formulation of paclitaxel that was initially developed more than a decade ago to overcome toxicities associated with the solvents used in the formulation of standard paclitaxel and to potentially improve efficacy. Nab-paclitaxel has demonstrated an advantage over solvent-based paclitaxel by being able to deliver a higher dose of paclitaxel to tumors and decrease the incidence of serious toxicities, including severe allergic reactions. To date, nab-paclitaxel has been indicated for the treatment of three solid tumors in the USA. It was first approved for the treatment of metastatic breast cancer in 2005, followed by locally advanced or metastatic non-small-cell lung cancer in 2012, and most recently for metastatic pancreatic cancer in 2013. Nab-paclitaxel is also under investigation for the treatment of a number of other solid tumors. This review highlights key clinical efficacy and safety outcomes of nab-paclitaxel in the solid tumors for which it is currently indicated, discusses ongoing trials that may provide new data for the expansion of nab-paclitaxel’s indications into other solid tumors, and provides a clinical perspective on the use of nab-paclitaxel in practice. PMID:26244011

  8. Identification of genes associated with tumor development in CaSki cells in the cosmic space.

    PubMed

    Guo, Fengjie; Li, Yalin; Liu, Yan; Huang, Jian; Zhang, Zhijie; Wang, Jiajia; Li, Yuehui; Hu, Jinyue; Li, Guancheng

    2012-06-01

    It is important to understand the mechanisms of tumor development for curing cervical cancer. However, the molecular basis determining the different characteristics of tumor remains unclear. Space environment as a special study model can expand the study field of tumor development. To approach this, after human cervical carcinoma CaSki cells were flown on “Shen Zhou IV” space shuttle mission, the cell morphology and proliferation was investigated after flying to ground. We found that the growth of 48A9 CaSki cell (flight group) became slow compared with ground groups. Observation of cells by light microscopy revealed differences in cell morphology between ground controls and flight groups, and the flight group exhibited morphologic differences, characterized by rounder, smoother, decreased, smaller and low-adhension cells. Transmission electron microscope images showed the structure of the ultrastructural characteristics of 48A9 CaSki cells were clearly distinct from those of the ground CaSki cells in aspects of mitochondrion, cytoplasm, nucleus and ribosomes. MTT and soft agar assay showed that 48A9 CaSki cells grew slowly compared to ground control. Furthermore, suppression subtractive hybridization combining with reverse Northern blot was used to identify differently expression genes between flight and ground groups. These differentially expressed genes included cytoskeleton, cell differentiation, cell apoptosis, signal transduction, DNA repair, protein synthesis, substance metabolism, and antigen presentation. The identification of differently expressed genes which is likely to increase our understanding of the molecular processes underlying tumor development will provide new insight into tumor development mechanisms, and may facilitate the development of new anticancer strategies.

  9. DNA methylation mediated control of gene expression is critical for development of crown gall tumors.

    PubMed

    Gohlke, Jochen; Scholz, Claus-Juergen; Kneitz, Susanne; Weber, Dana; Fuchs, Joerg; Hedrich, Rainer; Deeken, Rosalia

    2013-01-01

    Crown gall tumors develop after integration of the T-DNA of virulent Agrobacterium tumefaciens strains into the plant genome. Expression of the T-DNA-encoded oncogenes triggers proliferation and differentiation of transformed plant cells. Crown gall development is known to be accompanied by global changes in transcription, metabolite levels, and physiological processes. High levels of abscisic acid (ABA) in crown galls regulate expression of drought stress responsive genes and mediate drought stress acclimation, which is essential for wild-type-like tumor growth. An impact of epigenetic processes such as DNA methylation on crown gall development has been suggested; however, it has not yet been investigated comprehensively. In this study, the methylation pattern of Arabidopsis thaliana crown galls was analyzed on a genome-wide scale as well as at the single gene level. Bisulfite sequencing analysis revealed that the oncogenes Ipt, IaaH, and IaaM were unmethylated in crown galls. Nevertheless, the oncogenes were susceptible to siRNA-mediated methylation, which inhibited their expression and subsequently crown gall growth. Genome arrays, hybridized with methylated DNA obtained by immunoprecipitation, revealed a globally hypermethylated crown gall genome, while promoters were rather hypomethylated. Mutants with reduced non-CG methylation developed larger tumors than the wild-type controls, indicating that hypermethylation inhibits plant tumor growth. The differential methylation pattern of crown galls and the stem tissue from which they originate correlated with transcriptional changes. Genes known to be transcriptionally inhibited by ABA and methylated in crown galls became promoter methylated upon treatment of A. thaliana with ABA. This suggests that the high ABA levels in crown galls may mediate DNA methylation and regulate expression of genes involved in drought stress protection. In summary, our studies provide evidence that epigenetic processes regulate gene

  10. Gld-1, a Tumor Suppressor Gene Required for Oocyte Development in Caenorhabditis Elegans

    PubMed Central

    Francis, R.; Barton, M. K.; Kimble, J.; Schedl, T.

    1995-01-01

    We have characterized 31 mutations in the gld-1 (defective in germline development) gene of Caenorhabditis elegans. In gld-1(null) hermaphrodites, oogenesis is abolished and a germline tumor forms where oocyte development would normally occur. By contrast, gld-1(null) males are unaffected. The hermaphrodite germline tumor appears to derive from germ cells that enter the meiotic pathway normally but then exit pachytene and return to the mitotic cycle. Certain gld-1 partial loss-of-function mutations also abolish oogenesis, but germ cells arrest in pachytene rather than returning to mitosis. Our results indicate that gld-1 is a tumor suppressor gene required for oocyte development. The tumorous phenotype suggests that gld-1(+) may function to negatively regulate proliferation during meiotic prophase and/or act to direct progression through meiotic prophase. We also show that gld-1(+) has an additional nonessential role in germline sex determination: promotion of hermaphrodite spermatogenesis. This function of gld-1 is inferred from a haplo-insufficient phenotype and from the properties of gain-of-function gld-1 mutations that cause alterations in the sexual identity of germ cells. PMID:7713419

  11. gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans

    SciTech Connect

    Francis, R.; Schedl, T.; Barton, M.K.; Kimble, J.

    1995-02-01

    We have characterized 31 mutations in the gld-1 (defective in germline development) gene of Caenorhabditis elegans. In gld-1 (null) hermaphrodites, oogenesis is abolished and a germline tumor forms where oocyte development would normally occur. By contrast, gld-1 (null) males are unaffected. The hermaphrodite germline tumor appears to derive from germ cells that enter the meiotic pathway normally but then exit pachytene and return to the mitotic cycle. Certain gld-1 partial loss-of-function mutations also abolish oogenesis, but germ cells arrest in pachytene rather than returning to mitosis. Our results indicate that gld-1 is a tumor suppressor gene required for oocyte development. The tumorous phenotype suggests that gld-1(+) may function to negatively regulate proliferation during meiotic prophase and/or act to direct progression through meiotic prophase. We also show that gld-1(+) has an additional nonessential role in germline sex determination: promotion of hermaphrodite spermatogenesis. This function of gld-1 is inferred from a haplo-insufficient phenotype and from the properties of gain-of-function gld-1 mutations that cause alterations in the sexual identity of germ cells. 69 refs., 10 figs., 8 tabs.

  12. Sensitive periods in affective development: nonlinear maturation of fear learning.

    PubMed

    Hartley, Catherine A; Lee, Francis S

    2015-01-01

    At specific maturational stages, neural circuits enter sensitive periods of heightened plasticity, during which the development of both brain and behavior are highly receptive to particular experiential information. A relatively advanced understanding of the regulatory mechanisms governing the initiation, closure, and reinstatement of sensitive period plasticity has emerged from extensive research examining the development of the visual system. In this article, we discuss a large body of work characterizing the pronounced nonlinear changes in fear learning and extinction that occur from childhood through adulthood, and their underlying neural substrates. We draw upon the model of sensitive period regulation within the visual system, and present burgeoning evidence suggesting that parallel mechanisms may regulate the qualitative changes in fear learning across development.

  13. A novel family of small proteins that affect plant development

    SciTech Connect

    John Charles Walker

    2011-04-29

    The DVL genes represent a new group of plant proteins that influence plant growth and development. Overexpression of DVL1, and other members of the DVL family, causes striking phenotypic changes. The DVL proteins share sequence homology in their C-terminal half. Point mutations in the C-terminal domain show it is necessary and deletion studies demonstrate the C-terminal domain is sufficient to confer the overexpression phenotypes. The phenotypes observed, and the conservation of the protein sequence in the plant kingdom, does suggest the DVL proteins have a role in modulating plant growth and development. Our working hypothesis is the DVL proteins function as regulators of cellular signaling pathways that control growth and development.

  14. Developing Culturally Competent Faculty: A Cognitive, Affective, and Spiritual Model

    ERIC Educational Resources Information Center

    Taylor, Deborah L.; Van Zandt, Cassandra; Menjares, Pete C.

    2013-01-01

    The past decade has evidenced significant dialogue on faith-based campuses about the persistent gap between the increasing ethnic diversity of the student population and that of the faculty. While campus administrators and leaders acknowledge the need to address this concern through faculty development, there is a disturbing lack of successful…

  15. Early Social Experience Affects the Development of Eye Gaze Processing.

    PubMed

    Senju, Atsushi; Vernetti, Angélina; Ganea, Natasa; Hudry, Kristelle; Tucker, Leslie; Charman, Tony; Johnson, Mark H

    2015-12-01

    Eye gaze is a key channel of non-verbal communication in humans. Eye contact with others is present from birth, and eye gaze processing is crucial for social learning and adult-infant communication. However, little is known about the effect of selectively different experience of eye contact and gaze communication on early social and communicative development. To directly address this question, we assessed 14 sighted infants of blind parents (SIBPs) longitudinally at 6-10 and 12-16 months. Face scanning and gaze following were assessed using eye tracking. In addition, naturalistic observations were made when the infants were interacting with their blind parent and with an unfamiliar sighted adult. Established measures of emergent autistic-like behaviors and standardized tests of cognitive, motor, and linguistic development were also collected. These data were then compared with those obtained from a group of infants of sighted parents. Despite showing typical social skills development overall, infants of blind parents allocated less attention to adult eye movements and gaze direction, an effect that increased between 6-10 and 12-16 months of age. The results suggest that infants adjust their use of adults' eye gaze depending on gaze communication experience from early in life. The results highlight that human functional brain development shows selective experience-dependent plasticity adaptive to the individual's specific social environment.

  16. Beyond Brain Growth: Other Factors Affecting Cognitive Development.

    ERIC Educational Resources Information Center

    Stefanich, Greg; Aldridge, Mary Nan

    The intellectual model of Jean Piaget asserts that individuals pass through a series of various intellectual stages as they mature. Human development is categorized into four basic stages: (1) sensory motor stage, which lasts from birth to about eighteen months; (2) preoperational stage, lasting from eighteen months to about seven years; (3)…

  17. Professional Development: Designing for the Cognitive and Affective Domains

    ERIC Educational Resources Information Center

    Doherty, Iain

    2014-01-01

    This paper critically reflects on the pedagogical approach underlying a professional development course in eLearning. The aim of the course was to teach faculty based eLearning officers the necessary practical and theoretical skills to fulfil their roles in supporting Faculties with eLearning initiatives. Whilst the course was successful--judged…

  18. Factors affecting early seedling development in whole pine tree substrates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Wood-based materials derived from pine trees, such as processed whole pine tree (WPT), can be a viable option for producers looking to offset pine bark or peatmoss usage in container substrates. Reduced root development of stem cuttings rooted in WPT compared with pine bark (PB) has been observed, b...

  19. Factors Affecting the Professional Development of Elementary English Teachers

    ERIC Educational Resources Information Center

    Zein, Subhan

    2016-01-01

    The poor classroom practices of English teachers at elementary level in Indonesia have been attributed to the inadequacy of pre-service education. Yet, whether in-service professional development (PD) also plays a role is unknown. This study investigated the perspectives of 23 teachers, 14 teacher educators and 3 school principals regarding the…

  20. The maize rachis affects Aspergillus flavus movement during ear development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aspergillus flavus expressing green fluorescent protein (GFP) was used to follow infection in ears of maize hybrids resistant and susceptible to the fungus. Developing ears were needle-inoculated with GFP-transformed A. flavus 20 days after silk emergence, and GFP fluorescence in the pith was evalu...

  1. Traumatic Experience in Infancy: How Responses to Stress Affect Development

    ERIC Educational Resources Information Center

    Witten, Molly Romer

    2010-01-01

    Responses to traumatic stress during the earliest years of life can change quickly and can be difficult to identify because of the young child's rapid rate of development. The symptoms of traumatic stress will depend on the child's developmental level and individual coping styles, as well as the quality and nature of the child's most important…

  2. Starting Smart: How Early Experiences Affect Brain Development. Second Edition.

    ERIC Educational Resources Information Center

    Hawley, Theresa

    Based on recent research, it is now believed that brain growth is highly dependent upon children's early experiences. Neurons allow communication and coordinated functioning among various brain areas. Brain development after birth consists of an ongoing process of wiring and rewiring the connections among neurons. The forming and breaking of…

  3. Maternal seizures can affect the brain developing of offspring.

    PubMed

    Cossa, Ana Carolina; Lima, Daiana Correia; do Vale, Tiago Gurgel; de Alencar Rocha, Anna Karynna Alves; da Graça Naffah-Mazzacoratti, Maria; da Silva Fernandes, Maria José; Amado, Debora

    2016-08-01

    To elucidate the impact of maternal seizures in the developing rat brain, pregnant Wistar rats were subjected to the pilocarpine-induced seizures and pups from different litters were studied at different ages. In the first 24 h of life, blood glucose and blood gases were analyzed. (14)C-leucine [(14)C-Leu] incorporation was used to analyze protein synthesis at PN1, and Western Blot method was used to analyze protein levels of Bax, Bcl-2 and Poly(ADP-ribose) polymerase-1 (PARP-1) in the hippocampus (PN3-PN21). During the first 22 days of postnatal life, body weight gain, length, skull measures, tooth eruption, eye opening and righting reflex have been assessed. Pups from naive mothers were used as controls. Experimental pups showed a compensated metabolic acidosis and hyperglycemia. At PN1, the [(14)C-Leu] incorporation into different studied areas of experimental pups was lower than in the control pups. During development, the protein levels of Bax, Bcl-2 and PARP-1 in the hippocampus of experimental pups were altered when compared with control pups. A decreased level of pro- and anti-apoptotic proteins was verified in the early postnatal age (PN3), and an increased level of pro-apoptotic proteins concomitant with a reduced level of anti-apoptotic protein was observed at the later stages of the development (PN21). Experimental pups had a delay in postnatal growth and development beyond disturb in protein synthesis and some protein expression during development. These changes can be result from hormonal alterations linked to stress and/or hypoxic events caused by maternal epileptic seizures during pregnancy. PMID:27085526

  4. Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes.

    PubMed

    Baxter, Patricia A; Lin, Qi; Mao, Hua; Kogiso, Mari; Zhao, Xiumei; Liu, Zhigang; Huang, Yulun; Voicu, Horatiu; Gurusiddappa, Sivashankarappa; Su, Jack M; Adesina, Adekunle M; Perlaky, Laszlo; Dauser, Robert C; Leung, Hon-chiu Eastwood; Muraszko, Karin M; Heth, Jason A; Fan, Xing; Lau, Ching C; Man, Tsz-Kwong; Chintagumpala, Murali; Li, Xiao-Nan

    2014-01-01

    Clinical outcome of children with malignant glioma remains dismal. Here, we examined the role of over-expressed BMI1, a regulator of stem cell self-renewal, in sustaining tumor formation in pediatric glioma stem cells. Our investigation revealed BMI1 over-expression in 29 of 54 (53.7%) pediatric gliomas, 8 of 8 (100%) patient derived orthotopic xenograft (PDOX) mouse models, and in both CD133+ and CD133- glioma cells. We demonstrated that lentiviral-shRNA mediated silencing of suppressed cell proliferation in vitro in cells derived from 3 independent PDOX models and eliminated tumor-forming capacity of CD133+ and CD133- cells derived from 2 PDOX models in mouse brains. Gene expression profiling showed that most of the molecular targets of BMI1 ablation in CD133+ cells were different from that in CD133- cells. Importantly, we found that silencing BMI1 in CD133+ cells derived from 3 PDOX models did not affect most of the known genes previously associated with the activated BMI1, but modulated a novel set of core genes, including RPS6KA2, ALDH3A2, FMFB, DTL, API5, EIF4G2, KIF5c, LOC650152, C20ORF121, LOC203547, LOC653308, and LOC642489, to mediate the elimination of tumor formation. In summary, we identified the over-expressed BMI1 as a promising therapeutic target for glioma stem cells, and suggest that the signaling pathways associated with activated BMI1 in promoting tumor growth may be different from those induced by silencing BMI1 in blocking tumor formation. These findings highlighted the importance of careful re-analysis of the affected genes following the inhibition of abnormally activated oncogenic pathways to identify determinants that can potentially predict therapeutic efficacy.

  5. Development of drug loaded nanoparticles for tumor targeting. Part 2: Enhancement of tumor penetration through receptor mediated transcytosis in 3D tumor models

    NASA Astrophysics Data System (ADS)

    El-Dakdouki, Mohammad H.; Puré, Ellen; Huang, Xuefei

    2013-04-01

    We report that receptor mediated transcytosis can be utilized to facilitate tumor penetration by drug loaded nanoparticles (NPs). We synthesized hyaluronan (HA) coated silica nanoparticles (SNPs) containing a highly fluorescent core to target CD44 expressed on the cancer cell surface. Although prior studies have primarily focused on CD44 mediated endocytosis to facilitate cellular uptake of HA-NPs by cancer cells, we discovered that, once internalized, the HA-SNPs could be transported out of the cells with their cargo. The exported NPs could be taken up by neighboring cells. This enabled the HA-SNPs to penetrate deeper inside tumors and reach a much greater number of tumor cells in 3D tumor models, presumably through tandem cycles of CD44 mediated endocytosis and exocytosis. When doxorubicin (DOX) was loaded onto the NPs, better penetration of multilayered tumor cells was observed with much improved cytotoxicities against both drug sensitive and drug resistant cancer spheroids compared to the free drug. Thus, targeting receptors such as CD44 that can readily undergo recycling between the cell surface and interior of the cells can become a useful strategy to enhance the tumor penetration potential of NPs and the efficiency of drug delivery through receptor mediated transcytosis.We report that receptor mediated transcytosis can be utilized to facilitate tumor penetration by drug loaded nanoparticles (NPs). We synthesized hyaluronan (HA) coated silica nanoparticles (SNPs) containing a highly fluorescent core to target CD44 expressed on the cancer cell surface. Although prior studies have primarily focused on CD44 mediated endocytosis to facilitate cellular uptake of HA-NPs by cancer cells, we discovered that, once internalized, the HA-SNPs could be transported out of the cells with their cargo. The exported NPs could be taken up by neighboring cells. This enabled the HA-SNPs to penetrate deeper inside tumors and reach a much greater number of tumor cells in 3D tumor

  6. Factors affecting the development of adverse drug reactions (Review article)

    PubMed Central

    Alomar, Muaed Jamal

    2013-01-01

    Objectives To discuss the effect of certain factors on the occurrence of Adverse Drug Reactions (ADRs). Data Sources A systematic review of the literature in the period between 1991 and 2012 was made based on PubMed, the Cochrane database of systematic reviews, EMBASE and IDIS. Key words used were: medication error, adverse drug reaction, iatrogenic disease factors, ambulatory care, primary health care, side effects and treatment hazards. Summary Many factors play a crucial role in the occurrence of ADRs, some of these are patient related, drug related or socially related factors. Age for instance has a very critical impact on the occurrence of ADRs, both very young and very old patients are more vulnerable to these reactions than other age groups. Alcohol intake also has a crucial impact on ADRs. Other factors are gender, race, pregnancy, breast feeding, kidney problems, liver function, drug dose and frequency and many other factors. The effect of these factors on ADRs is well documented in the medical literature. Taking these factors into consideration during medical evaluation enables medical practitioners to choose the best drug regimen. Conclusion Many factors affect the occurrence of ADRs. Some of these factors can be changed like smoking or alcohol intake others cannot be changed like age, presence of other diseases or genetic factors. Understanding the different effects of these factors on ADRs enables healthcare professionals to choose the most appropriate medication for that particular patient. It also helps the healthcare professionals to give the best advice to patients. Pharmacogenomics is the most recent science which emphasizes the genetic predisposition of ADRs. This innovative science provides a new perspective in dealing with the decision making process of drug selection. PMID:24648818

  7. Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling.

    PubMed

    Young, Christian D; Pfefferle, Adam D; Owens, Philip; Kuba, María G; Rexer, Brent N; Balko, Justin M; Sánchez, Violeta; Cheng, Hailing; Perou, Charles M; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L

    2013-07-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110α via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CA(H1047R)-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CA(H1047R)-expressing tumors. However, the p110α-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110α and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CA(H1047R). These data suggest that PIK3CA(H1047R)-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110α and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations.

  8. Reading Instruction Affects the Cognitive Skills Supporting Early Reading Development

    ERIC Educational Resources Information Center

    McGeown, Sarah P.; Johnston, Rhona S.; Medford, Emma

    2012-01-01

    This study examined the cognitive skills associated with early reading development when children were taught by different types of instruction. Seventy-nine children (mean age at pre-test 4;10 (0.22 S.D.) and post-test 5;03 (0.21 S.D.)) were taught to read either by an eclectic approach which included sight-word learning, guessing from context and…

  9. Pediatric Adrenocortical Tumors: What They Can Tell Us on Adrenal Development and Comparison with Adult Adrenal Tumors

    PubMed Central

    Lalli, Enzo; Figueiredo, Bonald C.

    2015-01-01

    Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors. A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H). Children ACT have specific features distinguishing them from adult tumors in their pathogenetic mechanisms, genomic profiles, and prognosis. Epidemiological and molecular evidence suggests that in most cases they are derived from the fetal adrenal. PMID:25741319

  10. The LKB1 tumor suppressor differentially affects anchorage independent growth of HPV positive cervical cancer cell lines

    SciTech Connect

    Mack, Hildegard I.D.; Munger, Karl

    2013-11-15

    Infection with high-risk human papillomaviruses is causally linked to cervical carcinogenesis. However, most lesions caused by high-risk HPV infections do not progress to cancer. Host cell mutations contribute to malignant progression but the molecular nature of such mutations is unknown. Based on a previous study that reported an association between liver kinase B1 (LKB1) tumor suppressor loss and poor outcome in cervical cancer, we sought to determine the molecular basis for this observation. LKB1-negative cervical and lung cancer cells were reconstituted with wild type or kinase defective LKB1 mutants and we examined the importance of LKB1 catalytic activity in known LKB1-regulated processes including inhibition of cell proliferation and elevated resistance to energy stress. Our studies revealed marked differences in the biological activities of two kinase defective LKB1 mutants in the various cell lines. Thus, our results suggest that LKB1 may be a cell-type specific tumor suppressor. - Highlights: • LKB1 is a tumor suppressor that is linked to Peutz-Jeghers syndrome. • Peutz-Jeghers syndrome patients have a high incidence of cervical cancer. • Cervical cancer is caused by HPV infections. • This study investigates LKB1 tumor suppressor activity in cervical cancer.

  11. Antenatal glucocorticoid treatment affects hippocampal development in mice.

    PubMed

    Noorlander, Cornelle W; Tijsseling, Deodata; Hessel, Ellen V S; de Vries, Willem B; Derks, Jan B; Visser, Gerard H A; de Graan, Pierre N E

    2014-01-01

    Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

  12. Early development of Xenopus embryos is affected by simulated gravity

    NASA Technical Reports Server (NTRS)

    Yokota, Hiroki; Neff, Anton W.; Malacinski, George M.

    1994-01-01

    Early amphibian (Xenopus laevis) development under clinostat-simulated weightlessness and centrifuge-simulated hypergravity was studied. The results revealed significant effects on (i) 'morphological patterning' such as the cleavage furrow pattern in the vegetal hemisphere at the eight-cell stage and the shape of the dorsal lip in early gastrulae and (ii) 'the timing of embryonic events' such as the third cleavage furrow completion and the dorsal lip appearance. Substantial variations in sensitivity to simulated force fields were observed, which should be considered in interpreting spaceflight data.

  13. Clinical development of BLZ-100 for real-time optical imaging of tumors during resection

    NASA Astrophysics Data System (ADS)

    Franklin, Heather L.; Miller, Dennis M.; Hedges, Teresa; Perry, Jeff; Parrish-Novak, Julia

    2016-03-01

    Complete initial resection can give cancer patients the best opportunity for long-term survival. There is unmet need in surgical oncology for optical imaging that enables simple and precise visualization of tumors and consistent contrast with surrounding normal tissues. Near-infrared (NIR) contrast agents and camera systems that can detect them represent an area of active research and development. The investigational Tumor Paint agent BLZ-100 is a conjugate of a chlorotoxin peptide and the NIR dye indocyanine green (ICG) that has been shown to specifically bind to a broad range of solid tumors. Clinical efficacy studies with BLZ-100 are in progress, a necessary step in bringing the product into clinical practice. To ensure a product that will be useful for and accepted by surgeons, the early clinical development of BLZ- 100 incorporates multiple tumor types and imaging devices so that surgeon feedback covers the range of anticipated clinical uses. Key contrast agent characteristics include safety, specificity, flexibility in timing between dose and surgery, and breadth of tumor types recognized. Imaging devices should use wavelengths that are optimal for the contrast agent, be sensitive enough that contrast agent dosing can be adjusted for optimal contrast, include real-time video display of fluorescence and white light image, and be simple for surgeons to use with minimal disruption of surgical flow. Rapid entry into clinical studies provides the best opportunity for early surgeon feedback, enabling development of agents and devices that will gain broad acceptance and provide information that helps surgeons achieve more complete and precise resections.

  14. Does bilingual experience affect early visual perceptual development?

    PubMed Central

    Schonberg, Christina; Sandhofer, Catherine M.; Tsang, Tawny; Johnson, Scott P.

    2014-01-01

    Visual attention and perception develop rapidly during the first few months after birth, and these behaviors are critical components in the development of language and cognitive abilities. Here we ask how early bilingual experiences might lead to differences in visual attention and perception. Experiments 1–3 investigated the looking behavior of monolingual and bilingual infants when presented with social (Experiment 1), mixed (Experiment 2), or non-social (Experiment 3) stimuli. In each of these experiments, infants' dwell times (DT) and number of fixations to areas of interest (AOIs) were analyzed, giving a sense of where the infants looked. To examine how the infants looked at the stimuli in a more global sense, Experiment 4 combined and analyzed the saccade data collected in Experiments 1–3. There were no significant differences between monolingual and bilingual infants' DTs, AOI fixations, or saccade characteristics (specifically, frequency, and amplitude) in any of the experiments. These results suggest that monolingual and bilingual infants process their visual environments similarly, supporting the idea that the substantial cognitive differences between monolinguals and bilinguals in early childhood are more related to active vocabulary production than perception of the environment. PMID:25566116

  15. Community history affects the predictability of microbial ecosystem development

    PubMed Central

    Pagaling, Eulyn; Strathdee, Fiona; Spears, Bryan M; Cates, Michael E; Allen, Rosalind J; Free, Andrew

    2014-01-01

    Microbial communities mediate crucial biogeochemical, biomedical and biotechnological processes, yet our understanding of their assembly, and our ability to control its outcome, remain poor. Existing evidence presents conflicting views on whether microbial ecosystem assembly is predictable, or inherently unpredictable. We address this issue using a well-controlled laboratory model system, in which source microbial communities colonize a pristine environment to form complex, nutrient-cycling ecosystems. When the source communities colonize a novel environment, final community composition and function (as measured by redox potential) are unpredictable, although a signature of the community's previous history is maintained. However, when the source communities are pre-conditioned to their new habitat, community development is more reproducible. This situation contrasts with some studies of communities of macro-organisms, where strong selection under novel environmental conditions leads to reproducible community structure, whereas communities under weaker selection show more variability. Our results suggest that the microbial rare biosphere may have an important role in the predictability of microbial community development, and that pre-conditioning may help to reduce unpredictability in the design of microbial communities for biotechnological applications. PMID:23985743

  16. Does vitamin C deficiency affect cognitive development and function?

    PubMed

    Hansen, Stine Normann; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

    2014-09-01

    Vitamin C is a pivotal antioxidant in the brain and has been reported to have numerous functions, including reactive oxygen species scavenging, neuromodulation, and involvement in angiogenesis. Absence of vitamin C in the brain has been shown to be detrimental to survival in newborn SVCT2(-/-) mice and perinatal deficiency have shown to reduce hippocampal volume and neuron number and cause decreased spatial cognition in guinea pigs, suggesting that maternal vitamin C deficiency could have severe consequences for the offspring. Furthermore, vitamin C deficiency has been proposed to play a role in age-related cognitive decline and in stroke risk and severity. The present review discusses the available literature on effects of vitamin C deficiency on the developing and aging brain with particular focus on in vivo experimentation and clinical studies.

  17. Does Vitamin C Deficiency Affect Cognitive Development and Function?

    PubMed Central

    Hansen, Stine Normann; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

    2014-01-01

    Vitamin C is a pivotal antioxidant in the brain and has been reported to have numerous functions, including reactive oxygen species scavenging, neuromodulation, and involvement in angiogenesis. Absence of vitamin C in the brain has been shown to be detrimental to survival in newborn SVCT2(−/−) mice and perinatal deficiency have shown to reduce hippocampal volume and neuron number and cause decreased spatial cognition in guinea pigs, suggesting that maternal vitamin C deficiency could have severe consequences for the offspring. Furthermore, vitamin C deficiency has been proposed to play a role in age-related cognitive decline and in stroke risk and severity. The present review discusses the available literature on effects of vitamin C deficiency on the developing and aging brain with particular focus on in vivo experimentation and clinical studies. PMID:25244370

  18. Community violence as it affects child development: issues of definition.

    PubMed

    Trickett, Penelope K; Durán, Lorena; Horn, John L

    2003-12-01

    The state of the art of definition of community violence as it relates to child development was examined in terms of the definitions used in 23 empirical studies. In all cases community violence was defined in terms of what were assumed to be measurements obtained as linear combinations of a priori numerical weighting of responses to questions--asked either of a child or of the parent of a child--about experiencing and/or witnessing and/or hearing about instances of violence. Thus, the definitions can be seen to represent the perspectives of 2 kinds of observers--the child or the child's parent--and 3 levels of closeness to violence--experiencing, witnessing, or hearing about violence. Combining these perspectives and levels, the following 8 different definitions could be seen to be used in the practice of 1 or more of the 23 empirical studies: Child Self-Report (perception) of either (1) experiencing, or (2) witnessing, or (3) experiencing and witnessing, and hearing about violence; or Parent Report (perception) of the Child (4) experiencing, or (5) witnessing, or (6) experiencing and witnessing and hearing about violence, or (7) = (1) + (4), or (8) = (3) + (6). In almost all the examples of research definitions it was assumed implicitly and without test of the assumption that different violent events were interchangeable, and usually it was assumed (again without test) that the magnitudes of different violence events were equal. Usually, an unstated theory of stress appeared to guide the measurement definition, but in one study definitions were developed and tested in terms of a clearly-stated theory of learning. It was concluded that definition of community violence is a measurement problem; that very likely it is multidimensional; that it could be more nearly solved if better attention were given to specifying it in terms of theory that can be put to test and by attending to basic assumptions and principles of measurement.

  19. [Evaluation of environmental factors affecting embryo development in vitro].

    PubMed

    Noda, Y

    1992-08-01

    Human in vitro fertilization and embryo transfer (IVF-ET) became an indispensable modality for treating infertile patients. The principle of this method is simple: that is, recovery of gametes from the gonads of men and women and transfer of the embryos into the uterus. This method can be expected, therefore, to be applied to many patients with a variety of causes of infertility. Unfortunately, the success rates are not satisfactory in the majority of clinics in the 14 years since the first report of a test tube in 1978. In view of improving the success rate, one major issue is the protocol used for ovulation induction, which may influence the quality of eggs as well as the environmental conditions in the endometrium at the time of embryo replacement. Another major issue should be the technique for embryo culture because, in general, mammalian embryos, including humans', are known to exhibit developmental retardation in vitro. In a significant number of embryos, cleavage is arrested at the first or second cell cycle when cultured under the conventional culture conditions. This phenomenon in rodents is known as "block to development in vitro" or "two-cell block in vitro". Recently, the mouse two-cell block was found to be attenuated by the addition of superoxide dismutase (SOD) to the culture medium. SOD is the enzyme that catalyzes the dismutation reaction of superoxide anion radicals: 2O2- + 2H(+)----H2O2 + O2. This suggests that developmental retardation in vitro may be related to the potential oxygen toxicity that embryos encounter in vitro. Following to this finding, a variety of culture conditions have been found to attenuate blocking phenomenon and to increase blastulation rate in the mouse embryos. By the addition of chemicals to the culture medium such as L-Cysteine, L-Ascorbic acid, EDTA, DTPA or thiredoxine, blastulation rates could be increased overcoming blocking phenomenon. From these findings, it seemed possible to hypothesize that developmental

  20. 48 CFR 335.071 - Special determinations and findings affecting research and development contracting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... findings affecting research and development contracting. 335.071 Section 335.071 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES SPECIAL CATEGORIES OF CONTRACTING RESEARCH AND DEVELOPMENT CONTRACTING 335.071 Special determinations and findings affecting research and development contracting....

  1. Evidence of cellular senescence during the development of estrogen-induced pituitary tumors.

    PubMed

    Sabatino, Maria Eugenia; Petiti, Juan Pablo; Sosa, Liliana Del Valle; Pérez, Pablo Anibal; Gutiérrez, Silvina; Leimgruber, Carolina; Latini, Alexandra; Torres, Alicia Inés; De Paul, Ana Lucía

    2015-06-01

    Although pituitary adenomas represent 25% of intracranial tumors, they are usually benign, with the mechanisms by which these tumors usually avoid an invasive profile and metastatic growth development still remaining unclear. In this context, cellular senescence might constitute a plausible explanation for the benign nature of pituitary adenomas. In this study, we investigated the emergence of cellular senescence as a growth control mechanism during the progression of estrogen-induced pituitary tumors. The quantification of Ki67-immunopositive cells in the pituitaries of estrogenized male rats after 10, 20, 40, and 60 days revealed that the mitogenic potential rate was not sustained for the whole period analyzed and successively decreased after 10 days of estrogen exposure. In addition, the expression of cellular senescence features, such as the progressive rise in the enzymatic senescence-associated b-galactosidase (SA-b-gal) activity, IL6, IL1b, and TGFb expression, was observed throughout pituitary tumor development. Furthermore, tumoral pituitary cells also displayed nuclear pATM expression, indicating activated DNA damage signaling, with a significant increase in p21 expression also being detected. The associations among DNA damage signaling activation, SA-b-gal expression, and p21 may provide a reliable combination of senescence-associated markers for in vivo pituitary senescence detection. These results suggest a role for this cellular process in the regulation of pituitary cell growth. Thus, cellular senescence should be conceived as a contributing component to the benign nature of pituitary adenomas, thereby influencing the capability of the pituitary gland to avoid unregulated cell proliferation. PMID:25792544

  2. Isolated Diffusion Restriction Precedes the Development of Enhancing Tumor in a Subset of Patients with Glioblastoma

    PubMed Central

    Karimi, S.; Sood, S.; Zhang, Z.; Mo, Q.; Gutin, P.H.

    2014-01-01

    BACKGROUND AND PURPOSE Most response criteria for patients with glioblastoma rely on increases in the contrast enhancing abnormality to determine tumor progression. Our aim was to determine retrospectively in patients with glioblastoma whether diffusion restriction can predict the development of new enhancing mass lesions. MATERIALS AND METHODS We reviewed the brain MR imaging scans (including DWI and ADC maps) of 208 patients with glioblastoma. Patients with restricted diffusion in or adjacent to the tumor were identified, with further analysis only performed on those patients with low-ADC lesions without enhancement. These patients were followed to determine if new concordant enhancement developed at the site of the low-ADC lesion. A Wilcoxon signed rank test, competing risk analysis, and Kaplan-Meier curves were used to compare the mean drop in ADC values, assess enhancement-free survival, and determine overall survival, respectively. RESULTS In 67 of the 208 patients (32.2%), visibly detectable restricted diffusion was seen during treatment. The study cohort was formed by the 27 patients with low-ADC lesions and no corresponding enhancement. Twenty-three (85.2%) patients developed gadolinium-enhancing tumor at the site of restricted diffusion a median of 3.0 months later (95% CI, 2.6–4.1 months). The mean decrease in ADC was 22.9% from baseline (P < .001). The 3-month enhancement-free survival probability was 0.481 (95% CI, 0.288–0.675). The 12-month overall survival probability was 0.521 (95% CI, 0.345–0.788). Restricted diffusion predicted enhancement regardless of antiangiogenic therapy with bevacizumab. CONCLUSIONS In a subset of patients with glioblastoma, development of a new focus of restricted diffusion during treatment may precede the development of new enhancing tumor. PMID:21596805

  3. Pituitary Tumors

    MedlinePlus

    ... pituitary is the "master control gland" - it makes hormones that affect growth and the functions of other glands in the body. Pituitary tumors are common, but often they don't cause health ... tumor produces hormones and disrupts the balance of hormones in your ...

  4. Effects of social stress on tumor development in dominant male mice with diverse behavioral activity profiles.

    PubMed

    Cacho Fernández, Raúl; Garmendia Rezola, Larraitz; Vegas Moreno, Oscar; Azpíroz Sánchez, Arantxa

    2008-11-01

    We examined the influence of individual psychological profile and social behavior on tumor development in dominant male mice. Male OF1 mice were subjected to an open field test (OFT) to observe their motor activity and latency. Subsequently, the animals were divided into three groups: Stress-Non-Inoculated (SNI), Stress-Inoculated (SI) and Control-Inoculated (CI). The SI and CI groups were inoculated with tumor cells and the SNI group with vehicle. SNI and SI were exposed to social stress with an anosmic intruder six (T1) and twenty one (T2) days after inoculation and their behavior was analyzed. After T2, subjects were put down and the pulmonary metastatic foci counted. SI developed greater pulmonary metastasis than CI, indicating an effect of stress despite the animal's dominant status. Active animals developed less pulmonary metastasis than their passive counterparts. No differences were found in social behavior at T1. Differences were found, however, in some behavioral categories at T2 between SI and SNI, and between active and passive animals. These differences indicate an effect of tumor development on social behavior that is more evident in passive subjects.

  5. Strategies for Developing the Affective Work Competencies of Marketing Education Students.

    ERIC Educational Resources Information Center

    Meyer, Earl C.

    Effective strategies for developing the affective work competencies of marketing education students include teaching procedures, acquisition of skills and materials for teaching in the affective domain, and implementation considerations. Affective concerns in marketing can be grouped into three broad types of performance categories--self-concept,…

  6. Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats

    SciTech Connect

    Singh, Bhupendra; Mense, Sarah M.; Bhat, Nimee K.; Putty, Sandeep; Guthiel, William A.; Remotti, Fabrizio; Bhat, Hari K.

    2010-09-01

    Phytoestrogens are plant compounds that structurally mimic the endogenous estrogen 17{beta}-estradiol (E{sub 2}). Despite intense investigation, the net effect of phytoestrogen exposure on the breast remains unclear. The objective of the current study was to examine the effects of quercetin on E{sub 2}-induced breast cancer in vivo. Female ACI rats were given quercetin (2.5 g/kg food) for 8 months. Animals were monitored weekly for palpable tumors, and at the end of the experiment, rats were euthanized, breast tumor and different tissues excised so that they could be examined for histopathologic changes, estrogen metabolic activity and oxidant stress. Quercetin alone did not induce mammary tumors in female ACI rats. However, in rats implanted with E{sub 2} pellets, co-exposure to quercetin did not protect rats from E{sub 2}-induced breast tumor development with 100% of the animals developing breast tumors within 8 months of treatment. No changes in serum quercetin levels were observed in quercetin and quercetin + E{sub 2}-treated groups at the end of the experiment. Tumor latency was significantly decreased among rats from the quercetin + E{sub 2} group relative to those in the E{sub 2} group. Catechol-O-methyltransferase (COMT) activity was significantly downregulated in quercetin-exposed mammary tissue. Analysis of 8-isoprostane F{sub 2{alpha}} (8-iso-PGF{sub 2{alpha}}) levels as a marker of oxidant stress showed that quercetin did not decrease E{sub 2}-induced oxidant stress. These results indicate that quercetin (2.5 g/kg food) does not confer protection against breast cancer, does not inhibit E{sub 2}-induced oxidant stress and may exacerbate breast carcinogenesis in E{sub 2}-treated ACI rats. Inhibition of COMT activity by quercetin may expose breast cells chronically to E{sub 2} and catechol estrogens. This would permit longer exposure times to the carcinogenic metabolites of E{sub 2} and chronic exposure to oxidant stress as a result of metabolic redox

  7. Development of spectrophotometer for breast tumor diagnostic spectrometer based on virtual instruments

    NASA Astrophysics Data System (ADS)

    Ren, Zhong; Liu, Guodong; Liu, Ying; Huang, Zhen

    2013-12-01

    Although some progresses have been achieved by the traditional diagnostic methods, such as X mammography, computer tomography (CT) imaging and magnetic resonance imaging (MRI) etc, their applications are limited by some drawbacks to some extent. As a more promising alternative method, the breast tumor diagnosis method based on infrared spectrometer was introduced. According to the theory of spectral unique characteristics for matter, i.e. the spectrums are different for the matter with different properties, so the spectrums are different between the tumor and normal tissues. Therefore, a spectrometer system was developed to diagnose the breast tumor in this paper. Meanwhile, a spectrophotometer for breast tumor diagnostic spectrometer was designed, and the plane holography concave (PHV) grating was used as the dispersion device in this spectrophotometer because of excellent performances. In this system, linear CCD detector combined with PCI data acquisition card was used as the spectral detector, and the virtual instruments (VI) technique was used to control the data acquisition and data processing. In experiments, the spectral calibration based on mercury lamp was performed. Experimental results illustrated that the construction of the spectrophotometer system is available, the spectral range is from 300-850nm, its wavelength resolution reached 2nm. The simulation experimental result proved that the design of the diagnostic system was very satisfied and diagnostic method was also feasible.

  8. SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth.

    PubMed

    Yang, Hui; Zhou, Lisha; Shi, Qian; Zhao, Yuzheng; Lin, Huaipeng; Zhang, Mengli; Zhao, Shimin; Yang, Yi; Ling, Zhi-Qiang; Guan, Kun-Liang; Xiong, Yue; Ye, Dan

    2015-04-15

    The malate-aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate-aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD(+) redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate-aspartate NADH shuttle activity and oxidative protection. PMID:25755250

  9. SIRT3-dependent GOT2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth

    PubMed Central

    Yang, Hui; Zhou, Lisha; Shi, Qian; Zhao, Yuzheng; Lin, Huaipeng; Zhang, Mengli; Zhao, Shimin; Yang, Yi; Ling, Zhi-Qiang; Guan, Kun-Liang; Xiong, Yue; Ye, Dan

    2015-01-01

    The malate–aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth. The malate–aspartate shuttle is operated by two pairs of enzymes that localize to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). Here, we show that mitochondrial GOT2 is acetylated and that deacetylation depends on mitochondrial SIRT3. We have identified that acetylation occurs at three lysine residues, K159, K185, and K404 (3K), and enhances the association between GOT2 and MDH2. The GOT2 acetylation at these three residues promotes the net transfer of cytosolic NADH into mitochondria and changes the mitochondrial NADH/NAD+ redox state to support ATP production. Additionally, GOT2 3K acetylation stimulates NADPH production to suppress ROS and to protect cells from oxidative damage. Moreover, GOT2 3K acetylation promotes pancreatic cell proliferation and tumor growth in vivo. Finally, we show that GOT2 K159 acetylation is increased in human pancreatic tumors, which correlates with reduced SIRT3 expression. Our study uncovers a previously unknown mechanism by which GOT2 acetylation stimulates the malate–aspartate NADH shuttle activity and oxidative protection. PMID:25755250

  10. Tumor suppressor KAI1 affects integrin {alpha}v{beta}3-mediated ovarian cancer cell adhesion, motility, and proliferation

    SciTech Connect

    Ruseva, Zlatna; Geiger, Pamina Xenia Charlotte; Hutzler, Peter; Kotzsch, Matthias; Luber, Birgit; Schmitt, Manfred; Gross, Eva; Reuning, Ute

    2009-06-10

    The tetraspanin KAI1 had been described as a metastasis suppressor in many different cancer types, a function for which associations of KAI1 with adhesion and signaling receptors of the integrin superfamily likely play a role. In ovarian cancer, integrin {alpha}v{beta}3 correlates with tumor progression and its elevation in vitro provoked enhanced cell adhesion accompanied by significant increases in cell motility and proliferation in the presence of its major ligand vitronectin. In the present study, we characterized integrin {alpha}v{beta}3-mediated tumor biological effects as a function of cellular KAI1 restoration and proved for the first time that KAI1, besides its already known physical crosstalk with {beta}1-integrins, also colocalizes with integrin {alpha}v{beta}3. Functionally, elevated KAI1 levels drastically increased integrin {alpha}v{beta}3/vitronectin-dependent ovarian cancer cell adhesion. Since an intermediate level of cell adhesive strength is required for optimal cell migration, we next studied ovarian cancer cell motility as a function of KAI1 restoration. By time lapse video microscopy, we found impaired integrin {alpha}v{beta}3/vitronectin-mediated cell migration most probably due to strongly enhanced cellular immobilization onto the adhesion-supporting matrix. Moreover, KAI1 reexpression significantly diminished cell proliferation. These data strongly indicate that KAI1 may suppress ovarian cancer progression by inhibiting integrin {alpha}v{beta}3/vitronectin-provoked tumor cell motility and proliferation as important hallmarks of the oncogenic process.

  11. Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes

    PubMed Central

    Löser, Reik; Pietzsch, Jens

    2015-01-01

    Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge toward their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes. PMID:26157794

  12. Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes

    NASA Astrophysics Data System (ADS)

    Löser, Reik; Pietzsch, Jens

    2015-06-01

    Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge towards their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

  13. Mechanisms of tumor development and anti-angiogenic therapy in glioblastoma multiforme.

    PubMed

    Onishi, Manabu; Kurozumi, Kazuhiko; Ichikawa, Tomotsugu; Date, Isao

    2013-01-01

    Despite advances in surgical and medical therapy, glioblastoma multiforme (GBM) remains a fatal disease. There has been no significant increase in survival for patients with this disease over the last 20 years. Tumor vasculature formation and glioma cell invasion along the white matter tracts both play a pivotal role in glioma development. Angiogenesis and invasion are the major factors believed to be responsible for treatment resistance in tumors, and a better understanding of the glioma invasion and angiogenesis mechanisms will lead to the development of potential new treatments. In this review, we focus on the molecular characteristics of angiogenesis and invasion in human malignant glioma. We discuss bevacizumab and cilengitide, which are used to inhibit angiogenesis in GBM.

  14. Forecasting new development of tumor areas using spatial and temporal distribution profiles of hemoglobin saturation in a mouse model

    PubMed Central

    Ossandon, Miguel R.; Phatak, Dhananjay S.; Sorg, Brian S.; Kalpakis, Konstantinos

    2014-01-01

    Abstract. Features of the tumor microenvironment (TME), such as hemoglobin saturation (HbSat), can provide valuable information on early development and progression of tumors. HbSat correlates with high metabolism and precedes the formation of angiogenic tumors; therefore, changes in HbSat profile can be used as a biomarker for early cancer detection. In this project, we develop a methodology to evaluate HbSat for forecasting early tumor development in a mouse model. We built a delta (δ) cumulative feature that includes spatial and temporal distribution of HbSat for classifying tumor/normal areas. Using a two-class (normal and tumor) logistic regression, the δ feature successfully forecasts tumor areas in two window chamber mice (AUC=0.90 and 0.85). To assess the performance of the logistic regression-based classifier utilizing the δ feature of each region, we conduct a 10-fold cross-validation analysis (AUC of the ROC=0.87). These results show that the TME features based on HbSat can be used to evaluate tumor progression and forecast new occurrences of tumor areas. PMID:26158025

  15. Targeting of Antigens to B Lymphocytes via CD19 As A Means for Tumor Vaccine Development

    PubMed Central

    Ma, Yunfeng; Xiang, Dong; Sun, Jinwen; Ding, Chuanlin; Liu, Min; Hu, Xiaoling; Li, Guoxin; Kloecker, Goetz; Zhang, Huang-ge; Yan, Jun

    2013-01-01

    Ab therapy against surface Ags on tumor cells has demonstrated significant efficacy for some cancers. However, it is costly and patients frequently develop acquired resistance over time. In cases of Ab therapy resistance, T cell responses have been shown to be essential in controlling disease progression. Thus, vaccination that generates a sustained Ab response as well as a T cell response may be more effective and economical. Here, we have developed a vaccination strategy by targeting protein Ags to B cells via a CD19 single chain variable fragment miniAb. By using the tumor-associated Ag (TAA) her-2/neu extracellular domain (ECD), we showed that the co-engagement of CD19 and BCR induced full B cell activation to produce a high titer of Abs and enhanced CD4 Th2 response and CD8 T cell activation and differentiation. These Abs competitively inhibited humanized her-2/neu Ab binding and were capable of activating the complement and inhibiting human breast cancer growth in vitro. Therapeutic efficacy was demonstrated in vivo using murine mammary carcinomas models. Furthermore, four different ECDs of her-2/neu could be targeted to B cells to generate Abs against particular domains with different anti-tumor properties. This approach may offer a new avenue for vaccine development with significantly lower cost which may be usable not only for cancer therapy but also for infectious agents. PMID:23630363

  16. The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

    NASA Astrophysics Data System (ADS)

    Finke, Daniela; Luther, Sanjiv A.; Acha-Orbea, Hans

    2003-01-01

    Mouse mammary tumor virus (MMTV) infection establishes chronic germinal centers and a lifelong neutralizing Ab response. We show that removal of the draining lymph node after establishment of the germinal center reaction led to complete loss of neutralizing Abs despite comparable infection levels in peripheral lymphocytes. Importantly, in the absence of neutralization, only the exocrine organs mammary gland, salivary gland, pancreas, and skin showed strikingly increased infection, resulting in accelerated mammary tumor development. Induction of stronger neutralization did not influence chronic infection levels of peripheral lymphoid organs but strongly inhibited mammary gland infection and virus transmission to the next generation. Taken together, we provide evidence that a tight equilibrium in virus neutralization allows limited infection of exocrine organs and controls cancer development in susceptible mouse strains. These experiments show that a strong neutralizing Ab response induced after infection is not able to control lymphoid MMTV infection. Strong neutralization, however, is capable of blocking amplification of mammary gland infection, tumor development, and virus transmission to the next generation. The results also indicate a role of neutralization in natural resistance to MMTV infection.

  17. Cell position during larval development affects postdiapause development in Megachile rotundata (Hymenoptera: Megachilidae).

    PubMed

    Yocum, George D; Rinehart, Joseph P; Kemp, William P

    2014-08-01

    Megachile rotundata (F.) (Hymenoptera: Megachilidae) is the primary pollinator of alfalfa in the northwestern United States and western Canada and provides pollination services for onion, carrot, hybrid canola, various legumes, and other specialty crops. M. rotundata females are gregarious, nest in cavities either naturally occurring or in artificial nesting blocks, where they construct a linear series of brood cells. Because of the physical layout of the nest, the age of the larvae within the nest and the microenvironment the individual larvae experience will vary. These interacting factors along with other maternal inputs affect the resulting phenotypes of the nest mates. To further our understanding of in-nest physiology, gender and developmental rates were examined in relationship to cell position within the nest. Eighty-two percent of the females were located within the first three cells, those furthest from the nest entrance. For those individuals developing in cells located in the deepest half of the nest, the sex of the previous bee had a significant effect on the female decision of the gender of the following nest mate. Removing the prepupae from the nest and rearing them under identical conditions demonstrated that position within the nest during larval development had a significant effect on the postdiapause developmental rates, with males whose larval development occurred deeper in the nest developing more slowly than those toward the entrance. No positional effect on postdiapause developmental rates was noted for the females. The cell position effect on male postdiapause developmental rate demonstrates that postdiapause development is not a rigid physiological mechanism uniform in all individuals, but is a dynamic plastic process shaped by past environmental conditions. PMID:24914676

  18. Development and Validation of Children's Environmental Affect (Attitude, Sensitivity and Willingness to Take Action) Scale

    ERIC Educational Resources Information Center

    Erdogan, Mehmet; Marcinkowski, Thomas

    2015-01-01

    This study focuses on the design, development, validation, and psychometric properties of the Children's Environmental Affect Scale (CEAS). The following steps were taken in developing the CEAS. A substantial review of literature on environmental affect and EL helped the researchers identify several scales and questionnaires that, in turn, help…

  19. Development of a Patient-Derived Xenograft Model Using Brain Tumor Stem Cell Systems to Study Cancer.

    PubMed

    Chokshi, Chirayu; Dhillon, Manvir; McFarlane, Nicole; Venugopal, Chitra; Singh, Sheila K

    2016-01-01

    Patient-derived xenograft (PDX) models provide an excellent platform to understand cancer initiation and development in vivo. In the context of brain tumor initiating cells (BTICs), PDX models allow for characterization of tumor formation, growth, and recurrence, in a clinically relevant in vivo system. Here, we detail procedures to harvest, culture, characterize, and orthotopically inject human BTICs derived from patient samples.

  20. Maternal regulation of child affect in externalizing and typically-developing children.

    PubMed

    Lougheed, Jessica P; Hollenstein, Tom; Lichtwarck-Aschoff, Anna; Granic, Isabela

    2015-02-01

    Temporal contingencies between children's affect and maternal behavior play a role in the development of children's externalizing problems. The goal of the current study was to use a microsocial approach to compare dyads with externalizing dysregulation (N =191) to healthy controls (N = 54) on maternal supportive regulation of children's negative and positive affect. Children were between the ages of 8 and 12 years. Mother-child dyads participated in conflict and positive discussions, and child affect and maternal supportive affect regulation were coded in real time. First, no group differences on overall levels of mother supportive regulation or child affect were found. Second, three event history analyses in a 2-level Cox hazard regression framework were used to predict the hazard rate of (a) maternal supportiveness, and of children's transitions (b) out of negative affect and (c) into positive affect. The hazard rate of maternal supportiveness, regardless of child affect, was not different between groups. However, as expected, the likelihood of mothers' supportive responses to children's negative affect was lower in externalizing than comparison dyads. In addition, children with externalizing problems were significantly less likely than typically developing children to transition out of negative affect in response to maternal supportiveness. The likelihood of both typically developing children and children with externalizing problems transitioning into positive affect were not related to specific occurrences of maternal supportiveness. Results of the current study show the importance of temporal dynamics in mother-child interactions in the emergence of children's externalizing problems.

  1. Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging

    PubMed Central

    Glasgow, Micah D. K.; Chougule, Mahavir B.

    2016-01-01

    Nanotechnology and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug’s therapeutic effectiveness while reducing adverse side effects associated with high dosage by improving their pharmacokinetics. Taking advantage of molecular markers over-expressing on tumor tissues compared to normal cells, an “active” molecular marker targeted approach would be beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concentration at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery of various drugs for a combinational chemotherapy approach to cancer treatment and imaging. PMID:26554150

  2. Early ipsilateral breast tumor recurrences after breast conservation affect survival: An analysis of the National Cancer Institute randomized trial

    SciTech Connect

    Brooks, Joseph P.; Danforth, David N.; Albert, Paul; Sciuto, Linda C. B.S.N.; Smith, Sharon L.; Camphausen, Kevin A.; Poggi, Matthew M. . E-mail: MMPoggi@Bethesda.med.navy.mil

    2005-07-01

    Purpose: To evaluate the effect of an ipsilateral breast tumor recurrence (IBTR) after breast-conservation therapy (BCT) on survival. Methods and Materials: One hundred twenty-one women were randomized to BCT. Patients with an IBTR were analyzed to determine survival. Analysis was performed with Kaplan-Meier estimates, log-rank tests, and time-dependent covariate Cox models. Results: At a median follow-up of 18.4 years, 27 patients had an IBTR. The median survival time after IBTR was 13.1 years. The 5-year survival rate was 91.8% (95% confidence interval [CI], 81.5-100%). The 10-year survival rate was 54.3% (95% CI, 35.8-82.6%). According to a Cox model with time-dependent covariates, the hazard ratio or relative risk of dying for those with an IBTR at <5.3 years after BCT relative to patients without an IBTR after BCT is 1.47 (95% CI, 1.02-2.12%; p = 0.04). The hazard ratio for those who relapse after 5.3 years is 0.59 (95% CI, 0.22-1.61%; p = 0.31). Age at randomization, original tumor size, and the presence of positive regional nodes at initial presentation were not found to be associated with decreased survival. Conclusions: There seems to be a significant association of early IBTR after BCT with decreased survival. Local control should be maximized.

  3. Involvement of Mouse Constitutive Androstane Receptor in Acifluorfen-Induced Liver Injury and Subsequent Tumor Development.

    PubMed

    Kuwata, Kazunori; Inoue, Kaoru; Ichimura, Ryohei; Takahashi, Miwa; Kodama, Yukio; Shibutani, Makoto; Yoshida, Midori

    2016-06-01

    Acifluorfen (ACI), a protoporphyrinogen oxidase (PROTOX) inhibitor herbicide, promotes the accumulation of protoporphyrin IX (PPIX), and induces tumors in the rodent liver. Porphyria is a risk factor for liver tumors in humans; however, the specific mechanisms through which ACI induces hepatocarcinogenesis in rodents are unclear. Here, we investigated the mode of action of ACI-induced hepatocarcinogenesis, focusing on constitutive androstane receptor (CAR, NR1I3), which is essential for the development of rodent liver tumors in response to certain cytochrome P450 (CYP) 2B inducers. Dietary treatment with 2500 ppm ACI for up to 13 weeks increased Cyp2b10 expression in the livers of wild-type (WT) mice, but not in CAR-knockout (CARKO) mice. Microscopically, ACI treatment-induced cytotoxic changes, including hepatocellular necrosis and inflammation, and caused regenerative changes accompanied by prolonged increases in the numbers of proliferating cell nuclear antigen-positive hepatocytes in WT mice. In contrast, these cytotoxic and regenerative changes in hepatocytes were significantly attenuated, but still observed, in CARKO mice. ACI treatment also increased liver PPIX levels similarly in both genotypes; however, no morphological evidence of porphyrin deposition was found in hepatocytes from either genotype. Treatment with 2500 ppm ACI for 26 weeks after initiation with diethylnitrosamine increased the incidence and multiplicities of altered foci and adenomas in hepatocytes from WT mice; these effects were significantly reduced in CARKO mice. These results indicated that prolonged cytotoxicity in the liver was a key factor for ACI-induced hepatocarcinogenesis, and that CAR played an important role in ACI-induced liver injury and tumor development in mice. PMID:26928356

  4. [Tumors caused by methylcholanthrene and lapachol. Follow-up of development with cytology].

    PubMed

    de Sandoval, N A; Rodríguez, C P; de Martínez, N R

    1996-01-01

    This present work was carried out in order to study the effect of Lapachol (LAP) administrated to rats simultaneously with a chemical carcinogen 20-Methylcholanthrene (MCA). Animals were divided in 4 groups: A-Group treated with 80 mg of MCA I(n = 11 rats), B-Group treated with 80 mg of MCA+LAP 100 mg/kg weight/day, (n = 15 rats), C-Group treated with LAP 100 mg/kg weight/day (n = 12 rats), D-Group control-no treatment (n = 13 rats). Cytological studies as well as cytochemical techniques allowed the recognition of benign and malignant conditions at the time of the tumor appearance. Histopathological evaluation posteriorly confirmed the development of tumors in 53% of the animals in group B. Morphologically consistent with poorly differentiated adenocarcinomas of the salivary glands and fibroadenomas of the breast in 18.2% (2/11) of the rats in group A. Besides the presence of one or several supra-hepatic nodules in vecinity of the suspensory ligament corresponding to nodular hyperplasia were observed in 33% (4/12) of group C and in 13.3% (12/15) of group B. No nodules were observed in groups A and D. Tubular dilatation of kidneys were noted in 60% (9/15) and 83.3/ (10/12) of the rats in group E and C respectively. From the original salivary gland tumor a series of transplantables tumors were developed and followed by cytological evaluations. The importance of the cytological and histopathological diagnosis for the pharmacological effects studies of certain drugs like Lapachol that are widely used as antitumoral agents without exact knowledge of the adverse effects is emphasized.

  5. Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice

    PubMed Central

    Sasada, Tatsunari; Hinoi, Takao; Saito, Yasufumi; Adachi, Tomohiro; Takakura, Yuji; Kawaguchi, Yasuo; Sotomaru, Yusuke; Sentani, Kazuhiro; Oue, Naohide; Yasui, Wataru; Ohdan, Hideki

    2015-01-01

    The gastrointestinal tract is continuously exposed to a variety of chemicals and commensal bacteria. Recent studies have shown that changes in gut microbial populations caused by chlorine or other chemicals in the drinking water influence the development of human colorectal cancer, although the mechanism of tumorigenesis in the gut epithelium is obfuscated by the diversity of microflora and complexity of the tumor microenvironment. In this regard, mouse models that recapitulate human colorectal cancer are an invaluable tool. In this study, we used two conditional adenomatous polyposis coli (Apc) knockout mouse models to investigate the effect of chlorinated water on tumorigenesis in the digestive tract. Mice with colon-specific carcinoma—caused by either chromosomal (CDX2P 9.5-NLS Cre;Apc+/flox, abbreviated to CPC;Apc) or microsatellite (CDX2P9.5-G19Cre;Apcflox/flox and CDX2P9.5-G22Cre;Apcflox/flox) instability, respectively—were administered chlorinated (10.0 mg/L chlorine) or tap (0.7 mg/L chlorine) water and evaluated for colon polyp formation. In CPC;Apc mice given chlorinated drinking water, tumors tended to develop in the colon, whereas in those that drank tap water, tumors were mostly observed in the small intestine. There was no difference in the rate of tumor formation of CDX2P9.5-G19Cre;Apcflox/flox and CDX2P9.5-G22Cre;Apcflox/flox mice consuming chlorinated as compared to tap water, suggesting that microsatellite instability in the Apc gene does not significantly affect tumorigenesis. Chlorinated water altered the enteric environment by reducing the fecal populations of the obligatory anaerobes Clostridium perfringens and C. difficile, as well as species belonging to the Atopobium cluster, including Enterobacteriaceae and Staphylococcus sp., which was associated with colon tumorigenesis in CPC;Apc mice. These results suggest that differences in tumorigenesis among CPC;Apc mice consuming chlorinated versus tap water may be due to differences in

  6. Chlorinated Water Modulates the Development of Colorectal Tumors with Chromosomal Instability and Gut Microbiota in Apc-Deficient Mice.

    PubMed

    Sasada, Tatsunari; Hinoi, Takao; Saito, Yasufumi; Adachi, Tomohiro; Takakura, Yuji; Kawaguchi, Yasuo; Sotomaru, Yusuke; Sentani, Kazuhiro; Oue, Naohide; Yasui, Wataru; Ohdan, Hideki

    2015-01-01

    The gastrointestinal tract is continuously exposed to a variety of chemicals and commensal bacteria. Recent studies have shown that changes in gut microbial populations caused by chlorine or other chemicals in the drinking water influence the development of human colorectal cancer, although the mechanism of tumorigenesis in the gut epithelium is obfuscated by the diversity of microflora and complexity of the tumor microenvironment. In this regard, mouse models that recapitulate human colorectal cancer are an invaluable tool. In this study, we used two conditional adenomatous polyposis coli (Apc) knockout mouse models to investigate the effect of chlorinated water on tumorigenesis in the digestive tract. Mice with colon-specific carcinoma--caused by either chromosomal (CDX2P 9.5-NLS Cre;Apc(+/flox), abbreviated to CPC;Apc) or microsatellite (CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox)) instability, respectively--were administered chlorinated (10.0 mg/L chlorine) or tap (0.7 mg/L chlorine) water and evaluated for colon polyp formation. In CPC;Apc mice given chlorinated drinking water, tumors tended to develop in the colon, whereas in those that drank tap water, tumors were mostly observed in the small intestine. There was no difference in the rate of tumor formation of CDX2P9.5-G19Cre;Apc(flox/flox) and CDX2P9.5-G22Cre;Apc(flox/flox) mice consuming chlorinated as compared to tap water, suggesting that microsatellite instability in the Apc gene does not significantly affect tumorigenesis. Chlorinated water altered the enteric environment by reducing the fecal populations of the obligatory anaerobes Clostridium perfringens and C. difficile, as well as species belonging to the Atopobium cluster, including Enterobacteriaceae and Staphylococcus sp., which was associated with colon tumorigenesis in CPC;Apc mice. These results suggest that differences in tumorigenesis among CPC;Apc mice consuming chlorinated versus tap water may be due to differences

  7. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors

    PubMed Central

    Shern, Jack F.; Chen, Li; Chmielecki, Juliann; Wei, Jun S.; Patidar, Rajesh; Rosenberg, Mara; Ambrogio, Lauren; Auclair, Daniel; Wang, Jianjun; Song, Young K.; Tolman, Catherine; Hurd, Laura; Liao, Hongling; Zhang, Shile; Bogen, Dominik; Brohl, Andrew S.; Sindiri, Sivasish; Catchpoole, Daniel; Badgett, Thomas; Getz, Gad; Mora, Jaume; Anderson, James R.; Skapek, Stephen X.; Barr, Frederic G.; Meyerson, Matthew; Hawkins, Douglas S.; Khan, Javed

    2015-01-01

    Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma (RMS) remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in RMS tumors; those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in RMS is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations of NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, we found novel recurrent mutations in FBXW7, and BCOR providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases providing a framework for genomics directed therapies that might improve outcomes for RMS patients. PMID:24436047

  8. Development of affective theory of mind across adolescence: disentangling the role of executive functions.

    PubMed

    Vetter, Nora C; Altgassen, Mareike; Phillips, Louise; Mahy, Caitlin E V; Kliegel, Matthias

    2013-01-01

    Theory of mind, the ability to understand mental states, involves inferences about others' cognitive (cognitive theory of mind) and emotional (affective theory of mind) mental states. The current study explored the role of executive functions in developing affective theory of mind across adolescence. Affective theory of mind and three subcomponents of executive functions (inhibition, updating, and shifting) were measured. Affective theory of mind was positively related to age, and all three executive functions. Specifically, inhibition explained the largest amount of variance in age-related differences in affective theory of mind.

  9. E2f8 mediates tumor suppression in postnatal liver development

    PubMed Central

    Kent, Lindsey N.; Rakijas, Jessica B.; Pandit, Shusil K.; Westendorp, Bart; Chen, Hui-Zi; Huntington, Justin T.; Tang, Xing; Bae, Sooin; Srivastava, Arunima; Senapati, Shantibhusan; Martin, Chelsea K.; Cuitino, Maria C.; Perez, Miguel; Clouse, Julian M.; Chokshi, Veda; Shinde, Neelam; Kladney, Raleigh; Sun, Daokun; Perez-Castro, Antonio; Matondo, Ramadhan B.; Nantasanti, Sathidpak; Mokry, Michal; Machiraju, Raghu; Fernandez, Soledad; Rosol, Thomas J.; Pohar, Kamal S.; Pipas, James M.; Schmidt, Carl R.; de Bruin, Alain

    2016-01-01

    E2F-mediated transcriptional repression of cell cycle–dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8’s tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8’s DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development. PMID:27454291

  10. Production Conditions Affect the In Vitro Anti-Tumoral Effects of a High Concentration Multi-Strain Probiotic Preparation

    PubMed Central

    Cinque, Benedetta; La Torre, Cristina; Lombardi, Francesca; Palumbo, Paola; Van der Rest, Michel

    2016-01-01

    A careful selection of the probiotic agent, standardization of the dose and detailed characterization of the beneficial effects are essential when considering use of a probiotic for the dietary management of serious diseases. However, changes in the manufacturing processes, equipment or facilities can result in differences in the product itself due to the live nature of probiotics. The need to reconfirm safety and/or efficacy for any probiotic product made at a different factory is therefore mandatory. Recently, under the brand VSL#3®, a formulation produced by a manufacturer different from the previous one, has been commercialized in some European countries (the UK and Holland). VSL#3 is a high concentration multi-strain preparation which has been recognized by the main Gastroenterology Associations for the dietary management of pouchitis as well as ulcerative colitis. We have compared the “original” VSL#3 produced in USA with the “newfound” VSL#3 produced in Italy. According to our results, the “newfound” VSL#3 has 130–150% more “dead bacteria” compared to the “original” product, raising concerns for the well-known association between dead microbes with adverse effects. The abilities of bacterial lysates from the two formulations to influence in vitro viability and proliferation of different tumor cell lines also resulted different. The repair of previously scratched monolayers of various adherent tumor cell lines (i.e. HT1080, and Caco-2 cells) was inhibited more significantly by the “original” VSL#3 when compared to the “newfound” VSL#3. Tumor cell cycle profile, in particular cell cycle arrest and apoptotic death of the cancer cells, further confirms that the “original” VSL#3 has a better functional profile than the “newfound” VSL#3, at least in in vitro. Our data stress the importance of the production conditions for the “newfound” VSL#3 considering that this product is intended to be used for the dietary management

  11. A rare case of extraskeletal Ewing's sarcoma/primitive neuroectodermal tumor developing in maxillary sinus of an old patient.

    PubMed

    Kulkarni, Maithili Mandar; Khandeparkar, Siddhi Gaurish Sinai; Joshi, Avinash R; Barpande, Chitrangi

    2016-01-01

    Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) family of tumors is an uncommon group of malignant neoplasms that may present in both skeletal and extraskeletal sites. PNET outside the central nervous system is called peripheral PNET (pPNET) developing from migrating embryonal cells of the neural crest. Very few cases of pPNET of the maxilla are reported in English literature. These tumors may be difficult to diagnose due to their primitive morphology. These tumors occur predominantly in infancy or early childhood. The occurrence of extraskeletal ES/PNET in the maxillary sinus in an old age is very rare. We report a case of extraskeletal ES/PNET developing in maxillary sinus in a 60-year-old woman. The ES/PNET should be included in the differential diagnosis of a small round cell tumor and immunohistochemical analysis with a panel of immunomarkers should be done for correct diagnosis and proper treatment. PMID:27601837

  12. A rare case of extraskeletal Ewing's sarcoma/primitive neuroectodermal tumor developing in maxillary sinus of an old patient

    PubMed Central

    Kulkarni, Maithili Mandar; Khandeparkar, Siddhi Gaurish Sinai; Joshi, Avinash R; Barpande, Chitrangi

    2016-01-01

    Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) family of tumors is an uncommon group of malignant neoplasms that may present in both skeletal and extraskeletal sites. PNET outside the central nervous system is called peripheral PNET (pPNET) developing from migrating embryonal cells of the neural crest. Very few cases of pPNET of the maxilla are reported in English literature. These tumors may be difficult to diagnose due to their primitive morphology. These tumors occur predominantly in infancy or early childhood. The occurrence of extraskeletal ES/PNET in the maxillary sinus in an old age is very rare. We report a case of extraskeletal ES/PNET developing in maxillary sinus in a 60-year-old woman. The ES/PNET should be included in the differential diagnosis of a small round cell tumor and immunohistochemical analysis with a panel of immunomarkers should be done for correct diagnosis and proper treatment. PMID:27601837

  13. Development and characterization of a three-dimensional co-culture model of tumor T cell infiltration.

    PubMed

    Alonso-Nocelo, M; Abuín, C; López-López, R; de la Fuente, M

    2016-04-14

    Tumor growth and metastasis entangle the alteration and recruitment of non-malignant cells to the primary tumor, among them immune cells, constituting the tumor microenvironment (TME). Communication between tumor cells and their stroma has been shown as a fundamental driving force of the tumoral process. A great deal of effort has been focused on depicting their specific interactions and crosstalk. However, most research has been carried out in 2D conventional cultures that alter cell morphology and intracellular signaling processes. Considering these premises, we have developed a 3D cell co-culture model to mimic T cell infiltration into the tumor mass and explore tumor-immune cells interactions in the TME. Expression of specific cell markers and assessment of cell proliferation were carried out to characterize the proposed 3D co-culture model. Additionally, the study and profiling of the secretome revealed a subset of particular cancer-related inflammation proteins prompted upon 3D cultivation of tumor cells in presence of lymphocytes, pointing out an intercellular communication. Altogether, these results suggest that our 3D cell co-culture model can be a useful tool to identify and study critical factors mediating the crosstalk between tumor and immune cells in the TME. Finally, the potential of this model as a drug-screening platform has been explored using docetaxel as a model antitumoral compound.

  14. The Janus Face of Lipids in Human Breast Cancer: How Polyunsaturated Fatty Acids Affect Tumor Cell Hallmarks

    PubMed Central

    Chénais, Benoît; Blanckaert, Vincent

    2012-01-01

    For several years, lipids and especially n − 3 and n − 6 polyunsaturated fatty acids (PUFAs) receive much attention in human health. Epidemiological studies tend to correlate a PUFA-rich diet with a reduced incidence of cancer, including breast cancer. However, the molecular and cellular mechanisms supporting the effect of PUFAs in breast cancer cells remain relatively unknown. Here, we review some recent progress in understanding the impact that PUFA may have on breast cancer cell proliferation, apoptosis, migration, and invasion. While most of the results obtained with docosahexaenoic acid and/or eicosapentaenoic acid show a decrease of tumor cell proliferation and/or aggressivity, there is some evidence that other lipids, which accumulate in breast cancer tissues, such as arachidonic acid may have opposite effects. Finally, lipids and especially PUFAs appear as potential adjuvants to conventional cancer therapy. PMID:22811918

  15. Comparative VEGF receptor tyrosine kinase modeling for the development of highly specific inhibitors of tumor angiogenesis.

    PubMed

    Schmidt, Ulrike; Ahmed, Jessica; Michalsky, Elke; Hoepfner, Michael; Preissner, Robert

    2008-01-01

    The Vascular Endothelial Growth Factor receptors (VEGF-Rs) play a significant role in tumor development and tumor angiogenesis and are therefore interesting targets in cancer therapy. Targeting the VEGF-R is of special importance as the feed of the tumor has to be reduced. In general, this can be carried out by inhibiting the tyrosine kinase function of the VEGF-R. Nevertheless, there arise some problems with the specificity of known kinase inhibitors: they bind to the ATP-binding site and inhibit a number of kinases, moreover the so far most specific inhibitors act at least on these three major types of VEGF-Rs: Flt-1, Flk-1/KDR, Flt-4. The goal is a selective VEGF-R-2 (Flk-1/KDR) inhibitor, because this receptor triggers rather unspecific signals from VEGF-A, -C, -D and -E. Here, we describe a protocol starting from an established inhibitor (Vatalanib) with 2D-/3D-searching and property filtering of the in silico screening hits and the "negative docking approach". With this approach we were able to identify a compound, which shows a fourfold higher reduction of the proliferation rate of endothelial cells compared to the reduction effect of the lead structure.

  16. Development of a portable multiphoton photo-acoustic spectroscopy system for tumor diagnostics

    NASA Astrophysics Data System (ADS)

    Chandrasekharan, Nirmala; Kiser, John B.; Cullum, Brian M.

    2004-12-01

    In this paper we describe the development of a novel fiber optic probe for subsurface tumor diagnostics, based on non-resonant multiphoton photoacoustic spectroscopy (NMPPAS). In this technique, endogenous biomarkers present in tissues are irradiated in the near infrared, using a tunable high-power laser. The resulting multiphoton excitation events are detected as an acoustic (i.e. ultrasonic) signal, using an ultrasonic piezoelectric transducer. The signal from the piezoelectric transducer is then corrected for laser power fluctuations by normalizing the NMPPAS signal at each wavelength with the laser intensity recorded, from an optical diode. By scanning the laser excitation over the appropriate wavelength range for the tissue of interest, absorption differences between normal and tumor tissues can be measured and analyzed. The fiber optic probe was characterized and optimized for transmission efficiency as well as its time dependent response to high power laser pulses. The focusing optics were optimized and a piezoelectric transducer film detector chosen based on its sensitivity in the ultrasonic frequency range of interest. Using this probe system NMPPAS measurements were performed on several common fluorescent dyes including rhodamine 6G as well as well-characterized biomarkers like tryptophan. Furthermore, the technique was further successfully applied to the differentiation of tumorous and healthy human brain tissues.

  17. Aurora B Overexpression Causes Aneuploidy and p21Cip1 Repression during Tumor Development

    PubMed Central

    González-Loyola, Alejandra; Fernández-Miranda, Gonzalo; Trakala, Marianna; Partida, David; Samejima, Kumiko; Ogawa, Hiromi; Cañamero, Marta; de Martino, Alba; Martínez-Ramírez, Ángel; de Cárcer, Guillermo; Pérez de Castro, Ignacio; Earnshaw, William C.

    2015-01-01

    Aurora kinase B, one of the three members of the mammalian Aurora kinase family, is the catalytic component of the chromosomal passenger complex, an essential regulator of chromosome segregation in mitosis. Aurora B is overexpressed in human tumors although whether this kinase may function as an oncogene in vivo is not established. Here, we report a new mouse model in which expression of the endogenous Aurkb locus can be induced in vitro and in vivo. Overexpression of Aurora B in cultured cells induces defective chromosome segregation and aneuploidy. Long-term overexpression of Aurora B in vivo results in aneuploidy and the development of multiple spontaneous tumors in adult mice, including a high incidence of lymphomas. Overexpression of Aurora B also results in a reduced DNA damage response and decreased levels of the p53 target p21Cip1 in vitro and in vivo, in line with an inverse correlation between Aurora B and p21Cip1 expression in human leukemias. Thus, overexpression of Aurora B may contribute to tumor formation not only by inducing chromosomal instability but also by suppressing the function of the cell cycle inhibitor p21Cip1. PMID:26240282

  18. FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development.

    PubMed

    Liu, Zhilin; Ren, Yi A; Pangas, Stephanie A; Adams, Jaye; Zhou, Wei; Castrillon, Diego H; Wilhelm, Dagmar; Richards, JoAnne S

    2015-07-01

    The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of

  19. SNF5/INI1 Deficiency Redefines Chromatin Remodeling Complex Composition During Tumor Development

    PubMed Central

    Wei, Darmood; Goldfarb, Dennis; Song, Shujie; Cannon, Courtney; Yan, Feng; Sakellariou-Thompson, Donastas; Emanuele, Michael; Major, Michael B.; Weissman, Bernard E.; Kuwahara, Yasumichi

    2014-01-01

    Malignant Rhabdoid Tumors (MRTs), a pediatric cancer that most frequently appears in the kidney and brain, generally lack SNF5 (SMARCB1/INI1), a subunit of the SWI/SNF chromatin-remodeling complex. Recent studies have established that multiple SWI/SNF complexes exist due to the presence or absence of different complex members. Therefore, the effect of SNF5 loss upon SWI/SNF complex formation was investigated in human MRT cells. MRT cells and primary human tumors exhibited reduced levels of many complex proteins. Furthermore, re-expression of SNF5 increased SWI/SNF complex protein levels without concomitant increases in mRNA. Proteomic analysis, using mass spectrometry, of MRT cells before and after SNF5 re-expression indicated the recruitment of different components into the complex along with the expulsion of others. IP-Western blotting confirmed these results and demonstrated similar changes in other MRT cell lines. Finally, reduced expression of SNF5 in normal human fibroblasts led to altered levels of these same complex members. These data establish that SNF5 loss during MRT development alters the repertoire of available SWI/SNF complexes, generally disrupting those associated with cellular differentiation. These findings support a model where SNF5 inactivation blocks the conversion of growth promoting SWI/SNF complexes to differentiation inducing ones. Therefore, restoration of these complexes in tumors cells provides an attractive approach for the treatment of malignant rhabdoid tumors. Implications SNF5 loss dramatically alters SWI/SNF complex composition and prevents formation of complexes required for cellular differentiation. PMID:25009291

  20. Effect of 3-methoxybenzamide on the induction and development of hamster-pouch tumors

    SciTech Connect

    Miller, E.G.; Rivera-Hidalgo, F.; Binnie, W.H.

    1987-01-01

    Data from this laboratory and others has suggested that inhibitors of poly(ADP-ribose) polymerase might be able to augment the action of chemical carcinogens. The purpose of this study was to see if one of these inhibitors, 3-methoxybenzamide (MBA), could enhance the carcinogenic effects of 7,12-dimethylbenz(a)anthracene (DMBA). Thirty-two female Syrian hamsters were divided into two equal experimental groups. The left buccal pouches of the animals in Group I were painted three times weekly, first with a solution of dimethylsulfoxide (DMSO) and then with a 0.5% solution of DMBA in mineral oil. In Group II the basic treatment was the same except that the DMSO contained MBA (2.5%). After a total of 50 treatments (16 1/2 weeks), the animals were sacrificed and autopsied. The data indicated that the hamsters in Group II had approximately twice as many tumors as the animals in Group I. The average size of the tumors in the two groups was essentially the same. Using the two-stage mechanism for tumorigenesis it would appear the MBA affected the initiating phase of DMBA-induced carcinogenesis.

  1. Mesenchymal Stem Cells Develop Tumor Tropism but Do Not Accelerate Breast Cancer Tumorigenesis in a Somatic Mouse Breast Cancer Model

    PubMed Central

    Usha, Lydia; Rao, Geetha; Christopherson II, Kent; Xu, Xiulong

    2013-01-01

    The role of mesenchymal stem cells (MSCs) on breast cancer progression, growth and tumorigenesis remains controversial or unknown. In the present study, we investigated the role of MSCs on breast tumor induction and growth in a clinically relevant somatic breast cancer model. We first conducted in vitro studies and found that conditioned media (CM) of RCAS-Neu and RCAS-PyMT breast cancer cell lines and tumor cells themselves dramatically increased the proliferation and motility of MSCs and induced morphological changes of MSCs and differentiation into fibroblast-like cells. In contrast, the CM of MSCs inhibited the proliferation of two breast cancer cell lines by arresting the cell cycle at the G0/G1 phase. In vivo studies revealed that fluorescence dye-labeled MSCs migrated into tumor tissues. Unexpectedly, single or multiple intravenous injections of MSCs did not affect the latency of breast cancer in TVA- transgenic mice induced by intraductal injection of the RCAS vector encoding polyoma middle-T antigen (PyMT) or Neu oncogenes. Moreover, MSCs had no effect on RCAS-Neu tumor growth in a syngeneic ectopic breast cancer model. While our studies consistently demonstrated the ability of breast cancer cells to profoundly induce MSCs migration, differentiation, and proliferation, the anti-proliferative effect of MSCs on breast tumor cells observed in vitro could not be translated into an antitumor activity in vivo, probably reflecting the antagonizing or complex effects of MSCs on tumor environment and tumor cells themselves. PMID:24069135

  2. The role of tumor necrosis factor receptor superfamily members in mammalian brain development, function and homeostasis

    PubMed Central

    Twohig, Jason P.; Cuff, Simone M.; Yong, Audrey A.; Wang, Eddie C.Y.

    2012-01-01

    Tumor necrosis factor receptor superfamily (TNFRSF) members were initially identified as immunological mediators, and are still commonly perceived as immunological molecules. However, our understanding of the diversity of TNFRSF members’ roles in mammalian physiology has grown significantly since the first discovery of TNFRp55 (TNFRSF1) in 1975. In particular, the last decade has provided evidence for important roles in brain development, function and the emergent field of neuronal homeostasis. Recent evidence suggests that TNFRSF members are expressed in an overlapping regulated pattern during neuronal development, participating in the regulation of neuronal expansion, growth, differentiation and regional pattern development. This review examines evidence for non-immunological roles of TNFRSF members in brain development, function and maintenance under normal physiological conditions. In addition, several aspects of brain function during inflammation will also be described, when illuminating and relevant to the non-immunological role of TNFRSF members. Finally, key questions in the field will be outlined. PMID:21861782

  3. PET and SPECT Imaging of Tumor Biology: New Approaches towards Oncology Drug Discovery and Development

    PubMed Central

    Van Dort, Marcian E.; Rehemtulla, Alnawaz; Ross, Brian D.

    2009-01-01

    Spiraling drug developmental costs and lengthy time-to-market introduction are two critical challenges facing the pharmaceutical industry. The clinical trials success rate for oncology drugs is reported to be 5% as compared to other therapeutic categories (11%) with most failures often encountered late in the clinical development process. PET and SPECT nuclear imaging technologies could play an important role in facilitating the drug development process improving the speed, efficiency and cost of drug development. This review will focus on recent studies of PET and SPECT radioligands in oncology and their application in the investigation of tumor biology. The use of clinically-validated radioligands as imaging-based biomarkers in oncology could significantly impact new cancer therapeutic development. PMID:19809593

  4. Is rumen development in newborn calves affected by different liquid feeds and small intestine development?

    PubMed

    Górka, P; Kowalski, Z M; Pietrzak, P; Kotunia, A; Jagusiak, W; Zabielski, R

    2011-06-01

    fed MR. Significant positive Pearson correlations were found between small intestine and reticulorumen weights as well as between activity of brush border lactase, maltase, aminopeptidase A, and aminopeptidase N and reticulorumen weight. Different liquid feeds affect small intestine development, animal growth, solid feed intake and metabolic status of calves and this effect can indirectly influence the development of forestomachs.

  5. The Development and Application of Affective Assessment in an Upper-Level Cell Biology Course

    ERIC Educational Resources Information Center

    Kitchen, Elizabeth; Reeve, Suzanne; Bell, John D.; Sudweeks, Richard R.; Bradshaw, William S.

    2007-01-01

    This study exemplifies how faculty members can develop instruments to assess affective responses of students to the specific features of the courses they teach. Means for assessing three types of affective responses are demonstrated: (a) student attitudes towards courses with differing instructional objectives and methodologies, (b) student…

  6. Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development.

    PubMed

    Ma, Yunfeng; Xiang, Dong; Sun, Jinwen; Ding, Chuanlin; Liu, Min; Hu, Xiaoling; Li, Guoxin; Kloecker, Goetz; Zhang, Huang-Ge; Yan, Jun

    2013-06-01

    Ab therapy against surface Ags on tumor cells has demonstrated significant efficacy for some cancers. However, it is costly and patients frequently develop acquired resistance over time. In cases of Ab therapy resistance, T cell responses have been shown to be essential in controlling disease progression. Thus, vaccination that generates a sustained Ab response as well as a T cell response may be more effective and economical. In this article, we have developed a vaccination strategy by targeting protein Ags to B cells via a CD19 single-chain variable fragment miniAb. Using the tumor-associated Ag her-2/neu extracellular domain, we showed that the coengagement of CD19 and BCR induced full B cell activation to produce a high titer of Abs and enhanced CD4 Th2 response and CD8 T cell activation and differentiation. These Abs competitively inhibited humanized her-2/neu Ab binding and were capable of activating the complement and inhibiting human breast cancer growth in vitro. Therapeutic efficacy was demonstrated in vivo using murine mammary carcinoma models. Furthermore, four different extracellular domains of her-2/neu could be targeted to B cells to generate Abs against particular domains with different antitumor properties. This approach may offer a new avenue for vaccine development with significantly lower cost, which may be of use not only for cancer therapy but also for infectious agents.

  7. Regulation of Differentiation by Calcium-Sensing Receptor in Normal and Tumoral Developing Nervous System

    PubMed Central

    Mateo-Lozano, Silvia; García, Marta; Rodríguez-Hernández, Carlos J.; de Torres, Carmen

    2016-01-01

    During normal development of the nervous system (NS), neural progenitor cells (NPCs) produce specialized populations of neurons and glial cells upon cell fate restriction and terminal differentiation. These sequential processes require the dynamic regulation of thousands of genes. The calcium-sensing receptor (CaSR) is temporally and spatially regulated in both neurons and glial cells during development of the NS. In particular, CaSR expression and function have been shown to play a significant role during differentiation of NPCs toward the oligodendrocyte lineage and also in maturation of cerebellar granule cell precursors (GCPs). Moreover, CaSR regulates axonal and dendritic growth in both central and peripheral nervous systems (PNSs), a process necessary for proper construction of mature neuronal networks. On the other hand, several lines of evidence support a role for CaSR in promotion of cell differentiation and inhibition of proliferation in neuroblastoma, a tumor arising from precursor cells of developing PNS. Thus, among the variety of NS functions in which the CaSR participates, this mini-review focuses on its role in differentiation of normal and tumoral cells. Current knowledge of the mechanisms responsible for CaSR regulation and function in these contexts is also discussed, together with the therapeutic opportunities provided by CaSR allosteric modulators. PMID:27242543

  8. High-throughput screening with nanoimprinting 3D culture for efficient drug development by mimicking the tumor environment.

    PubMed

    Yoshii, Yukie; Furukawa, Takako; Waki, Atsuo; Okuyama, Hiroaki; Inoue, Masahiro; Itoh, Manabu; Zhang, Ming-Rong; Wakizaka, Hidekatsu; Sogawa, Chizuru; Kiyono, Yasushi; Yoshii, Hiroshi; Fujibayashi, Yasuhisa; Saga, Tsuneo

    2015-05-01

    Anti-cancer drug development typically utilizes high-throughput screening with two-dimensional (2D) cell culture. However, 2D culture induces cellular characteristics different from tumors in vivo, resulting in inefficient drug development. Here, we report an innovative high-throughput screening system using nanoimprinting 3D culture to simulate in vivo conditions, thereby facilitating efficient drug development. We demonstrated that cell line-based nanoimprinting 3D screening can more efficiently select drugs that effectively inhibit cancer growth in vivo as compared to 2D culture. Metabolic responses after treatment were assessed using positron emission tomography (PET) probes, and revealed similar characteristics between the 3D spheroids and in vivo tumors. Further, we developed an advanced method to adopt cancer cells from patient tumor tissues for high-throughput drug screening with nanoimprinting 3D culture, which we termed Cancer tissue-Originated Uniformed Spheroid Assay (COUSA). This system identified drugs that were effective in xenografts of the original patient tumors. Nanoimprinting 3D spheroids showed low permeability and formation of hypoxic regions inside, similar to in vivo tumors. Collectively, the nanoimprinting 3D culture provides easy-handling high-throughput drug screening system, which allows for efficient drug development by mimicking the tumor environment. The COUSA system could be a useful platform for drug development with patient cancer cells.

  9. Modeling Tumor Invasion: Effects of Native Vascularity and Tumor Metabolism

    NASA Astrophysics Data System (ADS)

    Gawlinski, Edward

    2001-03-01

    A hybrid cellular automaton model is described and used to simulate early tumor growth and examine the roles of host tissue vascular density and tumor metabolism in the ability of a small number of monoclonal transformed cells to develop into an invasive tumor. The model incorporates normal cells, tumor cells, necrotic or empty space, and a random network of native microvessels as components of a cellular automaton state vector. Diffusion of glucose and lactic acid (the latter resulting from the tumor's excessive reliance on anaerobic metabolism) to and from the microvessels, and their utilization or production by cells, is modeled through the solution of differential equations. In this way, the cells and microvessels affect the extracellular concentrations of glucose and acid which, in turn, affect the rules governing the evolution of the automaton's state vector. Simulations of the model demonstrate that: (i) high tumor acid production is favorable for tumor growth and invasion, however for every acid production rate, there exists a range of optimal microvessel densities (leading to a local pH favorable to tumor but not to normal cells) for which growth and invasion is most effective, (ii) at vascular densities below this range, both tumor and normal cells die due to excessively low pH, (iii) for vascular densities above the optimal range the microvessel network is highly efficient at removing acid and therefore the tumor cells lose their advantage over normal cells gained by high local acid concentration. While significant spatial gradients of glucose formed, no regions of detrimentally poor glucose perfusion (for either cell type) were observed, regardless of microvessel density. Depending on metabolic phenotype, a variety of tumor morphologies similar to those clinically observed were realized in the simulations. Lastly, a sharp transition (analogous to that of the adenoma-carcinoma sequence) between states of initial tumor confinement and efficient

  10. Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon

    PubMed Central

    Rocha, Cecilia; Papon, Laura; Cacheux, Wulfran; Marques Sousa, Patricia; Lascano, Valeria; Tort, Olivia; Giordano, Tiziana; Vacher, Sophie; Lemmers, Benedicte; Mariani, Pascale; Meseure, Didier; Medema, Jan Paul; Bièche, Ivan; Hahne, Michael; Janke, Carsten

    2014-01-01

    TTLL3 and TTLL8 are tubulin glycine ligases catalyzing posttranslational glycylation of microtubules. We show here for the first time that these enzymes are required for robust formation of primary cilia. We further discover the existence of primary cilia in colon and demonstrate that TTLL3 is the only glycylase in this organ. As a consequence, colon epithelium shows a reduced number of primary cilia accompanied by an increased rate of cell division in TTLL3-knockout mice. Strikingly, higher proliferation is compensated by faster tissue turnover in normal colon. In a mouse model for tumorigenesis, lack of TTLL3 strongly promotes tumor development. We further demonstrate that decreased levels of TTLL3 expression are linked to the development of human colorectal carcinomas. Thus, we have uncovered a novel role for tubulin glycylation in primary cilia maintenance, which controls cell proliferation of colon epithelial cells and plays an essential role in colon cancer development. PMID:25180231

  11. Dysregulated Expression of Glycolipids in Tumor Cells: From Negative Modulator of Anti-tumor Immunity to Promising Targets for Developing Therapeutic Agents

    PubMed Central

    Daniotti, Jose Luis; Lardone, Ricardo D.; Vilcaes, Aldo A.

    2016-01-01

    Glycolipids are complex molecules consisting of a ceramide lipid moiety linked to a glycan chain of variable length and structure. Among these are found the gangliosides, which are sialylated glycolipids ubiquitously distributed on the outer layer of vertebrate plasma membranes. Changes in the expression of certain species of gangliosides have been described to occur during cell proliferation, differentiation, and ontogenesis. However, the aberrant and elevated expression of gangliosides has been also observed in different types of cancer cells, thereby promoting tumor survival. Moreover, gangliosides are actively released from the membrane of tumor cells, having a strong impact on impairing anti-tumor immunity. Beyond the undesirable effects of gangliosides in cancer cells, a substantial number of cancer immunotherapies have been developed in recent years that have used gangliosides as the main target. This has resulted in successful immune cell- or antibody-responses against glycolipids, with promising results having been obtained in clinical trials. In this review, we provide a general overview on the metabolism of glycolipids, both in normal and tumor cells, as well as examining glycolipid-mediated immune modulation and the main successes achieved in immunotherapies using gangliosides as molecular targets. PMID:26779443

  12. Productive Infection of Bovine Papillomavirus Type 2 in the Placenta of Pregnant Cows Affected with Urinary Bladder Tumors

    PubMed Central

    Roperto, Sante; Borzacchiello, Giuseppe; Esposito, Iolanda; Riccardi, Marita; Urraro, Chiara; Lucà, Roberta; Corteggio, Annunziata; Tatè, Rosarita; Cermola, Michele; Paciello, Orlando; Roperto, Franco

    2012-01-01

    Papillomaviruses (PVs) are believed to be highly epitheliotropic as they usually establish productive infections within stratified epithelia. In vitro, various PVs appear to complete their entire life-cycle in different trophoblastic cell lines. In this study, infection by and protein expression of bovine papillomavirus type 2 (BPV-2) in the uterine and chorionic epithelium of the placenta has been described in four cows suffering from naturally occurring papillomavirus-associated urothelial bladder tumors. E5 oncoprotein was detected both by Western blot analysis and immunohistochemically. It appears to be complexed and perfectly co-localized with the activated platelet-derived growth factor ß receptor (PDGFßR) by laser scanning confocal microscopy. The activated PDGFßR might be involved in organogenesis and neo-angiogenesis rather than in cell transformation during pregnancy. The major capsid protein, L1, believed to be only expressed in productive papillomavirus infection has been detected by Western blot analysis. Immunohistochemical investigations confirmed the presence of L1 protein both in the cytoplasm and nuclei of cells of the uterine and chorionic epithelium. Trophoblastic cells appear to be the major target for L1 protein expression. Finally, the early protein E2, required for viral DNA replication and known to be expressed during a productive infection, has been detected by Western blot and immunohistochemically. Electron microscopic investigations detected viral particles in nuclei of uterine and chorionic epithelium. This study shows that both active and productive infections by BPV-2 in the placenta of pregnant cows can occur in vivo. PMID:22479413

  13. Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

    PubMed Central

    Wu, Huali; Infante, Jeffrey R; Keedy, Vicki L; Jones, Suzanne F; Chan, Emily; Bendell, Johanna C; Lee, Wooin; Kirschbrown, Whitney P; Zamboni, Beth A; Ikeda, Satoshi; Kodaira, Hiroshi; Rothenberg, Mace L; Burris, Howard A; Zamboni, William C

    2015-01-01

    IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes. PMID:25709442

  14. Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors

    PubMed Central

    Yamashiro, Darrell J.; Fox, Elizabeth

    2011-01-01

    Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers. PMID:22042784

  15. Anti-Tumor Effects of Second Generation β-Hydroxylase Inhibitors on Cholangiocarcinoma Development and Progression

    PubMed Central

    Chung, Waihong; de la Monte, Suzanne; Thomas, John-Michael; Olsen, Mark; Carlson, Rolf; Yu, Tunan; Dong, Xiaoqun; Wands, Jack

    2016-01-01

    Cholangiocarcinoma (CCA) has a poor prognosis due to widespread intrahepatic spread. Aspartate β-hydroxylase (ASPH) is a transmembrane protein and catalyzes the hydroxylation of aspartyl and asparaginyl residues in calcium binding epidermal growth factor (cbEGF)-like domains of various proteins, including Notch receptors and ligands. ASPH is highly overexpressed (>95%) in human CCA tumors. We explored the molecular mechanisms by which ASPH mediated the CCA malignant phenotype and evaluated the potential of ASPH as a therapeutic target for CCA. The importance of expression and enzymatic activity of ASPH for CCA growth and progression was examined using shRNA “knockdown” and a mutant construct that reduced its catalytic activity. Second generation small molecule inhibitors (SMIs) of β-hydroxylase activity were developed and used to target ASPH in vitro and in vivo. Subcutaneous and intrahepatic xenograft rodent models were employed to determine anti-tumor effects on CCA growth and development. It was found that the enzymatic activity of ASPH was critical for mediating CCA progression, as well as inhibiting apoptosis. Mechanistically, ASPH overexpression promoted Notch activation and modulated CCA progression through a Notch1-dependent cyclin D1 pathway. Targeting ASPH with shRNAs or a SMI significantly suppressed CCA growth in vivo. PMID:26954680

  16. Development of the research on the application of chlorotoxin in imaging diagnostics and targeted therapies for tumors.

    PubMed

    Wu, Xiao-Shan; Jian, Xin-Chun; Yin, Bing; He, Zhi-Jing

    2010-06-01

    Precisely locating tumors always proves to be difficult. To find a molecule that can specifically bind to tumor cells is the key. Recently, chlorotoxin (CTX) has been proved to be able to bind to many kinds of tumor cells. The CTX receptor on the cell surface has been demonstrated to be matrix metalloproteinase-2 (MMP-2). Many researchers have combined CTX with other molecules, including 131I, Cy5.5, iron oxide nanoparticles coated by polyethylene glycol (NP-PEG), and so on, and thus synthesized various types of probes that can be detected by gamma-camera, single photon emission computed tomography (SPECT) or magnetic resonance imaging (MRI). With these methods, the binding degree of CTX could be assessed. These studies demonstrated that CTX has a highly specific binding ability, high stability, and security. CTX could also inhibit or kill the tumor cells. A nonviral nanovector has been developed for gene therapy. As a result, it gradually develops into a new method of diagnosis and targeted therapy of tumors. This article reviews the current progress on CTX including the origin, chemical construction, the mechanism of binding with tumor cells, and the application to tumor imaging diagnosis and therapy.

  17. The Drosophila Wilms׳ Tumor 1-Associating Protein (WTAP) homolog is required for eye development.

    PubMed

    Anderson, Abigail M; Weasner, Brandon P; Weasner, Bonnie M; Kumar, Justin P

    2014-06-15

    Sine Oculis (So), the founding member of the SIX family of homeobox transcription factors, binds to sequence specific DNA elements and regulates transcription of downstream target genes. It does so, in part, through the formation of distinct biochemical complexes with Eyes Absent (Eya) and Groucho (Gro). While these complexes play significant roles during development, they do not account for all So-dependent activities in Drosophila. It is thought that additional So-containing complexes make important contributions as well. This contention is supported by the identification of nearly two-dozen additional proteins that complex with So. However, very little is known about the roles that these additional complexes play in development. In this report we have used yeast two-hybrid screens and co-immunoprecipitation assays from Kc167 cells to identify a biochemical complex consisting of So and Fl(2)d, the Drosophila homolog of human Wilms׳ Tumor 1-Associating Protein (WTAP). We show that Fl(2)d protein is distributed throughout the entire eye-antennal imaginal disc and that loss-of-function mutations lead to perturbations in retinal development. The eye defects are manifested behind the morphogenetic furrow and result in part from increased levels of the pan-neuronal RNA binding protein Embryonic Lethal Abnormal Vision (Elav) and the RUNX class transcription factor Lozenge (Lz). We also provide evidence that So and Fl(2)d interact genetically in the developing eye. Wilms׳ tumor-1 (WT1), a binding partner of WTAP, is required for normal eye formation in mammals and loss-of-function mutations are associated with some versions of retinoblastoma. In contrast, WTAP and its homologs have not been implicated in eye development. To our knowledge, the results presented in this report are the first description of a role for WTAP in the retina of any seeing animal. PMID:24690230

  18. Developments in epidermal growth factor receptor-targeting therapy for solid tumors: focus on matuzumab (EMD 72000).

    PubMed

    Schiller, Joan H

    2008-02-01

    Expression of epidermal growth factor and its transmembrane receptor (EGFR) stimulates tumor growth. Matuzumab is a humanized anti-EGFR monoclonal antibody that blocks EGFR activation and downstream signaling, inhibits tumor growth, and provides a clinical benefit for some patients. The plasma half-life (6-10 days) and pharmacodynamic activity allow flexible dosing on weekly, every-2-week, and every-3-week schedules. Matuzumab has shown single-agent antitumor activity in heavily pretreated patients with a variety of tumors, with a favorable safety profile. Skin rash is the most common toxicity, but is severe (Grade 3) in < 1 percent. This article describes preclinical and clinical development of matuzumab.

  19. Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice

    PubMed Central

    Mohamad, Nora A; Cricco, Graciela P; Sambuco, Lorena A; Croci, Máximo; Medina, Vanina A; Gutiérrez, Alicia S; Bergoc, Rosa M; Rivera, Elena S; Martín, Gabriela A

    2009-01-01

    AIM: To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation, apoptosis, redox status and vascularization. METHODS: Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups: control and aminoguanidine treated. Tumor growth, survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS), catalase, copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). Finally, vascularization was determined by Massons trichromic staining, and by VEGF and CD34 expression. RESULTS: Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P < 0.01). Median survival of AG mice was significantly greater than control animals (P < 0.01). The appearance of both homolateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells, intratumoral vascularization (trichromic stain) and the expression of Ki-67, Bax, eNOS, CD34, VEGF, catalase, CuZnSOD and MnSOD were diminished in AG treated mice (P < 0.01), while the expression of Bcl-2 and GPx did not change. CONCLUSION: The antitumoral action of aminoguanidine is associated with decreased cell proliferation, reduced angiogenesis, and reduced expression of antioxidant enzymes. PMID:19266598

  20. Concise Review: NANOG in Cancer Stem Cells and Tumor Development: An Update and Outstanding Questions.

    PubMed

    Jeter, Collene R; Yang, Tao; Wang, Junchen; Chao, Hsueh-Ping; Tang, Dean G

    2015-08-01

    The homeobox domain transcription factor NANOG, a key regulator of embryonic development and cellular reprogramming, has been reported to be broadly expressed in human cancers. Functional studies have provided strong evidence that NANOG possesses protumorigenic attributes. In addition to promoting self-renewal and long-term proliferative potential of stem-like cancer cells, NANOG-mediated oncogenic reprogramming may underlie clinical manifestations of malignant disease. In this review, we examine the molecular origin, expression, biological activities, and mechanisms of action of NANOG in various malignancies. We also consider clinical implications such as correlations between NANOG expression and cancer prognosis and/or response to therapy. We surmise that NANOG potentiates the molecular circuitry of tumorigenesis, and thus may represent a novel therapeutic target or biomarker for the diagnosis, prognosis, and treatment outcome of cancer. Finally, we present critical pending questions relating NANOG to cancer stem cells and tumor development.

  1. Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration.

    PubMed

    Crowe, Andrew; Jackaman, Connie; Beddoes, Katie M; Ricciardo, Belinda; Nelson, Delia J

    2013-01-01

    Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4(+) T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes.

  2. Caveolin-1 affects tumor drug resistance in esophageal squamous cell carcinoma by regulating expressions of P-gp and MRP1.

    PubMed

    Zhang, Song; Cao, Wenbo; Yue, Mingjin; Zheng, Naigang; Hu, Tao; Yang, Shengli; Dong, Ziming; Lu, Shixin; Mo, Saijun

    2016-07-01

    Esophageal squamous cell carcinoma (ESCC) is the most common cancer in China, and multidrug resistance (MDR) remains one of the biggest problems in ESCC chemotherapy. In this study, we aimed to investigate the mechanism of Caveolin-1, an integral membrane protein, on regulating ESCC MDR. First, immunohistochemistry was used to check the protein expression of Caveolin-1, MDR-related protein of P-glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) in 84 pathologically characterized ESCC tissues, matched adjacent tumor, and adjacent normal-looking tissues. The results showed that Caveolin-1 expression level was elevated in ESCC tissues than that of matched adjacent tumor and adjacent normal-looking tissues (P < 0.05), and the expression of Caveolin-1 has close correlation with P-gp and MRP1 during tumor genesis of ESCC (P = 0.034, P = 0.009, respectively). Then, Caveolin-1 overexpression and knockdown were used to investigate its effect on expressions of P-gp and MRP1 in ESCC cell line Ec9706. The messenger RNA (mRNA) and protein expression levels of P-gp and MRP1 were checked by real-time quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB). The results showed that Caveolin-1 overexpression significantly promotes the mRNA and protein expression of MRP1 (P < 0.05), while almost has no effect on the mRNA and protein expression of P-gp (P > 0.05); Cavoelin-1 knockdown inhibits the mRNA and protein expressions of both P-gp and MRP1 (P < 0.05). The similar result was found in another ESCC cell line Eca109. So, it is concluded that Caveolin-1 affects ESCC MDR by regulating the expressions of P-gp and MRP1; therefore, it can be taken as a significant marker and target in tumor therapy.

  3. Developing high-frequency ultrasound tomography for testicular tumor imaging in rats: An in vitro study

    SciTech Connect

    Huang, Chih-Chung; Chen, Wei-Tsen

    2014-01-15

    Purpose: This paper describes a feasibility study for developing a 35-MHz high-frequency ultrasound computed-tomography (HFUCT) system for imaging rat testicles. Methods: The performances of two kinds of HFUCT-attenuation and sound-speed UCT-based on transmission and pulse-echo modes were investigated in this study. Experiments were carried out using phantoms and actual rat testiclesin vitro. HFUCT images were reconstructed using a filtered backprojection algorithm. Results: The phantom experimental results indicated that all types of HFUCT can determine the dimensions of a plastic cylinder with a diameter of 500μm. Compared to sound-speed HFUCT, attenuation HFUCT exhibited a better performance in recognizing a tiny sclerosed region in a gelatin phantom. Therefore, the in vitro testicular experiments were performed using attenuation HFUCT based on transmission and pulse-echo modes. The experimentally measured attenuation coefficient and sound speed for healthy rat testicles were 2.92 ± 0.25 dB/mm and 1537 ± 25 m/s, respectively. Conclusions: A homogeneous texture was evident for healthy testicles using both modes. An artificial sclerosed tumor could also be clearly observed using two- and three-dimensional attenuation HFUCT in both modes. However, an object artifact was apparent in pulse-echo mode because of ultrasound beam refraction. All of the obtained experimental results indicate the potential of using HFUCT as a novel tool for monitoring the preclinical responses of testicular tumors in small animals.

  4. Development and characterization of magnetic cationic liposomes for targeting tumor microvasculature.

    PubMed

    Dandamudi, Suman; Campbell, Robert B

    2007-03-01

    Cationic liposomes preferentially target tumor vasculature compared to vessels in normal tissues. The distribution of cationic liposomes along vascular networks is, however, patchy and heterogeneous. To target vessels more uniformly we combined the electrostatic properties of cationic liposomes with the strength of an external magnet. We report part I of development. We evaluated bilayer physical properties of our preparations. We investigated interaction of liposomes with target cells including the role of PEG (polyethylene-glycol), and determined whether magnetic cationic liposomes can respond to an external magnetic field. The inclusion of relatively high concentration of MAG-C (magnetite) at 2.5 mg/ml significantly increased the size of cationic liposomes from 105+/-26.64 to 267+/-27.43 nm and reduced the zeta potential from 64.55+/-16.68 to 39.82+/-5.26 mv. The phase transition temperature of cationic liposomes (49.97+/-1.34 degrees C) reduced with inclusion of MAG-C (46.05+/-0.21 degrees C). MAG-C cationic liposomes were internalized by melanoma (B16-F10 and HTB-72) and dermal endothelial (HMVEC-d) cells. PEG partially shielded cationic charge potential of MAG-C cationic liposomes, reduced their ability to interact with target cells in vitro, and uptake by major RES organs. Finally, application of external magnet enhanced tumor retention of magnetic cationic liposomes.

  5. Ovarian germ cell tumors with rhabdomyosarcomatous components and later development of growing teratoma syndrome: a case report

    PubMed Central

    2012-01-01

    Introduction Development of a sarcomatous component in a germ cell tumor is an uncommon phenomenon. Most cases reported have a grim prognosis. Growing teratoma syndrome is also an uncommon phenomenon and occurs in approximately 2% to 7% of non seminomatous germ cell tumors and should be treated surgically. Case presentation We report the case of a 12-year-old Asian girl with an ovarian mixed germ cell tumor containing a rhabdomyosarcomatous component. She was treated with a germ cell tumor chemotherapy regimen and rhabdomyosarcoma-specific chemotherapy. Towards the end of her treatment, she developed a retroperitoneal mass that was increasing in size. It was completely resected, revealing a mature teratoma, consistent with growing teratoma syndrome. She is still in complete remission approximately three years after presentation. Conclusion The presence of rhabdomyosarcoma in a germ cell tumor should be treated by a combined chemotherapy regimen (for germ cell tumor and rhabdomyosarcoma). In addition, development of a mass during or after therapy with normal serum markers should raise the possibility of growing teratoma syndrome that should be treated surgically. PMID:22248255

  6. Tumoral profile in Down syndrome: A step towards the understanding of the consequences of aneuploidy and the development of cancer

    SciTech Connect

    Stage, D.; Sommelet, D.; Geneix, A.

    1994-09-01

    A review of the tumoral profile observed in Down syndrome has been done. Besides the well-known presence of congenital leukemia (recurring during childhood in 25% of cases) and the excess of acute leukemias occurring in the first two years of life where the nonlymphocytic (FAB M7) type is much more common than the lymphocytic (pre-B) type, some solid tumors are also observed more frequently in Down syndrome patients than in the general population. For example, one observes in Down syndrome patients an excess of lymphoma, germ cell tumors (testicular and extra testicular) as well as bone and pancreatic tumors. These tumors are often observed in male Down syndrome patients and occur sometimes during the fetal life. On the contrary, some tumors are less frequently observed in a Down syndrome population than in the general population. For example, in children, kidney and neurological (central and peripheral) tumors and in adults, digestive, pulmonary, skin, kidney, breast and uterine cancers are rare. These data suggest that there might be on chromosome 21, genes that may predispose or protect for cancer. The positioning of these genes by centromeric mapping in patients with trisomy 21 might be useful for the understanding of the consequences of aneuploidy and the development of cancer.

  7. A key genetic factor for fucosyllactose utilization affects infant gut microbiota development

    PubMed Central

    Matsuki, Takahiro; Yahagi, Kana; Mori, Hiroshi; Matsumoto, Hoshitaka; Hara, Taeko; Tajima, Saya; Ogawa, Eishin; Kodama, Hiroko; Yamamoto, Kazuya; Yamada, Takuji; Matsumoto, Satoshi; Kurokawa, Ken

    2016-01-01

    Recent studies have demonstrated that gut microbiota development influences infants' health and subsequent host physiology. However, the factors shaping the development of the microbiota remain poorly understood, and the mechanisms through which these factors affect gut metabolite profiles have not been extensively investigated. Here we analyse gut microbiota development of 27 infants during the first month of life. We find three distinct clusters that transition towards Bifidobacteriaceae-dominant microbiota. We observe considerable differences in human milk oligosaccharide utilization among infant bifidobacteria. Colonization of fucosyllactose (FL)-utilizing bifidobacteria is associated with altered metabolite profiles and microbiota compositions, which have been previously shown to affect infant health. Genome analysis of infants' bifidobacteria reveals an ABC transporter as a key genetic factor for FL utilization. Thus, the ability of bifidobacteria to utilize FL and the presence of FL in breast milk may affect the development of the gut microbiota in infants, and might ultimately have therapeutic implications. PMID:27340092

  8. ''Vulnerability'' in AIDS-Affected States: Rethinking Child Rights, Educational Institutions, and Development Paradigms

    ERIC Educational Resources Information Center

    Kendall, Nancy

    2008-01-01

    The article interrogates current international development constructs of childhood, rights, vulnerability, and schooling in light of the daily experiences of two Malawian children affected by HIV/AIDS. It aims to better understand how development efforts targeted at these children function in practice, and suggests that current development…

  9. Factors Affecting Teachers' Participation in Continuing Professional Development (CPD): From Hong Kong Primary School Teachers' Perspectives

    ERIC Educational Resources Information Center

    Wan, Sally Wai-Yan.; Lam, Patrick Hak-Chung

    2010-01-01

    This paper presents the findings from a small-scale case study of Hong Kong primary teachers' perceptions of the factors affecting teachers' participation in continuing professional development (CPD). The study applies a multiple approach with mixed research methods, including using a self-developed survey questionnaire on the basis of the CPD…

  10. The Development of an Emotional Response to Writing Measure: The Affective Cognition Writing Survey

    ERIC Educational Resources Information Center

    Fischer, Ronald G.; Fischer, Jerome M.; Jain, Sachin

    2010-01-01

    This study was designed to develop and initiate the validation of the Affective Cognition Writing Survey (ACWS), a psychological instrument used to measure emotional expression through writing. Procedures for development and validation of the instrument are reported. Subsequently, factor analysis extracted six factors: Positive Processing,…

  11. Flor-Essence® herbal tonic does not inhibit estrogen receptor negative mammary tumor development in a transgenic mouse model

    PubMed Central

    Bennett, L. Michelle; Montgomery, Jennifer L.; Collins, N. Keith; Steinberg, Seth M.; Kulp, Kristen S.

    2012-01-01

    Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence® herbal tonic is a complex mixture of eight herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. In this study four experimental groups of female MMTV-Neu mice were left untreated or treated with 3% Flor-Essence® in utero, from birth until 5 weeks of age, or throughout their lifetime. Palpable mammary tumor incidence and body weight was determined weekly for each group. The mice were sacrificed at 28 weeks of age and mammary tumors were enumerated to determine average tumor incidence and multiplicity for each group. Female mice exposed to Flor-Essence® herbal tonic in utero weighed significantly more than the control group (p < 0.001). The average tumor incidence and tumor multiplicity in the experimental mice treated with Flor-Essence® herbal tonic did not differ from the control animals. Flor-Essence® does not inhibit mammary tumor incidence or mammary tumor multiplicity in MMTV-Neu transgenic mice. Flor-Essence® exposure in utero causes increased body weight in experimental animals. This conclusion challenges widely available anecdotal information as well as the hopes of the consumer that this product will inhibit or suppress tumor development. Lay Abstract Flor-Essence® herbal tonic is a complex mixture of eight herbal extracts often used by women with breast cancer in hopes that it will help cure disease or prevent recurrence. There is currently very little scientific data to support or refute its self-administration. We tested whether Flor-Essence® would influence tumor development in the mammary glands of a mouse model of Her2/neu breast cancer. The tonic was given at different life stages to determine if timing of the exposure influenced the response to treatment. This report shows that Flor

  12. Assessment of Environmental and Hereditary Influence on Development of Pituitary Tumors Using Dermatoglyphic Traits and Their Potential as Screening Markers

    PubMed Central

    Gradiser, Marina; Matovinovic Osvatic, Martina; Dilber, Dario; Bilic-Curcic, Ines

    2016-01-01

    The aim of this study was to assess environmental and hereditary influence on development of pituitary tumors using dermatoglyphic traits. The study was performed on 126 patients of both genders with pituitary tumors (60 non-functional and 66 functional pituitary tumor patients) in comparison to the control group of 400 phenotypically healthy individuals. Statistical analysis of quantitative and qualitative traits of digito-palmar dermatoglyphics was performed, and hormonal status was determined according to the standard protocols. Although we did not find markers that could specifically distinguish functional from non-functional tumors, we have found markers predisposing to the development of tumors in general (a small number of ridges between triradius of both hands, a smaller number of ridges between the triradius of c–d rc R), those for endocrine dysfunction (increased number of arches and reduced number of whorls, difference of pattern distribution in the I3 and I4 interdigital space), and some that could potentially be attributed to patients suffering from pituitary tumors (small number of ridges for variables FRR 5, smaller number of ridges in the FRL 4 of both hands and difference of pattern distribution at thenar of I1 and I2 interdigital space). The usage of dermatoglyphic traits as markers of predisposition of pituitary tumor development could facilitate the earlier detection of patients in addition to standard methods, and possibly earlier treatment and higher survival rate. Finally, our results are consistent with the hypothesis about multifactorial nature of pituitary tumor etiology comprised of both gene instability and environmental factors. PMID:26999178

  13. Assessment of Environmental and Hereditary Influence on Development of Pituitary Tumors Using Dermatoglyphic Traits and Their Potential as Screening Markers.

    PubMed

    Gradiser, Marina; Matovinovic Osvatic, Martina; Dilber, Dario; Bilic-Curcic, Ines

    2016-03-17

    The aim of this study was to assess environmental and hereditary influence on development of pituitary tumors using dermatoglyphic traits. The study was performed on 126 patients of both genders with pituitary tumors (60 non-functional and 66 functional pituitary tumor patients) in comparison to the control group of 400 phenotypically healthy individuals. Statistical analysis of quantitative and qualitative traits of digito-palmar dermatoglyphics was performed, and hormonal status was determined according to the standard protocols. Although we did not find markers that could specifically distinguish functional from non-functional tumors, we have found markers predisposing to the development of tumors in general (a small number of ridges between triradius of both hands, a smaller number of ridges between the triradius of c-d rc R), those for endocrine dysfunction (increased number of arches and reduced number of whorls, difference of pattern distribution in the I3 and I4 interdigital space), and some that could potentially be attributed to patients suffering from pituitary tumors (small number of ridges for variables FRR 5, smaller number of ridges in the FRL 4 of both hands and difference of pattern distribution at thenar of I1 and I2 interdigital space). The usage of dermatoglyphic traits as markers of predisposition of pituitary tumor development could facilitate the earlier detection of patients in addition to standard methods, and possibly earlier treatment and higher survival rate. Finally, our results are consistent with the hypothesis about multifactorial nature of pituitary tumor etiology comprised of both gene instability and environmental factors.

  14. Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics

    PubMed Central

    Corben, Adriana D.; Uddin, Mohammad M.; Crawford, Brooke; Farooq, Mohammad; Modi, Shanu; Gerecitano, John; Chiosis, Gabriela; Alpaugh, Mary L.

    2015-01-01

    The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy. PMID:25350385

  15. Ex vivo treatment response of primary tumors and/or associated metastases for preclinical and clinical development of therapeutics.

    PubMed

    Corben, Adriana D; Uddin, Mohammad M; Crawford, Brooke; Farooq, Mohammad; Modi, Shanu; Gerecitano, John; Chiosis, Gabriela; Alpaugh, Mary L

    2014-10-02

    The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy.

  16. Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics

    PubMed Central

    Crawford, Brooke; Farooq, Mohammad; Modi, Shanu; Gerecitano, John; Chiosis, Gabriela; Alpaugh, Mary L.

    2014-01-01

    The molecular analysis of established cancer cell lines has been the mainstay of cancer research for the past several decades. Cell culture provides both direct and rapid analysis of therapeutic sensitivity and resistance. However, recent evidence suggests that therapeutic response is not exclusive to the inherent molecular composition of cancer cells but rather is greatly influenced by the tumor cell microenvironment, a feature that cannot be recapitulated by traditional culturing methods. Even implementation of tumor xenografts, though providing a wealth of information on drug delivery/efficacy, cannot capture the tumor cell/microenvironment crosstalk (i.e., soluble factors) that occurs within human tumors and greatly impacts tumor response. To this extent, we have developed an ex vivo (fresh tissue sectioning) technique which allows for the direct assessment of treatment response for preclinical and clinical therapeutics development. This technique maintains tissue integrity and cellular architecture within the tumor cell/microenvironment context throughout treatment response providing a more precise means to assess drug efficacy. PMID:25350385

  17. Mandibular Brown Tumor of Secondary Hyperparathyroidism Requiring Extensive Resection: A Forgotten Entity in the Developed World?

    PubMed Central

    Qaisi, Mohammed; Loeb, Matthew; Montague, Lindsay; Caloss, Ron

    2015-01-01

    Brown tumor of hyperparathyroidism (BTHPT) is rare in the United States and not frequently seen in clinical practice. This is likely because early diagnosis and prompt treatment of this disease process prevent the progression and development of BTHPT. Conversely, BTHPT is more common in underdeveloped countries where fewer patients have access to health care and hyperparathyroidism (HPT) goes untreated. It has been reported that the incidence of BTHPT in underdeveloped countries can be as high as 58 to 69 percent in patients with primary HPT. We present a case report of a patient in the United States with a large mandibular BTHPT requiring an extensive resection in the setting of secondary HPT. Despite being rare in this country, it is important for nephrologists, primary care physicians, and oral health care providers to be able to recognize this entity, so that intervention may be rendered early. PMID:26413096

  18. Development of human serum albumin conjugated with near-infrared dye for photoacoustic tumor imaging

    NASA Astrophysics Data System (ADS)

    Kanazaki, Kengo; Sano, Kohei; Makino, Akira; Takahashi, Atsushi; Deguchi, Jun; Ohashi, Manami; Temma, Takashi; Ono, Masahiro; Saji, Hideo

    2014-09-01

    Photoacoustic (PA) imaging has emerged as a noninvasive diagnostic method which detects ultrasonic waves thermoelastically induced by optical absorbers irradiated with laser. For tumor diagnosis, PA contrast agent has been proposed to enhance the PA effect for detecting tumors sensitively. Here, we prepared a human serum albumin (HSA) conjugated with indocyanine green (ICG) as a PA contrast agent allowing enhanced permeability and retention effect for sensitive tumor imaging. The feasibility of PA imaging with HSA-ICG to detect allografted tumors was evaluated in tumor-bearing mice. In vivo fluorescence imaging and radiolabeled biodistribution study showed that the biodistribution dramatically changed as the number of ICG bound to HSA increased, and the maximum accumulation of ICG was achieved when around three ICG molecules were loaded on an HSA. In vivo PA imaging demonstrated a tumor-selective and dose-dependent increase of PA signal intensity in mice injected with HSA-ICG (R2=0.88, 387% increase for HSA-ICG, 104 nmol ICG). In conclusion, HSA-ICG clearly visualized the allografted tumors with high tumor-to-background ratios having high quantitative and spatial resolution for the sensitive PA imaging of tumors. HSA-ICG could be useful as a favorable contrast agent for PA tumor imaging for the management of cancer.

  19. Diet-induced obesity and mammary tumor development in MMTV-neu female mice.

    PubMed

    Cleary, Margot P; Grande, Joseph P; Juneja, Subhash C; Maihle, Nita J

    2004-01-01

    Obesity is a risk factor for postmenopausal breast cancer and is associated with shortened latency and/or increased mammary tumor (MT) incidence in animals. Elevated body weight is usually associated with hormone-responsive tumors. In agreement with these data we previously showed that latency of hormone-responsive MTs in MMTV-TGF-alpha mice with diet-induced obesity was significantly shortened. Here, we used the same protocol to determine the impact of diet-induced obesity on estrogen receptor-negative MT development in MMTV-neu (strain 202) mice. Mice were fed a low-fat diet (n=20) or a high-fat diet (n=54) from 10 wk of age. Body weight at 19 wk of age was used to assign high-fat mice to obesity-prone, overweight, and obesity-resistant groups. Mice were euthanized due to MT size or at 85 wk of age. Final body weights of obesity-prone mice were heaviest, and those of obesity-resistant and low-fat groups were similar. Fat pad weights were heaviest in obesity-prone mice followed by overweight and obesity-resistant groups, and lightest in low-fat mice. Serum IGF-I levels were similar for low-fat and high-fat mice, whereas leptin was higher in high-fat mice (P <0.0001). MT latency, incidence, metastasis, and burden were similar for all groups. These findings support that obesity is not a risk factor for development of estrogen-negative breast cancer.

  20. Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors

    PubMed Central

    Jin, Yingai Jane; Wang, Sally; Cho, Joshua; Selim, M. Angelica; Wright, Tim; Mosialos, George; Zhang, Jennifer Y.

    2016-01-01

    The deubiquitinase-encoding gene Cyld displays a dominant genetic linkage to a wide spectrum of skin-appendage tumors, which could be collectively designated as CYLD mutant–syndrome (CYLDm-syndrome). Despite recent advances, little is understood about the molecular mechanisms responsible for this painful and difficult-to-treat skin disease. Here, we generated a conditional mouse model with epidermis-targeted expression of a catalytically deficient CYLDm through K14-Cre–mediated deletion of exon 9 (hereafter refer to CyldEΔ9/Δ9). CyldEΔ9/Δ9 mice were born alive but developed hair and sebaceous gland abnormalities and dental defects at 100% and 60% penetrance, respectively. Upon topical challenge with DMBA/TPA, these animals primarily developed sebaceous and basaloid tumors resembling human CYLDm-syndrome as opposed to papilloma, which is most commonly induced in WT mice by this treatment. Molecular analysis revealed that TRAF6-K63-Ubiquitination (K63-Ub), c-Myc-K63-Ub, and phospho-c–Myc (S62) were markedly elevated in CyldEΔ9/Δ9 skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis in CyldEΔ9/Δ9 skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate that CyldEΔ9/Δ9 mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLDm-syndrome. PMID:27478875

  1. Radiation-induced mouse chimeras: a cellular analysis of the major lymphoid compartments, factors affecting lethal graft versus host disease and host-tumor interactions

    SciTech Connect

    Almaraz, R.

    1981-01-01

    The major lymphoid compartments of allogeneic bone marrow chimeras were evaluated for the extent of cell chimerism and distribution of Thy 1 and la bearing cells. These chimeras contained lymphoid cell primarily of donor origin. The bone marrow compartment was a mixture of host and donor origin cells. The distribution of Thy 1 and la bearing cells was similar as in normal mice. The effect of adult thymectomy alone or followed by whole-body irradiation and bone marrow reconstitution on the distribution of the Thy 1 positive cells was also investigated. Thymectomy with or without WBI and bone marrow reconstitution significantly lowered the number of Thy 1 bearing cells in the blood and spleen. The number of la bearing cells did not appear to be affected by thymectomy. The role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation induced fully allogeneic mouse chimeras was studied. Mice reconstituted with allogeneic bone marrow from bled donors had a statistically lower incidence of GVHD than those reconstituted with bone marrow from unbled donors. Addition of mature peripheral lymphocytes from blood to the reconstituting bone marrow cells from bled donors reduplicated the high incidence of lethal GVHD. It was demonstrated that the bone marrow of mice not exsanguinated prior to harvesting of bone marrow contained significant numbers of peripheral contaminating cells in the harvested bone marrow. The role of suppressor cell elimination in resisting tumor growth was investigated using radiation induced mouse chimeras. Local effects of irradiation alone at the site of tumor inoculation could account for this lack of growth.

  2. The Development of a Novel Cancer Immunotherapeutic Platform Using Tumor-targeting Mesenchymal Stem Cells and a Protein Vaccine

    PubMed Central

    Wei, Hon-Jian; Wu, Alexander TH; Hsu, Chung-Huei; Lin, Yi-Ping; Cheng, Wen-Fang; Su, Ching-Hua; Chiu, Wen-Ta; Whang-Peng, Jacqueline; Douglas, Frank L; Deng, Win-Ping

    2011-01-01

    An ideal anticancer strategy should target only the malignant cells but spare the normal ones. In this regard, we established a platform, consisting of an antigen-delivering vehicle and a protein vaccine, for developing an immunotherapeutic approach with the potential for eliminating various cancer types. Mesenchymal stem cells (MSCs) have been demonstrated capable of targeting tumors and integrating into the stroma. Moreover, we have developed a protein vaccine PE(ΔIII)-E7-KDEL3 which specifically recognized E7 antigen and elicited immunity against cervical cancer. Taking advantage of tumor-homing property of MSCs and PE(ΔIII)-E7-KDEL3, we used E6/E7-immortalized human MSCs (KP-hMSCs) as an E7 antigen-delivering vehicle to test if this protein vaccine could effectively eliminate non-E7-expressing tumor cells. Animals which received combined treatment of KP-hMSCs and PE(ΔIII)-E7-KDEL3 demonstrated a significant inhibition of tumor growth and lung-metastasis when compared to PE(ΔIII)-E7-KDEL3 only and KP-hMSCs only groups. The efficiency of tumor suppression correlated positively to the specific immune response induced by PE(ΔIII)-E7-KDEL3. In addition, this combined treatment inhibited tumor growth via inducing apoptosis. Our findings indicated that KP-hMSCs could be used as a tumor-targeting device and mediate antitumor effect of PE(ΔIII)-E7-KDEL3. We believe this strategy could serve as a platform for developing a universal vaccine for different cancer types. PMID:21792181

  3. Sequencing of Local Therapy Affects the Pattern of Treatment Failure and Survival in Children With Atypical Teratoid Rhabdoid Tumors of the Central Nervous System

    SciTech Connect

    Pai Panandiker, Atmaram S.; Merchant, Thomas E.; Beltran, Chris; Wu, Shengjie; Sharma, Shelly; Boop, Frederick A.; Jenkins, Jesse J.; Helton, Kathleen J.; Wright, Karen D.; Broniscer, Alberto; Kun, Larry E.; Gajjar, Amar

    2012-04-01

    Purpose: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). Methods and Materials: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. Results: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% {+-} 9%; progression-free survival was 33.2% {+-} 10%; and OS was 53.5% {+-} 10%. Children receiving delayed RT ({>=}1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. Conclusions: Delayed RT is associated with a higher rate of local and metastatic

  4. Cancer as a channelopathy: ion channels and pumps in tumor development and progression

    PubMed Central

    Litan, Alisa; Langhans, Sigrid A.

    2015-01-01

    Increasing evidence suggests that ion channels and pumps not only regulate membrane potential, ion homeostasis, and electric signaling in excitable cells but also play important roles in cell proliferation, migration, apoptosis and differentiation. Consistent with a role in cell signaling, channel proteins and ion pumps can form macromolecular complexes with growth factors, and cell adhesion and other signaling molecules. And while cancer is still not being cataloged as a channelopathy, as the non-traditional roles of ion pumps and channels are being recognized, it is increasingly being suggested that ion channels and ion pumps contribute to cancer progression. Cancer cell migration requires the regulation of adhesion complexes between migrating cells and surrounding extracellular matrix (ECM) proteins. Cell movement along solid surfaces requires a sequence of cell protrusions and retractions that mainly depend on regulation of the actin cytoskeleton along with contribution of microtubules and molecular motor proteins such as mysoin. This process is triggered and modulated by a combination of environmental signals, which are sensed and integrated by membrane receptors, including integrins and cadherins. Membrane receptors transduce these signals into downstream signaling pathways, often involving the Rho GTPase protein family. These pathways regulate the cytoskeletal rearrangements necessary for proper timing of adhesion, contraction and detachment of cells in order to find their way through extracellular spaces. Migration and adhesion involve continuous modulation of cell motility, shape and volume, in which ion channels and pumps play major roles. Research on cancer cells suggests that certain ion channels may be involved in aberrant tumor growth and channel inhibitors often lead to growth arrest. This review will describe recent research into the role of ion pumps and ion channels in cell migration and adhesion, and how they may contribute to tumor development

  5. Preemptive tumor profiling for biomarker-stratified early clinical drug development in metastatic breast cancer patients.

    PubMed

    Welt, Anja; Tewes, Mitra; Aktas, Bahriye; O Hoffmann, Oliver; Wiesweg, Marcel; Ting, Saskia; Reis, Henning; Worm, Karl; Richly, Heike; Hense, Jörg; Palmer, Michael R; Lee, Benjamin H; Wendling, Johanna; Kossow, Josef; Scheulen, Max E; Lehnerdt, Cathrin; Kohl, Marzena; Derks, Cordula; Skottky, Silke; Haus, Ulrike; Schmid, Kurt W; Kimmig, Rainer; Schuler, Martin; Kasper, Stefan

    2013-11-01

    Biomarker-stratified cancer pharmacotherapy was pioneered in the care of breast cancer patients. The utility of agents modulating hormone receptors, synthesis of steroid hormones, or HER2-targeting agents has been greatly enhanced by the detection of predictive biomarkers in diagnostic tumor samples. Based on deeper understanding of breast cancer biology multiple drug candidates have been developed to modulate additional molecular targets which may associate with specific biomarker profiles. Accordingly, exploratory biomarkers are increasingly incorporated in early clinical trials, thus demanding a new process of patient selection. Here, we describe the implementation of preemptive, multiplexed biomarker profiling linked to standard diagnostic algorithms for metastatic breast cancer patients treated at the West German Cancer Center. Profiling for experimental biomarkers was prospectively offered to patients with metastatic breast cancer who met generic clinical trial inclusion criteria. Formalin-fixed, paraffin-embedded tumor samples were retrieved and studied for potentially “actionable” biomarkers related to active clinical trials by immunohistochemistry, amplicon sequencing, and in situ hybridization. The clinical course of those “profiled” patients was closely monitored to offer trial participation whenever applicable. Here, we report results from the first 131 patients enrolled in this program. PIK3CA mutations (23 %) and amplifications (2 %), loss of PTEN expression (13 %), and FGFR1 amplifications (8 %) were detected next to established biomarkers such as estrogen (67 %) and progesterone receptor expression (52 %), and HER2 overexpression or amplification (23 %). So far 16 “profiled” patients (12 %) have been enrolled in biomarker-stratified early clinical trials. Preemptive profiling of investigational biomarkers can be integrated into the diagnostic algorithm of a large Comprehensive Cancer Center. Extensive administrative efforts are required

  6. Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development

    PubMed Central

    Hartwig, Sunny; Ho, Jacqueline; Pandey, Priyanka; MacIsaac, Kenzie; Taglienti, Mary; Xiang, Michael; Alterovitz, Gil; Ramoni, Marco; Fraenkel, Ernest; Kreidberg, Jordan A.

    2010-01-01

    Summary The Wilms' tumor suppressor 1 (WT1) gene encodes a DNA- and RNA-binding protein that plays an essential role in nephron progenitor differentiation during renal development. To identify WT1 target genes that might regulate nephron progenitor differentiation in vivo, we performed chromatin immunoprecipitation (ChIP) coupled to mouse promoter microarray (ChIP-chip) using chromatin prepared from embryonic mouse kidney tissue. We identified 1663 genes bound by WT1, 86% of which contain a previously identified, conserved, high-affinity WT1 binding site. To investigate functional interactions between WT1 and candidate target genes in nephron progenitors, we used a novel, modified WT1 morpholino loss-of-function model in embryonic mouse kidney explants to knock down WT1 expression in nephron progenitors ex vivo. Low doses of WT1 morpholino resulted in reduced WT1 target gene expression specifically in nephron progenitors, whereas high doses of WT1 morpholino arrested kidney explant development and were associated with increased nephron progenitor cell apoptosis, reminiscent of the phenotype observed in Wt1−/− embryos. Collectively, our results provide a comprehensive description of endogenous WT1 target genes in nephron progenitor cells in vivo, as well as insights into the transcriptional signaling networks controlled by WT1 that might direct nephron progenitor fate during renal development. PMID:20215353

  7. The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap

    PubMed Central

    Lavado, Alfonso; Ware, Michelle; Paré, Joshua; Cao, Xinwei

    2014-01-01

    The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation. Little is known about what controls the formation of the midline environment. We find that two components of the Hippo pathway, the tumor suppressor Nf2 (Merlin) and the transcriptional coactivator Yap (Yap1), regulate guidepost development and expression of the guidance cue Slit2 in mouse. During normal brain development, Nf2 suppresses Yap activity in neural progenitor cells to promote guidepost cell differentiation and prevent ectopic Slit2 expression. Loss of Nf2 causes malformation of midline guideposts and Slit2 upregulation, resulting in callosal agenesis. Slit2 heterozygosity and Yap deletion both restore callosal formation in Nf2 mutants. Furthermore, selectively elevating Yap activity in midline neural progenitors is sufficient to disrupt guidepost formation, upregulate Slit2 and prevent midline crossing. The Hippo pathway is known for its role in controlling organ growth and tumorigenesis. Our study identifies a novel role of this pathway in axon guidance. Moreover, by linking axon pathfinding and neural progenitor behaviors, our results provide an example of the intricate coordination between growth and wiring during brain development. PMID:25336744

  8. Tumor protein Tctp regulates axon development in the embryonic visual system

    PubMed Central

    Roque, Cláudio Gouveia; Wong, Hovy Ho-Wai; Lin, Julie Qiaojin; Holt, Christine E.

    2016-01-01

    The transcript encoding translationally controlled tumor protein (Tctp), a molecule associated with aggressive breast cancers, was identified among the most abundant in genome-wide screens of axons, suggesting that Tctp is important in neurons. Here, we tested the role of Tctp in retinal axon development in Xenopus laevis. We report that Tctp deficiency results in stunted and splayed retinotectal projections that fail to innervate the optic tectum at the normal developmental time owing to impaired axon extension. Tctp-deficient axons exhibit defects associated with mitochondrial dysfunction and we show that Tctp interacts in the axonal compartment with myeloid cell leukemia 1 (Mcl1), a pro-survival member of the Bcl2 family. Mcl1 knockdown gives rise to similar axon misprojection phenotypes, and we provide evidence that the anti-apoptotic activity of Tctp is necessary for the normal development of the retinotectal projection. These findings suggest that Tctp supports the development of the retinotectal projection via its regulation of pro-survival signalling and axonal mitochondrial homeostasis, and establish a novel and fundamental role for Tctp in vertebrate neural circuitry assembly. PMID:26903505

  9. Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development.

    PubMed

    Hartwig, Sunny; Ho, Jacqueline; Pandey, Priyanka; Macisaac, Kenzie; Taglienti, Mary; Xiang, Michael; Alterovitz, Gil; Ramoni, Marco; Fraenkel, Ernest; Kreidberg, Jordan A

    2010-04-01

    The Wilms' tumor suppressor 1 (WT1) gene encodes a DNA- and RNA-binding protein that plays an essential role in nephron progenitor differentiation during renal development. To identify WT1 target genes that might regulate nephron progenitor differentiation in vivo, we performed chromatin immunoprecipitation (ChIP) coupled to mouse promoter microarray (ChIP-chip) using chromatin prepared from embryonic mouse kidney tissue. We identified 1663 genes bound by WT1, 86% of which contain a previously identified, conserved, high-affinity WT1 binding site. To investigate functional interactions between WT1 and candidate target genes in nephron progenitors, we used a novel, modified WT1 morpholino loss-of-function model in embryonic mouse kidney explants to knock down WT1 expression in nephron progenitors ex vivo. Low doses of WT1 morpholino resulted in reduced WT1 target gene expression specifically in nephron progenitors, whereas high doses of WT1 morpholino arrested kidney explant development and were associated with increased nephron progenitor cell apoptosis, reminiscent of the phenotype observed in Wt1(-/-) embryos. Collectively, our results provide a comprehensive description of endogenous WT1 target genes in nephron progenitor cells in vivo, as well as insights into the transcriptional signaling networks controlled by WT1 that might direct nephron progenitor fate during renal development.

  10. The tumor suppressor Nf2 regulates corpus callosum development by inhibiting the transcriptional coactivator Yap.

    PubMed

    Lavado, Alfonso; Ware, Michelle; Paré, Joshua; Cao, Xinwei

    2014-11-01

    The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation. Little is known about what controls the formation of the midline environment. We find that two components of the Hippo pathway, the tumor suppressor Nf2 (Merlin) and the transcriptional coactivator Yap (Yap1), regulate guidepost development and expression of the guidance cue Slit2 in mouse. During normal brain development, Nf2 suppresses Yap activity in neural progenitor cells to promote guidepost cell differentiation and prevent ectopic Slit2 expression. Loss of Nf2 causes malformation of midline guideposts and Slit2 upregulation, resulting in callosal agenesis. Slit2 heterozygosity and Yap deletion both restore callosal formation in Nf2 mutants. Furthermore, selectively elevating Yap activity in midline neural progenitors is sufficient to disrupt guidepost formation, upregulate Slit2 and prevent midline crossing. The Hippo pathway is known for its role in controlling organ growth and tumorigenesis. Our study identifies a novel role of this pathway in axon guidance. Moreover, by linking axon pathfinding and neural progenitor behaviors, our results provide an example of the intricate coordination between growth and wiring during brain development.

  11. Development of a Novel PET Tracer [18F]AlF-NOTA-C6 Targeting MMP2 for Tumor Imaging

    PubMed Central

    Cheng, Chao; Zhang, Dazhi; Zhang, Anyu; Wang, Lizhen; Jiang, Hongdie; Wang, Tao; Liu, Hongrui; Xu, Yuping; Yang, Runlin; Chen, Fei; Yang, Min; Zuo, Changjing

    2015-01-01

    Background and Objective The overexpression of gelatinases, that is, matrix metalloproteinase MMP2 and MMP9, has been associated with tumor progression, invasion, and metastasis. To image MMP2 in tumors, we developed a novel ligand termed [18F]AlF-NOTA-C6, with consideration that: c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor; Cy5.5-C6 has been visualized in many in vivo tumor models; positron emission tomography (PET) has a higher detection sensitivity and a wider field of view than optical imaging; fluorine-18 (18F) is the optimal PET radioisotope, and the creation of a [18F]AlF-peptide complex is a simple procedure. Methods C6 was conjugated to the bifunctional chelator NOTA (1, 4, 7-triazacyclononanetriacetic acid) for radiolabeling [18F]AlF conjugation. The MMP2-binding characteristics and tumor-targeting efficacy of [18F]AlF-NOTA-C6 were tested in vitro and in vivo. Results The non-decay corrected yield of [18F]AlF-NOTA-C6 was 46.2–64.2%, and the radiochemical purity exceeded 95%. [18F]AlF-NOTA-C6 was favorably retained in SKOV3 and PC3 cells, determined by cell uptake. Using NOTA-C6 as a competitive ligand, the uptake of [18F]AlF-NOTA-C6 in SKOV3 cells decreased in a dose-dependent manner. In biodistribution and PET imaging studies, higher radioactivity concentrations were observed in tumors. Pre-injection of C6 caused a marked reduction in tumor tissue uptake. Immunohistochemistry showed MMP2 in tumor tissues. Conclusions [18F]AlF-NOTA-C6 was easy to synthesize and has substantial potential as an imaging agent that targets MMP2 in tumors. PMID:26540114

  12. FGF receptor antagonism does not affect adipose tissue development in nutritionally induced obesity.

    PubMed

    Scroyen, Ilse; Vranckx, Christine; Lijnen, Henri Roger

    2014-01-01

    The fibroblast growth factor (FGF)-FGF receptor (FGFR) system plays a role in angiogenesis and maintenance of vascular integrity, but its potential role in adipose tissue related angiogenesis and development is still unknown. Administration of SSR, a low molecular weight inhibitor of multiple FGFRs, did not significantly affect body weight nor weight of subcutaneous or gonadal (GON) fat, as compared with pair-fed control mice. Adipocyte hypertrophy and reduced adipocyte density were only observed in GON adipose tissues of treated mice. Adipose tissue angiogenesis was not affected by SSR treatment, as normalized blood vessel density was comparable in adipose tissues of both groups. Blocking the FGF-FGFR system in vivo does not markedly affect adipose tissue development in mice with nutritionally induced obesity.

  13. Soy Promotes Juvenile Granulosa Cell Tumor Development in Mice and in the Human Granulosa Cell Tumor-Derived COV434 Cell Line1

    PubMed Central

    Mansouri-Attia, Nadéra; James, Rebecca; Ligon, Alysse; Li, Xiaohui; Pangas, Stephanie A.

    2014-01-01

    ABSTRACT Soy attracts attention for its health benefits, such as lowering cholesterol or preventing breast and colon cancer. Soybeans contain isoflavones, which act as phytoestrogens. Even though isoflavones have beneficial health effects, a role for isoflavones in the initiation and progression of diseases including cancer is becoming increasingly recognized. While data from rodent studies suggest that neonatal exposure to genistein (the predominant isoflavone in soy) disrupts normal reproductive function, its role in ovarian cancers, particularly granulosa cell tumors (GCT), is largely unknown. Our study aimed to define the contribution of a soy diet in GCT development using a genetically modified mouse model for juvenile GCTs (JGCT; Smad1 Smad5 conditional double knockout mice) as well as a human JGCT cell line (COV434). While dietary soy cannot initiate JGCT development in mice, we show that it has dramatic effects on GCT growth and tumor progression compared to a soy-free diet. Loss of Smad1 and Smad5 alters estrogen receptor alpha (Esr1) expression in granulosa cells, perhaps sensitizing the cells to the effects of genistein. In addition, we found that genistein modulates estrogen receptor expression in the human JGCT cell line and positively promotes cell growth in part by suppressing caspase-dependent apoptosis. Combined, our work suggests that dietary soy consumption has deleterious effects on GCT development. PMID:25165122

  14. A modified neural network model of tumor cell interactions and subpopulation dynamics.

    PubMed

    Prideaux, J A; Mikulecky, D C; Clarke, A M; Ware, J L

    1993-01-01

    Tumors consist of phenotypically heterogeneous subpopulations of cells which are frequently affected by both autocrine and paracrine factors. Applying concepts from neural network theory, we have developed a computer model of chemical communication among hypothetical tumor cells, which simulates some of the complex epigenetic behavior of real tumors. Deletion of subpopulations often destabilized the whole population. The impact of deletion of specific subpopulations was affected by (a) which subpopulation was deleted, and (b) the timing of the deletion during tumor progression.

  15. A Dilemma about Homemakers' Involvement in Developing Public Policies That Affect the Family.

    ERIC Educational Resources Information Center

    Long, James S.

    As a society, we believe that persons affected by a public decision should be represented in the development of that policy. The Family Community Leadership program (FCL), recently launched in Alaska, Colorado, Hawaii, New Mexico, Oregon, and Washington, has been established to increase homemakers' understanding of social concerns that influence…

  16. Dogs in the Hall: A Case Study of Affective Skill Development in an Urban Veterinary Program

    ERIC Educational Resources Information Center

    Martin, Michael; Tummons, John; Ball, Anna; Bird, William

    2014-01-01

    The purpose of this bounded single case study was to explore how an urban high school veterinary program impacted students' affective skill development. The program was unique because students were required to participate in internships with local animal care businesses and care for animals within the school veterinary laboratory. The…

  17. A Sharing Experience: Development of a Group for Families Affected by HIV Infection.

    ERIC Educational Resources Information Center

    Melvin, Diane; Appleby, Sue

    1995-01-01

    Describes the establishment and development of a support group for the parents of children infected and/or affected by HIV infection. The group is hospital-based, meeting monthly since April 1992, facilitated by professionals but with a self-help and peer support emphasis. Explains the planning, setting, and running of the group. Identifies…

  18. Factors that Affect Emergent Literacy Development When Engaging with Electronic Books

    ERIC Educational Resources Information Center

    Salmon, Lynda G.

    2014-01-01

    This article reviews extant literature with the purpose of identifying factors that affect the potential efficacy of electronic books to support literacy development during early childhood. Selection criteria include experimental, quasi-experimental, and observational studies from peer-reviewed journals from 2000 to 2013 with a target population…

  19. On the Affective Challenges of Developing a Pedagogy of Teacher Education

    ERIC Educational Resources Information Center

    Ritter, Jason K.

    2011-01-01

    This article reports on the affective challenges I experienced while attempting to develop a pedagogy of teacher education during my first three years in teacher preparation. Data were collected systematically over the course of the study in the form of written interpretive accounts of my experiences. Analysis of these accounts revealed how…

  20. Early Experiences Can Alter Gene Expression and Affect Long-Term Development. Working Paper #10

    ERIC Educational Resources Information Center

    National Scientific Council on the Developing Child, 2010

    2010-01-01

    New scientific research shows that environmental influences can actually affect whether and how genes are expressed. Thus, the old ideas that genes are "set in stone" or that they alone determine development have been disproven. In fact, scientists have discovered that early experiences can determine how genes are turned on and off and even…

  1. Does Intellectual Disability Affect the Development of Dental Caries in Patients with Cerebral Palsy?

    ERIC Educational Resources Information Center

    Moreira, Rafaela Nogueira; Alcantara, Carlos Eduardo Pinto; Mota-Veloso, Isabella; Marinho, Sandra Aparecida; Ramos-Jorge, Maria L.; Oliveira-Ferreira, Fernanda

    2012-01-01

    The aim of this study was to evaluate if the severity of intellectual disability is a factor that affects the development of dental cavities in patients with cerebral palsy. This cross-sectional study was conducted on 165 individuals who were selected from a physical rehabilitation center, a special public school and a regular public school. Of…

  2. The Development of an Emotional Response to Literature Measure: The Affective Response to Literature Survey

    ERIC Educational Resources Information Center

    Fischer, Ronald G.; Fischer, Jerome M.

    2006-01-01

    Based on theories of emotional intelligence, adult education, psychology of reading, and emotions and literature, this study was designed to develop and validate the Affective Response to Literature Survey (ARLS), a psychological instrument used to measure an emotional response to literature. Initially, 27 items were generated by a review of…

  3. The Effect of Differentiation Approach Developed on Creativity of Gifted Students: Cognitive and Affective Factors

    ERIC Educational Resources Information Center

    Altintas, Esra; Özdemir, Ahmet S.

    2015-01-01

    The aim of the study is to develop a differentiation approach for the mathematics education of gifted middle school students and to determine the effect of the differentiation approach on creative thinking skills of gifted students based on both cognitive and affective factors. In this context, the answer to the following question was searched:…

  4. Applying a Cognitive-Affective Model of Conceptual Change to Professional Development

    ERIC Educational Resources Information Center

    Ebert, Ellen K.; Crippen, Kent J.

    2010-01-01

    This study evaluated Gregoire's (2003) Cognitive-Affective Conceptual Change model (CAMCC) for predicting and assessing conceptual change in science teachers engaged in a long-term professional development project set in a large school district in the southwestern United States. A multiple case study method with data from three teacher…

  5. Variables Affecting the Effects of Recasts on L2 Pronunciation Development

    ERIC Educational Resources Information Center

    Saito, Kazuya

    2015-01-01

    The current study investigated how recasts can promote the L2 pronunciation development of word-initial /?/ by Japanese learners of English in relation to two developmental stages of English /?/ acquisition (i.e. change in second formant [F2] ? change in third formant [F3]) as well as four affecting variables (i.e. the amount of recasts and…

  6. 75 FR 16490 - Prospective Grant of Exclusive License: Development of PANVAC and Tumor Associated Antigens as...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-01

    ... tumor-specific immune response. Specifically, these antigens serve as targets for the host immune system and elicit responses that results in tumor destruction. The initiation of an effective T-cell immune... antigens (TAAs) to activate T-cells and break the immune systems tolerance towards cancer cells. This...

  7. Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

    PubMed Central

    Kaiser, Sergio; Park, Young-Kyu; Franklin, Jeffrey L; Halberg, Richard B; Yu, Ming; Jessen, Walter J; Freudenberg, Johannes; Chen, Xiaodi; Haigis, Kevin; Jegga, Anil G; Kong, Sue; Sakthivel, Bhuvaneswari; Xu, Huan; Reichling, Timothy; Azhar, Mohammad; Boivin, Gregory P; Roberts, Reade B; Bissahoyo, Anika C; Gonzales, Fausto; Bloom, Greg C; Eschrich, Steven; Carter, Scott L; Aronow, Jeremy E; Kleimeyer, John; Kleimeyer, Michael; Ramaswamy, Vivek; Settle, Stephen H; Boone, Braden; Levy, Shawn; Graff, Jonathan M; Doetschman, Thomas; Groden, Joanna; Dove, William F; Threadgill, David W; Yeatman, Timothy J; Coffey, Robert J; Aronow, Bruce J

    2007-01-01

    Background The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5. Results We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear β-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF). Conclusion Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and

  8. Language Development and Learning to Read: The Scientific Study of How Language Development Affects Reading Skill

    ERIC Educational Resources Information Center

    McGuinness, Diane

    2005-01-01

    Research on reading has tried, and failed, to account for wide disparities in reading skill even among children taught by the same method. Why do some children learn to read easily and quickly while others, in the same classroom and taught by the same teacher, don't learn to read at all? In "Language Development and Learning to Read", Diane…

  9. Failure of ozone and nitrogen dioxide to enhance lung tumor development in hamsters. Research report, January 1989-March 1992

    SciTech Connect

    Witschi, H.; Breider, M.A.; Schuller, H.M.

    1993-09-01

    The authors tested the hypothesis that ozone and nitrogen dioxide modulate the development of respiratory tract tumors, in particular neuroendocrine cell tumors, in Syrian golden hamsters. The animals received subcutaneous injections of the carcinogen N-diethylnitrosamine (20 mg/kg) twice a week while being exposed continuously to an atmosphere of 0.8 parts per million (ppm) of ozone or 15 ppm nitrogen dioxide. Animals were killed 16 weeks or 24 to 32 weeks after the beginning of the treatment. For positive controls, animals were treated with N-diethylnitrosamine and exposed to 65% oxygen. Ozone delayed the incidence of tumors in the lung periphery. Ozone also seemed to mitigate development of hepatoxic lesions mediated by N-diethylnitrosamine. The role of ozone and nitrogen dioxide as possible additional risks in the pathogenesis of lung cancer in animals continues to remain uncertain.

  10. Influence of chronic prolactin suppression during puberty on the development of dimethylbenz(a)anthracene-induced mammary tumors (41163). [Rats

    SciTech Connect

    Cohen, L.A.

    1981-06-01

    In order to assess the effect of early prolactin suppression on the subsequent development of dimethylbenz(a)anthracene (DMBA)-induced mammary cancers, the dopamine agonist, CB-154, was chronically administered to female Sprague-Dawley rats from Day 35 to Day 50 of age. DMBA was then administered and tumor development assessed over a 25-week period. It was found that animals treated with CB-154 exhibited decreased tumor incidence, a longer latent period, and fewer tumors/animal, when compared to vehicle controls. These results are consistent with the hypothesis that the sensitivity of the mammary gland to polycyclic aromatic hydrocarbon (PAH) carcinogenesis is determined by the level of differentiation of the gland at the time of carcinogen administration. Accordingly, perturbations in prolactin secretion patterns, early in life, may accelerate or retard the differentiation of the mammary gland thereby rendering it less susceptible to the carcinogenic effects of PAH.

  11. The bad seed: Cancer stem cells in tumor development and resistance.

    PubMed

    Koren, Elle; Fuchs, Yaron

    2016-09-01

    Over the past two decades cancer stem cells (CSCs) have emerged as essential players in the pathogenesis of cancer, with the capacity to initiate, maintain and repopulate different tumors. Within the tumor bulk, CSCs represent a small subpopulation, bestowed with the capacity to self-renew and yield heterogeneous lineages of cancer cells. In many scenarios, CSCs exhibit increased resistance toward irradiation and chemotherapy, and given their spectacular ability to replenish the tumor, they constitute a substantial therapeutic challenge. In this review, we provide a brief overview of the concept of CSCs and the experimental methodology utilized for identifying and isolating these unique cells. We discuss how CSCs are regulated within the tumor microenvironment as well as the role they portray in seeding fresh tumors. Finally, we explore the mechanisms that enable CSCs to evade modern therapeutic approaches and the possible strategies that can be utilized to prevent CSCs from resurrecting the disease.

  12. The bad seed: Cancer stem cells in tumor development and resistance.

    PubMed

    Koren, Elle; Fuchs, Yaron

    2016-09-01

    Over the past two decades cancer stem cells (CSCs) have emerged as essential players in the pathogenesis of cancer, with the capacity to initiate, maintain and repopulate different tumors. Within the tumor bulk, CSCs represent a small subpopulation, bestowed with the capacity to self-renew and yield heterogeneous lineages of cancer cells. In many scenarios, CSCs exhibit increased resistance toward irradiation and chemotherapy, and given their spectacular ability to replenish the tumor, they constitute a substantial therapeutic challenge. In this review, we provide a brief overview of the concept of CSCs and the experimental methodology utilized for identifying and isolating these unique cells. We discuss how CSCs are regulated within the tumor microenvironment as well as the role they portray in seeding fresh tumors. Finally, we explore the mechanisms that enable CSCs to evade modern therapeutic approaches and the possible strategies that can be utilized to prevent CSCs from resurrecting the disease. PMID:27620951

  13. Photodynamic therapy: development of a treatment and dosimetry system adapted to superficial tumors of the bladder

    NASA Astrophysics Data System (ADS)

    Lignon, Dominique; Jaboin, Y.; Wolf, D.; Meunier-Reynes, Anne; Guillemin, Francois H.

    1993-06-01

    Superficial tumors of the bladder or in situ carcinoma could be interesting indications of Photodynamic Therapy (PDT), since a total mutilating cystectomy could be avoided. The plurifocality of the lesions requires a treatment of the whole mucose; the quantity of light energy must be homogenous and sufficient to induce a therapeutic effect, still non toxic for normal tissues. We therefore developed a system of treatment and intravesical dosimetry control so that the operator can have precise information on the light repartition in the bladder in real time to enable him to optimize the positioning of the irradiation source. This intravesical device consists of twelve light sensors with optical fiber distributed symmetrically against the walls of the bladder; the emitting source is constituted of a scattering isotropic sphere. The signals emitted by the sensors are converted into tension. The acquisition part of the system values consists of two parts : an analogic part, the values are multiplexed on a same oscilloscope track to see in real time their evolution according to the position of the emitting source. The other part is constituted by the numeric acquisition of values for further analysis. We developed, from a mathematical modelisation of the bladder, a centering program of the diffusor that indicates its position in the bladder, as well as a cartography program where the bladder is re-built by interpolation with the different lighting levels.

  14. AKT activation promotes PTEN hamartoma tumor syndrome-associated cataract development.

    PubMed

    Sellitto, Caterina; Li, Leping; Gao, Junyuan; Robinson, Michael L; Lin, Richard Z; Mathias, Richard T; White, Thomas W

    2013-12-01

    Mutations in the human phosphatase and tensin homolog (PTEN) gene cause PTEN hamartoma tumor syndrome (PHTS), which includes cataract development among its diverse clinical pathologies. Currently, it is not known whether cataract formation in PHTS patients is secondary to other systemic problems, or the result of the loss of a critical function of PTEN within the lens. We generated a mouse line with a lens-specific deletion of Pten (PTEN KO) and identified a regulatory function for PTEN in lens ion transport. Specific loss of PTEN in the lens resulted in cataract. PTEN KO lenses exhibited a progressive age-related increase in intracellular hydrostatic pressure, along with, increased intracellular sodium concentrations, and reduced Na+/K+-ATPase activity. Collectively, these defects lead to lens swelling, opacities and ultimately organ rupture. Activation of AKT was highly elevated in PTEN KO lenses compared to WT mice. Additionally, pharmacological inhibition of AKT restored normal Na+/K+-ATPase activity in primary cultured lens cells and reduced lens pressure in intact lenses from PTEN KO animals. These findings identify a direct role for PTEN in the regulation of lens ion transport through an AKT-dependent modulation of Na+/K+-ATPase activity, and provide a new animal model to investigate cataract development in PHTS patients. PMID:24270425

  15. Deiodinase knockdown during early zebrafish development affects growth, development, energy metabolism, motility and phototransduction.

    PubMed

    Bagci, Enise; Heijlen, Marjolein; Vergauwen, Lucia; Hagenaars, An; Houbrechts, Anne M; Esguerra, Camila V; Blust, Ronny; Darras, Veerle M; Knapen, Dries

    2015-01-01

    Thyroid hormone (TH) balance is essential for vertebrate development. Deiodinase type 1 (D1) and type 2 (D2) increase and deiodinase type 3 (D3) decreases local intracellular levels of T3, the most important active TH. The role of deiodinase-mediated TH effects in early vertebrate development is only partially understood. Therefore, we investigated the role of deiodinases during early development of zebrafish until 96 hours post fertilization at the level of the transcriptome (microarray), biochemistry, morphology and physiology using morpholino (MO) knockdown. Knockdown of D1+D2 (D1D2MO) and knockdown of D3 (D3MO) both resulted in transcriptional regulation of energy metabolism and (muscle) development in abdomen and tail, together with reduced growth, impaired swim bladder inflation, reduced protein content and reduced motility. The reduced growth and impaired swim bladder inflation in D1D2MO could be due to lower levels of T3 which is known to drive growth and development. The pronounced upregulation of a large number of transcripts coding for key proteins in ATP-producing pathways in D1D2MO could reflect a compensatory response to a decreased metabolic rate, also typically linked to hypothyroidism. Compared to D1D2MO, the effects were more pronounced or more frequent in D3MO, in which hyperthyroidism is expected. More specifically, increased heart rate, delayed hatching and increased carbohydrate content were observed only in D3MO. An increase of the metabolic rate, a decrease of the metabolic efficiency and a stimulation of gluconeogenesis using amino acids as substrates may have been involved in the observed reduced protein content, growth and motility in D3MO larvae. Furthermore, expression of transcripts involved in purine metabolism coupled to vision was decreased in both knockdown conditions, suggesting that both may impair vision. This study provides new insights, not only into the role of deiodinases, but also into the importance of a correct TH balance

  16. Deiodinase Knockdown during Early Zebrafish Development Affects Growth, Development, Energy Metabolism, Motility and Phototransduction

    PubMed Central

    Bagci, Enise; Heijlen, Marjolein; Vergauwen, Lucia; Hagenaars, An; Houbrechts, Anne M.; Esguerra, Camila V.; Blust, Ronny; Darras, Veerle M.; Knapen, Dries

    2015-01-01

    Thyroid hormone (TH) balance is essential for vertebrate development. Deiodinase type 1 (D1) and type 2 (D2) increase and deiodinase type 3 (D3) decreases local intracellular levels of T3, the most important active TH. The role of deiodinase-mediated TH effects in early vertebrate development is only partially understood. Therefore, we investigated the role of deiodinases during early development of zebrafish until 96 hours post fertilization at the level of the transcriptome (microarray), biochemistry, morphology and physiology using morpholino (MO) knockdown. Knockdown of D1+D2 (D1D2MO) and knockdown of D3 (D3MO) both resulted in transcriptional regulation of energy metabolism and (muscle) development in abdomen and tail, together with reduced growth, impaired swim bladder inflation, reduced protein content and reduced motility. The reduced growth and impaired swim bladder inflation in D1D2MO could be due to lower levels of T3 which is known to drive growth and development. The pronounced upregulation of a large number of transcripts coding for key proteins in ATP-producing pathways in D1D2MO could reflect a compensatory response to a decreased metabolic rate, also typically linked to hypothyroidism. Compared to D1D2MO, the effects were more pronounced or more frequent in D3MO, in which hyperthyroidism is expected. More specifically, increased heart rate, delayed hatching and increased carbohydrate content were observed only in D3MO. An increase of the metabolic rate, a decrease of the metabolic efficiency and a stimulation of gluconeogenesis using amino acids as substrates may have been involved in the observed reduced protein content, growth and motility in D3MO larvae. Furthermore, expression of transcripts involved in purine metabolism coupled to vision was decreased in both knockdown conditions, suggesting that both may impair vision. This study provides new insights, not only into the role of deiodinases, but also into the importance of a correct TH balance

  17. Development and Evaluation of a Tumor Marker for Prostate Cancer — EDRN Public Portal

    Cancer.gov

    Major strides in the early detection, staging, monitoring, and risk stratification of men with prostate cancer have been realized over the last few decades. We have recently witnessed a reduction in the death rate for prostate cancer, stage migration with increased numbers of men with local/regional disease, and a greater understanding of the natural history of progression following recurrence. These advances, while not solely dependant on biomarkers, can be attributed to the discovery of Prostate Specific Antigen (PSA) in the late 1970's. In the wake of these discoveries, we still continue to unnecessarily biopsy men at risk for having prostate cancer to identify the 1:4 with the disease, understage men with presumed local disease, continue to lack an accurate method for staging which can direct treatment options for the individual patient and continue to poorly understand the tumor biology and kinetics of disease progression. Clearly, discovery of a new tumor marker and validation/clinical investigation of the markers are mandatory to advance our knowledge and direct the care of men with prostate cancer. With this research, we intend to evaluate the clinical, diagnostic, and prognostic accuracy of new and existing biomarkers on a prospective serum bank collected from men either participating in early detection programs or engaging in pre or post treatment situations. By increasing our clinical research and specimen collections we hope to further advance the staging and direction for treatment in men with prostate cancer. This study approaches patients scheduled for a prostate biopsy, patients visiting the Urology Outpatient Clinic with PSA elevation, patients scheduled for radical prostatectomy, prostate cancer patients with scheduled appointments in Radiation Oncology and men participating in early prostate cancer detection screenings. Subjects will be excluded from the study if: 1) Subjects have any mental impairment that would hinder the ability to provide

  18. The K-Ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice

    SciTech Connect

    Plowman, Sarah J.; Arends, Mark J.; Brownstein, David G.; Luo Feijun; Devenney, Paul S.; Rose, Lorraine; Ritchie, Ann-Marie; Berry, Rachel L.; Harrison, David J.; Hooper, Martin L.; Patek, Charles E. . E-mail: Charles.Patek@ed.ac.uk

    2006-01-01

    Ras proteins function as molecular switches in signal transduction pathways, and, here, we examined the effects of the K-ras4A and 4B splice variants on cell function by comparing wild-type embryonic stem (ES) cells with K-ras {sup tm{delta}}{sup 4A/tm{delta}}{sup 4A} (exon 4A knock-out) ES cells which express K-ras4B only and K-ras {sup -/-} (exons 1-3 knock-out) ES cells which express neither splice variant, and intestinal epithelium from wild-type and K-ras {sup tm{delta}}{sup 4A/tm{delta}}{sup 4A} mice. RT-qPCR analysis found that K-ras4B expression was reduced in K-ras {sup tm{delta}}{sup 4A/tm{delta}}{sup 4A} ES cells but unaffected in small intestine. K-Ras deficiency did not affect ES cell growth, and K-Ras4A deficiency did not affect intestinal epithelial proliferation. K-ras {sup tm{delta}}{sup 4A/tm{delta}}{sup 4A} and K-ras {sup -/-} ES cells showed a reduced capacity for differentiation following LIF withdrawal, and K-ras {sup -/-} cells were least differentiated. K-Ras4A deficiency inhibited etoposide-induced apoptosis in ES cells and intestinal epithelial cells. However, K-ras {sup tm{delta}}{sup 4A/tm{delta}}{sup 4A} ES cells were more resistant to etoposide-induced apoptosis than K-ras {sup -/-} cells. The results indicate that (1) K-Ras4A promotes apoptosis while K-Ras4B inhibits it, and (2) K-Ras4B, and possibly K-Ras4A, promotes differentiation. The findings raise the possibility that alteration of the K-Ras4A/4B isoform ratio modulates tumorigenesis by differentially affecting stem cell survival and/or differentiation. However, K-Ras4A deficiency did not affect life expectancy or spontaneous overall tumor incidence in aging mice.

  19. Development of neuroendocrine tumors in the gastrointestinal tract of transgenic mice. Heterogeneity of hormone expression.

    PubMed Central

    Rindi, G.; Grant, S. G.; Yiangou, Y.; Ghatei, M. A.; Bloom, S. R.; Bautch, V. L.; Solcia, E.; Polak, J. M.

    1990-01-01

    Expression of hormones in endocrine tumors and derived cell lines of transgenic mice carrying insulin-promoted oncogenes has been investigated by histochemical, immunohistochemical, ultrastructural, and radioimmunologic means. Tumors of the pancreas, small intestine, mesentery, and liver were examined. Insulin-immunoreactive cells were prevalent in pancreatic tumors, with a significant subpopulation of pancreatic polypeptide-immunoreactive elements. Conventional ultrastructural and immunogold analysis identified insulin-storing beta granules in pancreatic tumor cells. In contrast, the largest immunoreactive subpopulation of intestinal tumors expressed secretin (53% of total cells), followed by proglucagon-related peptides (15%), glucose-dependent insulinotropic polypeptide (7%), gastrin (7%), pancreatic polypeptide (2%), neurotensin (2%), and somatostatin (1%). No detectable immunoreactivity for either insulin or serotonin was observed. Electron microscopy and immunogold labeling showed that intestinal tumor cells contained secretin-storing S-type granules. Lymph node and liver tumors contained secretin-immunoreactive cells with ultrastructural features similar to those of intestinal tumors. In addition, high levels of circulating insulinlike and secretinlike immunoreactants were detectable. Analogous hormone profiles were identified in tumor cell lines and culture media. Large T-antigen immunoreactivity was detected in all the nuclei of neoplastic cells, as well as in insulin-immunoreactive elements of non-neoplastic islets and pancreatic ducts and in some secretin-immunoreactive cells of small intestinal mucosa. These data indicate that neuroendocrine tumors arise both in beta cell and S-cell subpopulations of transgenic mice. Images Figure 5 Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:2162628

  20. Tumor necrosis factor alpha signaling in the development of experimental murine pre-hepatic portal hypertension

    PubMed Central

    Theodorakis, Nicholas G; Wang, Yining N; Wu, Jianmin; Maluccio, Mary A; Skill, Nicholas J

    2010-01-01

    The cytokine tumor necrosis factor alpha (TNFa) has previously been identified in the development of portal hypertension (PHT) by facilitating portal venous and systemic hyperemia. TNFa is reported to contribute to hyperemia via endothelial nitric oxide synthase (eNOS) induction and nitric oxide (NO) production. This study examines this hypothesis by utilizing TNFa receptor knockout mice and a murine model of pre-hepatic PHT. Plasma TNFa and NOx and tissue TNFa mRNA levels were determined in wild-type mice 0-7d post induction of pre-hepatic PHT by partial portal vein ligation (PVL). TNFa receptor knockout mice also received PVL or sham surgery and splenic pulp pressure, abdominal aortic flow and portal-systemic shunting were recorded 7d following. Portal pressure and systemic hyperemia developed rapidly following PVL. Plasma NOx was increased temporarily 2-3 days following PVL and returned to baseline by day 7. Circulating TNFa was below detectable limits of the ELISA used, as such no increase was observed. Hepatic and vascular TNFa mRNA levels were transiently changed after PVL otherwise there was no significant change. TNFa receptor targeted gene deletion did not ameliorate plasma NOx following PVL and had no effect on the development of PHT. TNFa receptor signaling plays no detectable role in the development of systemic hyperemia in the murine model of pre-hepatic PHT. Consequently, increased TNFa observed in intra-hepatic inflammatory models (CCl4) and in patients is probably related to inflammation associated with intra-hepatic pathology. Alternatively, TNFa may be signaling via a TNFa receptor independent mechanism. PMID:21383890

  1. Anthropogenic changes in sodium affect neural and muscle development in butterflies

    PubMed Central

    Snell-Rood, Emilie C.; Espeset, Anne; Boser, Christopher J.; White, William A.; Smykalski, Rhea

    2014-01-01

    The development of organisms is changing drastically because of anthropogenic changes in once-limited nutrients. Although the importance of changing macronutrients, such as nitrogen and phosphorus, is well-established, it is less clear how anthropogenic changes in micronutrients will affect organismal development, potentially changing dynamics of selection. We use butterflies as a study system to test whether changes in sodium availability due to road salt runoff have significant effects on the development of sodium-limited traits, such as neural and muscle tissue. We first document how road salt runoff can elevate sodium concentrations in the tissue of some plant groups by 1.5–30 times. Using monarch butterflies reared on roadside- and prairie-collected milkweed, we then show that road salt runoff can result in increased muscle mass (in males) and neural investment (in females). Finally, we use an artificial diet manipulation in cabbage white butterflies to show that variation in sodium chloride per se positively affects male flight muscle and female brain size. Variation in sodium not only has different effects depending on sex, but also can have opposing effects on the same tissue: across both species, males increase investment in flight muscle with increasing sodium, whereas females show the opposite pattern. Taken together, our results show that anthropogenic changes in sodium availability can affect the development of traits in roadside-feeding herbivores. This research suggests that changing micronutrient availability could alter selection on foraging behavior for some roadside-developing invertebrates. PMID:24927579

  2. Anthropogenic changes in sodium affect neural and muscle development in butterflies.

    PubMed

    Snell-Rood, Emilie C; Espeset, Anne; Boser, Christopher J; White, William A; Smykalski, Rhea

    2014-07-15

    The development of organisms is changing drastically because of anthropogenic changes in once-limited nutrients. Although the importance of changing macronutrients, such as nitrogen and phosphorus, is well-established, it is less clear how anthropogenic changes in micronutrients will affect organismal development, potentially changing dynamics of selection. We use butterflies as a study system to test whether changes in sodium availability due to road salt runoff have significant effects on the development of sodium-limited traits, such as neural and muscle tissue. We first document how road salt runoff can elevate sodium concentrations in the tissue of some plant groups by 1.5-30 times. Using monarch butterflies reared on roadside- and prairie-collected milkweed, we then show that road salt runoff can result in increased muscle mass (in males) and neural investment (in females). Finally, we use an artificial diet manipulation in cabbage white butterflies to show that variation in sodium chloride per se positively affects male flight muscle and female brain size. Variation in sodium not only has different effects depending on sex, but also can have opposing effects on the same tissue: across both species, males increase investment in flight muscle with increasing sodium, whereas females show the opposite pattern. Taken together, our results show that anthropogenic changes in sodium availability can affect the development of traits in roadside-feeding herbivores. This research suggests that changing micronutrient availability could alter selection on foraging behavior for some roadside-developing invertebrates. PMID:24927579

  3. Gravity changes during animal development affect IgM heavy-chain transcription and probably lymphopoiesis.

    PubMed

    Huin-Schohn, Cécile; Guéguinou, Nathan; Schenten, Véronique; Bascove, Matthieu; Koch, Guillemette Gauquelin; Baatout, Sarah; Tschirhart, Eric; Frippiat, Jean-Pol

    2013-01-01

    Our previous research demonstrated that spaceflight conditions affect antibody production in response to an antigenic stimulation in adult amphibians. Here, we investigated whether antibody synthesis is affected when animal development occurs onboard a space station. To answer this question, embryos of the Iberian ribbed newt, Pleurodeles waltl, were sent to the International Space Station (ISS) before the initiation of immunoglobulin heavy-chain expression. Thus, antibody synthesis began in space. On landing, we determined the effects of spaceflight on P. waltl development and IgM heavy-chain transcription. Results were compared with those obtained using embryos that developed on Earth. We find that IgM heavy-chain transcription is doubled at landing and that spaceflight does not affect P. waltl development and does not induce inflammation. We also recreated the environmental modifications encountered by the embryos during their development onboard the ISS. This strategy allowed us to demonstrate that gravity change is the factor responsible for antibody heavy-chain transcription modifications that are associated with NF-κB mRNA level variations. Taken together, and given that the larvae were not immunized, these data suggest a modification of lymphopoiesis when gravity changes occur during ontogeny.

  4. Weaning Markedly Affects Transcriptome Profiles and Peyer’s Patch Development in Piglet Ileum

    PubMed Central

    Inoue, Ryo; Tsukahara, Takamitsu; Nakatani, Masako; Okutani, Mie; Nishibayashi, Ryoichiro; Ogawa, Shohei; Harayama, Tomoko; Nagino, Takayuki; Hatanaka, Hironori; Fukuta, Kikuto; Romero-Pérez, Gustavo A.; Ushida, Kazunari; Kelly, Denise

    2015-01-01

    Transcriptome analyses were conducted on the ileal mucosa of 14- to 35-day-old piglets to investigate postnatal gut development during suckling and postweaning. The transcriptome profiles of 14-day-old suckling piglets showed a considerably higher number of differentially expressed genes than did those of 21-, 28-, and 35-day olds, indicating an intensive gut development during the first 14–21 postnatal days. In addition, the analysis of biological pathways indicated that Chemotaxis Leucocyte chemotaxis was the most significantly affected pathway in suckling piglets between 14 and 21 days of age. Weaning negatively affected pathways associated with acquired immunity, but positively affected those associated with innate immunity. Interestingly, pathway Chemotaxis Leucocyte chemotaxis was found positively affected when comparing 14- and 21-day-old suckling piglets, but negatively affected in 28-day-old piglets weaned at 21 days of age, when compared with 28-day-old suckling piglets. Genes CXCL13, SLA-DOA (MHC class II), ICAM1, VAV1, and VCAM1 were involved in the pathway Chemotaxis Leukocyte chemotaxis and they were found to significantly change between 14- and 21-day-old suckling piglets and between groups of suckling and weaned piglets. The expression of these genes significantly declined after weaning at 14, 21, and 28 days of age. This decline indicated that CXCL13, SLA-DOA, ICAM1, VAV1, and VCAM1 may be involved in the development of Peyer’s patches (PP) because lower gene expression clearly corresponded with smaller areas of PP in the ileal mucosa of piglets. Moreover, weaning piglets prior to a period of intensive gut development, i.e., 14 days of age, caused significant adverse effects on the size of PP, which were not reverted even 14 days postweaning. PMID:26697021

  5. Weaning Markedly Affects Transcriptome Profiles and Peyer's Patch Development in Piglet Ileum.

    PubMed

    Inoue, Ryo; Tsukahara, Takamitsu; Nakatani, Masako; Okutani, Mie; Nishibayashi, Ryoichiro; Ogawa, Shohei; Harayama, Tomoko; Nagino, Takayuki; Hatanaka, Hironori; Fukuta, Kikuto; Romero-Pérez, Gustavo A; Ushida, Kazunari; Kelly, Denise

    2015-01-01

    Transcriptome analyses were conducted on the ileal mucosa of 14- to 35-day-old piglets to investigate postnatal gut development during suckling and postweaning. The transcriptome profiles of 14-day-old suckling piglets showed a considerably higher number of differentially expressed genes than did those of 21-, 28-, and 35-day olds, indicating an intensive gut development during the first 14-21 postnatal days. In addition, the analysis of biological pathways indicated that Chemotaxis Leucocyte chemotaxis was the most significantly affected pathway in suckling piglets between 14 and 21 days of age. Weaning negatively affected pathways associated with acquired immunity, but positively affected those associated with innate immunity. Interestingly, pathway Chemotaxis Leucocyte chemotaxis was found positively affected when comparing 14- and 21-day-old suckling piglets, but negatively affected in 28-day-old piglets weaned at 21 days of age, when compared with 28-day-old suckling piglets. Genes CXCL13, SLA-DOA (MHC class II), ICAM1, VAV1, and VCAM1 were involved in the pathway Chemotaxis Leukocyte chemotaxis and they were found to significantly change between 14- and 21-day-old suckling piglets and between groups of suckling and weaned piglets. The expression of these genes significantly declined after weaning at 14, 21, and 28 days of age. This decline indicated that CXCL13, SLA-DOA, ICAM1, VAV1, and VCAM1 may be involved in the development of Peyer's patches (PP) because lower gene expression clearly corresponded with smaller areas of PP in the ileal mucosa of piglets. Moreover, weaning piglets prior to a period of intensive gut development, i.e., 14 days of age, caused significant adverse effects on the size of PP, which were not reverted even 14 days postweaning.

  6. Investigations into factors affecting the cascade developer used in ESDA--a review.

    PubMed

    Nic Daéid, N; Hayes, K; Allen, M

    2008-10-25

    The Electrostatic Detection Apparatus (ESDA) is a technique most commonly used for the visualisation of indented impressions on questioned documents. This work investigates some of the variables which are known to affect the results of ESDA and some variables which have, as yet, not been addressed. The investigation of variables included: examining the effects of different levels of indentation on different qualities of paper, chronological aging of cascade developer and the effects of repeated use of cascade developer on both the quality of results and the glass beads themselves, the effects of storage of cascade developer in a humidified environment and finally the effects of variation on the image development time. Results indicate that chronological aging of cascade developer does not have a negative effect on the quality of results and a 200 g portion of cascade developer will give good quality results for up to 30 traces before the quality will begin to deteriorate. Humidification of the cascade developer appears to have no advantages over storage in a normal environment and, in fact, the toner is lost sooner with humidification. The surface of the glass beads are affected through repeated use of cascade developer and appear to become visually smoother which may lead to a loss of attraction between them and the toner particles.

  7. Fixing the Problem With Empathy: Development and Validation of the Affective and Cognitive Measure of Empathy.

    PubMed

    Vachon, David D; Lynam, Donald R

    2016-04-01

    Low empathy is a criterion for most externalizing disorders, and empathy training is a regular component of treatment for aggressive people, from school bullies to sex offenders. However, recent meta-analytic evidence suggests that current measures of empathy explain only 1% of the variance in aggressive behavior. A new assessment of empathy was developed to more fully represent the empathy construct and better predict important outcomes--particularly aggressive behavior and externalizing psychopathology. Across three independent samples (N = 210-708), the 36-item Affective and Cognitive measure of Empathy (ACME) was internally consistent, structurally reliable, and invariant across sex. The ACME bore significant associations to important outcomes, which were incremental relative to other measures of empathy and generalizable across sex. Importantly, the affective scales of the ACME-particularly a new "Affective Dissonance" scale--yielded moderate to strong associations with aggressive behavior and externalizing disorders. The ACME is a short, reliable, and useful measure of empathy.

  8. Pim-2 Modulates Aerobic Glycolysis and Energy Production during the Development of Colorectal Tumors.

    PubMed

    Zhang, Xue-hui; Yu, Hong-liang; Wang, Fu-jing; Han, Yong-long; Yang, Wei-liang

    2015-01-01

    Tumor cells have higher rates of glucose uptake and aerobic glycolysis to meet energy demands for proliferation and metastasis. The characteristics of increased glucose uptake, accompanied with aerobic glycolysis, has been exploited for the diagnosis of cancers. Although much progress has been made, the mechanisms regulating tumor aerobic glycolysis and energy production are still not fully understood. Here, we demonstrate that Pim-2 is required for glycolysis and energy production in colorectal tumor cells. Our results show that Pim-2 is highly expressed in colorectal tumor cells, and may be induced by nutrient stimulation. Activation of Pim-2 in colorectal cells led to increase glucose utilization and aerobic glycolysis, as well as energy production. While knockdown of Pim-2 decreased energy production in colorectal tumor cells and increased their susceptibility to apoptosis. Moreover, the effects of Pim-2 kinase on aerobic glycolysis seem to be partly dependent on mTORC1 signaling, because inhibition of mTORC1 activity reversed the aerobic glycolysis mediated by Pim-2. Our findings suggest that Pim-2-mediated aerobic glycolysis is critical for monitoring Warburg effect in colorectal tumor cells, highlighting Pim-2 as a potential metabolic target for colorectal tumor therapy. PMID:26078709

  9. The possible interaction between periostin expressed by cancer stroma and tumor-associated macrophages in developing mycosis fungoides.

    PubMed

    Furudate, Sadanori; Fujimura, Taku; Kakizaki, Aya; Kambayashi, Yumi; Asano, Masayuki; Watabe, Akiko; Aiba, Setsuya

    2016-02-01

    Mycosis fungoides (MF) starts as an indolent disease, progresses from a patch stage to confluent plaques and ultimately develops skin tumors. Tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment in MF. The purpose of this study was to elucidate the involvement of TAMs in the lesional skin of different stages of MF. First, we immunohistologically examined the percentage of CD163+ macrophages and CD206+ cells, as well as the levels of periostin and IL-4 in cancer stroma. The percentage of CD206+ cells increased in parallel with tumor progression, while there was no significant difference in the percentage of CD163+ cells. Periostin was prominent in the stromal area at the patch and plaque stages but decreased at the tumor stage. In contrast, IL-4 was prominently stained at both plaque and tumor stages. To further elucidate the molecular mechanisms of the effects of these stromal factors on TAMs, we examined their effects on mRNA expression in monocyte-derived macrophages in vitro. Based on microarray analysis and gene ontology, we examined a series of chemokines and MMPs whose expression was strongly connected with periostin stimulation. The DNA microarray results were verified in M2 macrophages using real-time PCR. We further examined the mRNA expression of these chemokines and MMPs in the presence of periostin and IL-4 to simulate the advanced stages of MF and validated their protein expression by ELISA. Our present report suggests possible roles of periostin on TAMs in establishing the tumor microenvironment in MF. PMID:26441016

  10. Effects of selenium and low levels of lead on mammary tumor development and growth in MMTV-infected female mice.

    PubMed

    Schrauzer, G N

    2008-12-01

    Selenium (Se) has been demonstrated in previous studies to inhibit mammary tumorigenesis in C3H mice infected with the murine mammary tumorvirus, MMTV. The antitumorigenic effects of Se in this animal model of breast cancer were subsequently shown to be counteracted by Se-antagonistic elements. Lead (Pb), for example, was found to abolish the anticarcinogenic effects of Se at 5 ppm in the drinking water. The present study was undertaken to explore the effects of Pb at just 0.5 ppm in the water, i.e., at a level comparable to the concentrations of Pb that have been measured in the tap water of older homes in some communities. Groups of 30 female virgin C3H/St mice infected with MMTV maintained on Torula yeast-based diets containing either 0.15 or 0.65 ppm of yeast-based organic Se and received either deionized water or water containing 0.5 ppm Pb as the acetate over their entire postweaning lifespan. In the control group on deionized water and the 0.15 ppm Se feed, the tumor incidence was 78.6%, which is normal for this strain. Increasing the Se content of the feed to 0.65 ppm lowered the tumor incidence to 30%, demonstrating the antitumorigenic effect of Se. In the experimental groups, the Pb-exposed mice on the 0.15 ppm Se feed developed signs of chronic Pb toxicity as evidenced by diminished weight gain that persisted up to the age of 10 months, during which period the animals remained tumor-free. Thereafter, weight gains ensued to near the values of the controls, and the tumors began to develop in rapid succession until the final tumor incidence of 73.7% was reached. In the group of mice on the 0.65 ppm Se feed, the toxic effects of Pb were diminished, as evidenced by the normal weight gains during the first 10 months but with concomitant physiological inactivation of Se, causing 82.6% of the mice to develop tumors, with the first tumor to appear at the age of 5 months, 7 months earlier than in the Pb-unexposed controls. In addition, tumor growth rates in this

  11. HORMONAL CONTROL OF OVARIAN FUNCTION FOLLOWING CHLOROTRIAZINE EXPOSURE: EFFECT ON REPRODUCTIVE FUNCTION AND MAMMARY GLAND TUMOR DEVELOPMENT

    EPA Science Inventory

    Hormonal Control of Ovarian Function Following Chlorotriazine Exposure: Effect on Reproductive Function and Mammary Gland Tumor Development.

    Ralph L. Cooper, Susan C. Laws, Michael G. Narotsky, Jerome M. Goldman, and Tammy E. Stoker

    Abstract
    The studies review...

  12. Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Tumor progression locus 2 (TPL2), a serine threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unkn...

  13. Developing an algorithm for cost-effective, clinically judicious management of peripheral nerve tumors

    PubMed Central

    Birk, Harjus; Zygourakis, Corinna C.; Kliot, Michel

    2016-01-01

    Peripheral nerve tumors such as neurofibromas and schwannomas have become increasingly identified secondary to improved imaging modalities including magnetic resonance neurogram and ultrasound. Given that a majority of these peripheral nerve tumors are benign lesions, it becomes important to determine appropriate management of such asymptomatic masses. We propose a normal cost-effective management paradigm for asymptomatic peripheral nerve neurofibromas and schwannomas that has been paired with economic analyses. Specifically, our management paradigm identifies patients who would benefit from surgery for asymptomatic peripheral nerve tumors, while providing cost-effective recommendations regarding clinical exams and serial imaging for such patients. PMID:27625890

  14. Developing an algorithm for cost-effective, clinically judicious management of peripheral nerve tumors

    PubMed Central

    Birk, Harjus; Zygourakis, Corinna C.; Kliot, Michel

    2016-01-01

    Peripheral nerve tumors such as neurofibromas and schwannomas have become increasingly identified secondary to improved imaging modalities including magnetic resonance neurogram and ultrasound. Given that a majority of these peripheral nerve tumors are benign lesions, it becomes important to determine appropriate management of such asymptomatic masses. We propose a normal cost-effective management paradigm for asymptomatic peripheral nerve neurofibromas and schwannomas that has been paired with economic analyses. Specifically, our management paradigm identifies patients who would benefit from surgery for asymptomatic peripheral nerve tumors, while providing cost-effective recommendations regarding clinical exams and serial imaging for such patients.

  15. Developing an algorithm for cost-effective, clinically judicious management of peripheral nerve tumors.

    PubMed

    Birk, Harjus; Zygourakis, Corinna C; Kliot, Michel

    2016-01-01

    Peripheral nerve tumors such as neurofibromas and schwannomas have become increasingly identified secondary to improved imaging modalities including magnetic resonance neurogram and ultrasound. Given that a majority of these peripheral nerve tumors are benign lesions, it becomes important to determine appropriate management of such asymptomatic masses. We propose a normal cost-effective management paradigm for asymptomatic peripheral nerve neurofibromas and schwannomas that has been paired with economic analyses. Specifically, our management paradigm identifies patients who would benefit from surgery for asymptomatic peripheral nerve tumors, while providing cost-effective recommendations regarding clinical exams and serial imaging for such patients. PMID:27625890

  16. Regulatory T-cell Trafficking: From Thymic Development to Tumor-Induced Immune Suppression

    PubMed Central

    Mailloux, Adam W.; Young, M. Rita I.

    2011-01-01

    Regulatory T cells (Tregs) have become a priority for many investigators in immunology due to their potent immunosuppressive and tolerogenic effects. While Treg activity is required for normal immune homeostasis, dysregulation of their numbers can induce autoimmunity or aid in the pathogenesis of disease. Therefore, great effort has been made to understand the mechanisms by which Tregs accumulate in different areas of the body. Like other lymphocytes, Tregs migrate in response to a network of chemotactic stimuli involving chemokines, chemokine receptors, integrins, and their corresponding ligands. However, many of these stimuli are exclusive to Tregs, inducing their migration while leaving conventional populations unaffected. It is these selective stimuli that result in increased ratios of Tregs among conventional effector populations, leading to changes in immune suppression and homeostasis. This review explores selective Treg trafficking during thymic Treg development, migration to secondary lymphoid tissues and emigration into the periphery during homeostatic conditions, inflammation, and the tumor microenvironment, placing emphasis on stimuli that selectively recruits Tregs to target locations. PMID:21083525

  17. The Wilms' tumor gene Wt1 is required for normal development of the retina.

    PubMed

    Wagner, Kay-Dietrich; Wagner, Nicole; Vidal, Valerie P I; Schley, Gunnar; Wilhelm, Dagmar; Schedl, Andreas; Englert, Christoph; Scholz, Holger

    2002-03-15

    The Wilms' tumor gene Wt1 is known for its important functions during genitourinary and mesothelial formation. Here we show that Wt1 is necessary for neuronal development in the vertebrate retina. Mouse embryos with targeted disruption of Wt1 exhibit remarkably thinner retinas than age-matched wild-type animals. A large fraction of retinal ganglion cells is lost by apoptosis, and the growth of optic nerve fibers is severely disturbed. Strikingly, expression of the class IV POU-domain transcription factor Pou4f2 (formerly Brn-3b), which is critical for the survival of most retinal ganglion cells, is lost in Wt1(-/-) retinas. Forced expression of Wt1 in cultured cells causes an up-regulation of Pou4f2 mRNA. Moreover, the Wt1(-KTS) splice variant can activate a reporter construct carrying 5'-regulatory sequences of the human POU4F2. The lack of Pou4f2 and the ocular defects in Wt1(-/-) embryos are rescued by transgenic expression of a 280 kb yeast artificial chromosome carrying the human WT1 gene. Taken together, our findings demonstrate a continuous requirement for Wt1 in normal retina formation with a critical role in Pou4f2-dependent ganglion cell differentiation.

  18. Development of image-processing software for automatic segmentation of brain tumors in MR images.

    PubMed

    Vijayakumar, C; Gharpure, Damayanti Chandrashekhar

    2011-07-01

    Most of the commercially available software for brain tumor segmentation have limited functionality and frequently lack the careful validation that is required for clinical studies. We have developed an image-analysis software package called 'Prometheus,' which performs neural system-based segmentation operations on MR images using pre-trained information. The software also has the capability to improve its segmentation performance by using the training module of the neural system. The aim of this article is to present the design and modules of this software. The segmentation module of Prometheus can be used primarily for image analysis in MR images. Prometheus was validated against manual segmentation by a radiologist and its mean sensitivity and specificity was found to be 85.71±4.89% and 93.2±2.87%, respectively. Similarly, the mean segmentation accuracy and mean correspondence ratio was found to be 92.35±3.37% and 0.78±0.046, respectively. PMID:21897560

  19. Retrorectal tumors.

    PubMed

    Bullard Dunn, Kelli

    2010-02-01

    Retrorectal or presacral tumors are rare and can be challenging to diagnose and treat. Because the retrorectal space contains multiple embryologic remnants derived from various tissues, the tumors that develop in this space are heterogeneous. Most lesions are benign, but malignant neoplasms are not uncommon. Lesions are classified as congenital, neurogenic, osseous, inflammatory, or miscellaneous. Although treatment depends on diagnosis and anatomic location, most retrorectal lesions will require surgical resection.

  20. Emerging therapies and latest development in the treatment of unresectable pancreatic neuroendocrine tumors: an update for clinicians

    PubMed Central

    Sharma, Jaya; Duque, Marvin

    2013-01-01

    Pancreatic neuroendocrine tumors (pNETs) differ in their clinical behavior, presentation and prognosis based on their initial histological features and disease stage. While small resectable tumors can be treated surgically, metastatic and locally advanced disease carries a significant mortality and treatment options have been limited in terms of their efficacy. Streptozocin-based regimens were the only agents available before but recent advances have improved the armamentarium to treat pNETs. Newer chemotherapeutic agents such as temozolomide, somatostatin analogs and targeted therapies including everolimus and sunitinib are now available to treat these tumors. Several combination regimens with targeted therapies and newer agents such as pazopanib are being developed and tested in ongoing trials. PMID:24179483

  1. Function and mechanism of neurotensin (NTS) and its receptor 1 (NTSR1) in occurrence and development of tumors.

    PubMed

    Hu, Huan-rong; Dong, Zhen; Yi, Liang; He, Xiao-yan; Zhang, Yan-li; Liu, Ya-ling; Cui, Hong-juan

    2015-07-01

    As a neuropeptide, neurotensin (NTS) is widely expressed in central and peripheral nervous system, which is mainly mediated byneurotensin receptor1 (NTSR1) to activate the related downstream signaling pathways. After summarized the function and mechanism of NTS/NTSR1 in various malignant tumors, we found that NTS/NTSR1 played essential roles during tumor initiation and development. NTS/NTSR1 regulates tumor initiation, proliferation, apoptosis, metastasis and differentiation mainly through three pathways, including IP3/Ca2+ /PKC/MAPKs pathway, MMPs/EGFR/MAPKs (PI3K/Akt) pathway, or Rho-GTPsaes and non-receptor tyrosine kinase pathway. Besides, NTS/NTSR1 is also regulated by some upstream pathways and some traditional Chinese medicine preparations and traditional Chinese medicine therapies. In this article, we summarized the function of NTS/NTSR1 and its mechanisms, and discussed the prospective in its application to clinical diagnosis and drugs targeting.

  2. Development of nanostars as a biocompatible tumor contrast agent: toward in vivo SERS imaging.

    PubMed

    D'Hollander, Antoine; Mathieu, Evelien; Jans, Hilde; Vande Velde, Greetje; Stakenborg, Tim; Van Dorpe, Pol; Himmelreich, Uwe; Lagae, Liesbet

    2016-01-01

    The need for sensitive imaging techniques to detect tumor cells is an important issue in cancer diagnosis and therapy. Surface-enhanced Raman scattering (SERS), realized by chemisorption of compounds suitable for Raman spectroscopy onto gold nanoparticles, is a new method for detecting a tumor. As a proof of concept, we studied the use of biocompatible gold nanostars as sensitive SERS contrast agents targeting an ovarian cancer cell line (SKOV3). Due to a high intracellular uptake of gold nanostars after 6 hours of exposure, they could be detected and located with SERS. Using these nanostars for passive targeting after systemic injection in a xenograft mouse model, a detectable signal was measured in the tumor and liver in vivo. These signals were confirmed by ex vivo SERS measurements and darkfield microscopy. In this study, we established SERS nanostars as a highly sensitive contrast agent for tumor detection, which opens the potential for their use as a theranostic agent against cancer. PMID:27536107

  3. Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy

    PubMed Central

    Qiu, Yu; Li, Peng; Ji, Chunyan

    2015-01-01

    Hypoxia, which is common during tumor progression, plays important roles in tumor biology. Failure in cell death in response to hypoxia contributes to progression and metastasis of tumors. On the one hand, the metabolic and oxidative stress following hypoxia could lead to cell death by triggering signal cascades, like LKB1/AMPK, PI3K/AKT/mTOR, and altering the levels of effective components, such as the Bcl-2 family, Atg and p62. On the other hand, hypoxia-induced autophagy can serve as a mechanism to turn over nutrients, so as to mitigate the adverse condition and then avoid cell death potentially. Due to the effective role of hypoxia, this review focuses on the crosstalk in cell death under hypoxia in tumor progression. Additionally, the illumination of cell death in hypoxia could shed light on the clinical applications of cell death targeted therapy. PMID:26512660

  4. Development of nanostars as a biocompatible tumor contrast agent: toward in vivo SERS imaging

    PubMed Central

    D’Hollander, Antoine; Mathieu, Evelien; Jans, Hilde; Vande Velde, Greetje; Stakenborg, Tim; Van Dorpe, Pol; Himmelreich, Uwe; Lagae, Liesbet

    2016-01-01

    The need for sensitive imaging techniques to detect tumor cells is an important issue in cancer diagnosis and therapy. Surface-enhanced Raman scattering (SERS), realized by chemisorption of compounds suitable for Raman spectroscopy onto gold nanoparticles, is a new method for detecting a tumor. As a proof of concept, we studied the use of biocompatible gold nanostars as sensitive SERS contrast agents targeting an ovarian cancer cell line (SKOV3). Due to a high intracellular uptake of gold nanostars after 6 hours of exposure, they could be detected and located with SERS. Using these nanostars for passive targeting after systemic injection in a xenograft mouse model, a detectable signal was measured in the tumor and liver in vivo. These signals were confirmed by ex vivo SERS measurements and darkfield microscopy. In this study, we established SERS nanostars as a highly sensitive contrast agent for tumor detection, which opens the potential for their use as a theranostic agent against cancer. PMID:27536107

  5. Potentiated cyclophosphane: experimental study of the effect on tumor development and efficiency of cytostatic therapy.

    PubMed

    Amosova, E N; Zueva, E P; Razina, T G; Krylova, S G; Shilova, N V; Epstein, O I

    2003-01-01

    Experiments on animals with transplanted tumors (Lewis lung carcinoma and carcinosarcoma Walker-256) showed that combination treatment with cyclophosphane and its homeopathically potentiated forms increases antiblastic activity of the preparation.

  6. Altered cytokine network in gestational diabetes mellitus affects maternal insulin and placental-fetal development.

    PubMed

    Wedekind, Lauren; Belkacemi, Louiza

    2016-01-01

    Pregnancy is characterized by an altered inflammatory profile, compared to the non-pregnant state with an adequate balance between pro-and anti-inflammatory cytokines needed for normal development. Cytokines are small secreted proteins expressed mainly in immunocompetent cells in the reproductive system. From early developmental stages onward, the secretory activity of placenta cells clearly contributes to increase local as well as systemic levels of cytokines. The placental production of cytokines may affect mother and fetus independently. In turn because of this unique position at the maternal fetal interface, the placenta is also exposed to the regulatory influence of cytokines from maternal and fetal circulations, and hence, may be affected by changes in any of these. Gestational diabetes mellitus (GDM) is associated with an overall alteration of the cytokine network. This review discusses the changes that occur in cytokines post GDM and their negative effects on maternal insulin and placental-fetal development. PMID:27230834

  7. Lipoprotein(a) and vitamin C impair development of breast cancer tumors in Lp(a)+; Gulo-/- mice.

    PubMed

    Cha, John; Roomi, M Waheed; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-09-01

    Cancer progression is characterized by loss of extracellular matrix (ECM) integrity, which is a precondition for tumor growth and metastasis. In order to elucidate the precise mechanisms of ECM degradation in cancer we used a genetically modified mouse mimicking two distinct human metabolic features associated with carcinogenesis, the lack of endogenous vitamin C synthesis and the production of human Lp(a). Female Lp(a)+; Gulo(-/-) and control wild-type Balb/c mice without these two metabolic features were orthotopically inoculated with 4T1 breast cancer cells (5x105). The transgenic and control mice were divided into 4 different dietary groups in respect to dietary vitamin C intake: i) low ascorbate intake for 6 weeks; ii) high ascorbate intake for 6 weeks; iii) low ascorbate intake for 3 weeks followed by high ascorbate for 3 weeks; iv) high ascorbate intake for 3 weeks followed by low ascorbate for 3 weeks. After 6 weeks, all wild-type mice developed tumors. In contrast, Lp(a)+; Gulo(-/-) mice developed one third less primary tumors (low ascorbate diet) or no primary tumors at all (high ascorbate diet). Significantly, tumors from Lp(a)+; Gulo(-/-) mice immunostained positively for Lp(a) and their size was inversely proportional to Lp(a) serum levels. The results implicate that Lp(a) may play a role in controlling tumor growth and expansion. The most likely mechanism is the competitive inhibition of plasmin-induced ECM degradation due to the homology of Lp(a) components to plasminogen. The confirmation of this pathomechanism could lead to a universal therapeutic target for the prevention and treatment of cancer. PMID:27573077

  8. Lipoprotein(a) and vitamin C impair development of breast cancer tumors in Lp(a)+; Gulo−/− mice

    PubMed Central

    Cha, John; Roomi, M. Waheed; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Cancer progression is characterized by loss of extracellular matrix (ECM) integrity, which is a precondition for tumor growth and metastasis. In order to elucidate the precise mechanisms of ECM degradation in cancer we used a genetically modified mouse mimicking two distinct human metabolic features associated with carcinogenesis, the lack of endogenous vitamin C synthesis and the production of human Lp(a). Female Lp(a)+; Gulo(−/−) and control wild-type Balb/c mice without these two metabolic features were orthotopically inoculated with 4T1 breast cancer cells (5×105). The transgenic and control mice were divided into 4 different dietary groups in respect to dietary vitamin C intake: i) low ascorbate intake for 6 weeks; ii) high ascorbate intake for 6 weeks; iii) low ascorbate intake for 3 weeks followed by high ascorbate for 3 weeks; iv) high ascorbate intake for 3 weeks followed by low ascorbate for 3 weeks. After 6 weeks, all wild-type mice developed tumors. In contrast, Lp(a)+; Gulo(−/−) mice developed one third less primary tumors (low ascorbate diet) or no primary tumors at all (high ascorbate diet). Significantly, tumors from Lp(a)+; Gulo(−/−) mice immunostained positively for Lp(a) and their size was inversely proportional to Lp(a) serum levels. The results implicate that Lp(a) may play a role in controlling tumor growth and expansion. The most likely mechanism is the competitive inhibition of plasmin-induced ECM degradation due to the homology of Lp(a) components to plasminogen. The confirmation of this pathomechanism could lead to a universal therapeutic target for the prevention and treatment of cancer. PMID:27573077

  9. Development of a circulating miRNA assay to monitor tumor burden: From mouse to man

    PubMed Central

    Greystoke, Alastair; Ayub, Mahmood; Rothwell, Dominic G.; Morris, Dan; Burt, Deborah; Hodgkinson, Cassandra L.; Morrow, Christopher J.; Smith, Nigel; Aung, Kyaw; Valle, Juan; Carter, Louise; Blackhall, Fiona; Dive, Caroline; Brady, Ged

    2016-01-01

    Circulating miRNA stability suggests potential utility of miRNA based biomarkers to monitor tumor burden and/or progression, particularly in cancer types where serial biopsy is impractical. Assessment of miRNA specificity and sensitivity is challenging within the clinical setting. To address this, circulating miRNAs were examined in mice bearing human SCLC tumor xenografts and SCLC patient derived circulating tumor cell explant models (CDX). We identified 49 miRNAs using human TaqMan Low Density Arrays readily detectable in 10 μl tail vein plasma from mice carrying H526 SCLC xenografts that were low or undetectable in non-tumor bearing controls. Circulating miR-95 measured serially in mice bearing CDX was detected with tumor volumes as low as 10 mm3 and faithfully reported subsequent tumor growth. Having established assay sensitivity in mouse models, we identified 26 miRNAs that were elevated in a stage dependent manner in a pilot study of plasma from SCLC patients (n = 16) compared to healthy controls (n = 11) that were also elevated in the mouse models. We selected a smaller panel of 10 previously reported miRNAs (miRs 95, 141, 200a, 200b, 200c, 210, 335#, 375, 429) that were consistently elevated in SCLC, some of which are reported to be elevated in other cancer types. Using a multiplex qPCR assay, elevated levels of miRNAs across the panel were also observed in a further 66 patients with non-small cell lung, colorectal or pancreatic cancers. The utility of this circulating miRNA panel as an early warning of tumor progression across several tumor types merits further evaluation in larger studies. PMID:26654130

  10. Development and evaluation of copper-67 and samarium-153 labeled conjugates for tumor radioimmunotherapy

    SciTech Connect

    Srivastava, S.C.; Mausner, L.F.; Mease, R.C.; Meinken, G.E.; Joshi, V.; Kolsky, K.; Sweet, M.; Steplewski, Z.

    1995-02-01

    The potential of utilizing receptor-specific agents such as monoclonal antibodies (MAb), and MAb-derived smaller molecules, as carriers of radionuclides for the selective destruction of tumors has stimulated much research activity. The success of such applications depends on many factors, especially the tumor binding properties of the antibody reagent, the efficiency of labeling and in-vivo stability of the radioconjugate and, on the careful choice of the radionuclide best suited to treat the tumor under consideration. The radiolabeled antibody technique for radioimmunotherapy (RIT), however, has experienced many limitations, and its success has not matched the expectations that were raised more than a decade ago. The problems that have been identified include: (i) degradation of antibody immunoreactivity resulting from chemical manipulations required for labeling; (ii) lack of suitable radioisotopes and methods for stable attachment of the radiolabel; (iii) in-vivo instability of the radioimmunoconjugates; (iv) excessive accumulation of activity in non-target locations; and (v) lack of radioimmunoconjugate accessibility to cells internal to a tumor mass. A careful choice of the radionuclide(s) best suited to treat the tumor under consideration is one of the most important requirements for successful radioimmunotherapy. This study evaluates copper 67 and samarium 153 for tumor radioimmunotherapy.

  11. Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences

    PubMed Central

    Dean, Afshan; van den Driesche, Sander; Wang, Yili; McKinnell, Chris; Macpherson, Sheila; Eddie, Sharon L.; Kinnell, Hazel; Hurtado-Gonzalez, Pablo; Chambers, Tom J.; Stevenson, Kerrie; Wolfinger, Elke; Hrabalkova, Lenka; Calarrao, Ana; Bayne, Rosey AL; Hagen, Casper P.; Mitchell, Rod T.; Anderson, Richard A.; Sharpe, Richard M.

    2016-01-01

    Analgesics which affect prostaglandin (PG) pathways are used by most pregnant women. As germ cells (GC) undergo developmental and epigenetic changes in fetal life and are PG targets, we investigated if exposure of pregnant rats to analgesics (indomethacin or acetaminophen) affected GC development and reproductive function in resulting offspring (F1) or in the F2 generation. Exposure to either analgesic reduced F1 fetal GC number in both sexes and altered the tempo of fetal GC development sex-dependently, with delayed meiotic entry in oogonia but accelerated GC differentiation in males. These effects persisted in adult F1 females as reduced ovarian and litter size, whereas F1 males recovered normal GC numbers and fertility by adulthood. F2 offspring deriving from an analgesic-exposed F1 parent also exhibited sex-specific changes. F2 males exhibited normal reproductive development whereas F2 females had smaller ovaries and reduced follicle numbers during puberty/adulthood; as similar changes were found for F2 offspring of analgesic-exposed F1 fathers or mothers, we interpret this as potentially indicating an analgesic-induced change to GC in F1. Assuming our results are translatable to humans, they raise concerns that analgesic use in pregnancy could potentially affect fertility of resulting daughters and grand-daughters. PMID:26813099

  12. Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines

    PubMed Central

    Olsen, Aaron; Chen, Yong; Ji, Qingzhou; Zhu, Guofeng; De Silva, Aruna Dharshan; Vilchèze, Catherine; Weisbrod, Torin; Li, Weimin; Xu, Jiayong; Larsen, Michelle; Zhang, Jinghang; Porcelli, Steven A.; Jacobs, William R.

    2016-01-01

    ABSTRACT Tumor necrosis factor alpha (TNF) plays a critical role in the control of Mycobacterium tuberculosis, in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4+ T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8+ T cells). M. tuberculosis can evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components. We hypothesized that M. tuberculosis mutants with an increased capacity to induce host cell TNF production (TNF-enhancing mutants) and thus with enhanced immunogenicity can be useful for vaccine development. To identify mycobacterial genes that regulate host cell TNF production, we used a TNF reporter macrophage clone to screen an H37Rv M. tuberculosis cosmid library constructed in M. smegmatis. The screen has identified a set of TNF-downregulating mycobacterial genes that, when deleted in H37Rv, generate TNF-enhancing mutants. Analysis of mutants disrupted for a subset of TNF-downregulating genes, annotated to code for triacylglycerol synthases and fatty acyl-coenzyme A (acyl-CoA) synthetase, enzymes that concern lipid biosynthesis and metabolism, has revealed that these strains can promote macrophage phagolysosomal fusion and apoptosis better than wild-type (WT) bacilli. Immunization of mice with the TNF-enhancing M. tuberculosis mutants elicits CD4+ and CD8+ T cell responses that are superior to those engendered by WT H37Rv. The results suggest that TNF-upregulating M. tuberculosis genes can be targeted to enhance the immunogenicity of mycobacterial strains that can serve as the substrates for the development of novel anti-TB vaccines. PMID:27247233

  13. Pediatric Odontogenic Tumors.

    PubMed

    Abrahams, Joshua M; McClure, Shawn A

    2016-02-01

    Pediatric odontogenic tumors are rare, and are often associated with impacted teeth. Although they can develop anywhere in the jaws, odontogenic tumors mainly occur in the posterior mandible. This article discusses the diagnosis and treatment of the most common pediatric odontogenic tumors, such as ameloblastoma, keratocystic odontogenic tumor, odontoma, and cementoblastoma.

  14. ARTIE: An Integrated Environment for the Development of Affective Robot Tutors

    PubMed Central

    Imbernón Cuadrado, Luis-Eduardo; Manjarrés Riesco, Ángeles; De La Paz López, Félix

    2016-01-01

    Over the last decade robotics has attracted a great deal of interest from teachers and researchers as a valuable educational tool from preschool to highschool levels. The implementation of social-support behaviors in robot tutors, in particular in the emotional dimension, can make a significant contribution to learning efficiency. With the aim of contributing to the rising field of affective robot tutors we have developed ARTIE (Affective Robot Tutor Integrated Environment). We offer an architectural pattern which integrates any given educational software for primary school children with a component whose function is to identify the emotional state of the students who are interacting with the software, and with the driver of a robot tutor which provides personalized emotional pedagogical support to the students. In order to support the development of affective robot tutors according to the proposed architecture, we also provide a methodology which incorporates a technique for eliciting pedagogical knowledge from teachers, and a generic development platform. This platform contains a component for identiying emotional states by analysing keyboard and mouse interaction data, and a generic affective pedagogical support component which specifies the affective educational interventions (including facial expressions, body language, tone of voice,…) in terms of BML (a Behavior Model Language for virtual agent specification) files which are translated into actions of a robot tutor. The platform and the methodology are both adapted to primary school students. Finally, we illustrate the use of this platform to build a prototype implementation of the architecture, in which the educational software is instantiated with Scratch and the robot tutor with NAO. We also report on a user experiment we carried out to orient the development of the platform and of the prototype. We conclude from our work that, in the case of primary school students, it is possible to identify, without

  15. ARTIE: An Integrated Environment for the Development of Affective Robot Tutors.

    PubMed

    Imbernón Cuadrado, Luis-Eduardo; Manjarrés Riesco, Ángeles; De La Paz López, Félix

    2016-01-01

    Over the last decade robotics has attracted a great deal of interest from teachers and researchers as a valuable educational tool from preschool to highschool levels. The implementation of social-support behaviors in robot tutors, in particular in the emotional dimension, can make a significant contribution to learning efficiency. With the aim of contributing to the rising field of affective robot tutors we have developed ARTIE (Affective Robot Tutor Integrated Environment). We offer an architectural pattern which integrates any given educational software for primary school children with a component whose function is to identify the emotional state of the students who are interacting with the software, and with the driver of a robot tutor which provides personalized emotional pedagogical support to the students. In order to support the development of affective robot tutors according to the proposed architecture, we also provide a methodology which incorporates a technique for eliciting pedagogical knowledge from teachers, and a generic development platform. This platform contains a component for identiying emotional states by analysing keyboard and mouse interaction data, and a generic affective pedagogical support component which specifies the affective educational interventions (including facial expressions, body language, tone of voice,…) in terms of BML (a Behavior Model Language for virtual agent specification) files which are translated into actions of a robot tutor. The platform and the methodology are both adapted to primary school students. Finally, we illustrate the use of this platform to build a prototype implementation of the architecture, in which the educational software is instantiated with Scratch and the robot tutor with NAO. We also report on a user experiment we carried out to orient the development of the platform and of the prototype. We conclude from our work that, in the case of primary school students, it is possible to identify, without

  16. ARTIE: An Integrated Environment for the Development of Affective Robot Tutors.

    PubMed

    Imbernón Cuadrado, Luis-Eduardo; Manjarrés Riesco, Ángeles; De La Paz López, Félix

    2016-01-01

    Over the last decade robotics has attracted a great deal of interest from teachers and researchers as a valuable educational tool from preschool to highschool levels. The implementation of social-support behaviors in robot tutors, in particular in the emotional dimension, can make a significant contribution to learning efficiency. With the aim of contributing to the rising field of affective robot tutors we have developed ARTIE (Affective Robot Tutor Integrated Environment). We offer an architectural pattern which integrates any given educational software for primary school children with a component whose function is to identify the emotional state of the students who are interacting with the software, and with the driver of a robot tutor which provides personalized emotional pedagogical support to the students. In order to support the development of affective robot tutors according to the proposed architecture, we also provide a methodology which incorporates a technique for eliciting pedagogical knowledge from teachers, and a generic development platform. This platform contains a component for identiying emotional states by analysing keyboard and mouse interaction data, and a generic affective pedagogical support component which specifies the affective educational interventions (including facial expressions, body language, tone of voice,…) in terms of BML (a Behavior Model Language for virtual agent specification) files which are translated into actions of a robot tutor. The platform and the methodology are both adapted to primary school students. Finally, we illustrate the use of this platform to build a prototype implementation of the architecture, in which the educational software is instantiated with Scratch and the robot tutor with NAO. We also report on a user experiment we carried out to orient the development of the platform and of the prototype. We conclude from our work that, in the case of primary school students, it is possible to identify, without

  17. Parents and Early Life Environment Affect Behavioral Development of Laying Hen Chickens

    PubMed Central

    de Haas, Elske N.; Bolhuis, J. Elizabeth; Kemp, Bas; Groothuis, Ton G. G.; Rodenburg, T. Bas

    2014-01-01

    Severe feather pecking (SFP) in commercial laying hens is a maladaptive behavior which is associated with anxiety traits. Many experimental studies have shown that stress in the parents can affect anxiety in the offspring, but until now these effects have been neglected in addressing the problem of SFP in commercially kept laying hens. We therefore studied whether parental stock (PS) affected the development of SFP and anxiety in their offspring. We used flocks from a brown and white genetic hybrid because genetic background can affect SFP and anxiety. As SFP can also be influenced by housing conditions on the rearing farm, we included effects of housing system and litter availability in the analysis. Forty-seven rearing flocks, originating from ten PS flocks were followed. Behavioral and physiological parameters related to anxiety and SFP were studied in the PS at 40 weeks of age and in the rearing flocks at one, five, ten and fifteen weeks of age. We found that PS had an effect on SFP at one week of age and on anxiety at one and five weeks of age. In the white hybrid, but not in the brown hybrid, high levels of maternal corticosterone, maternal feather damage and maternal whole-blood serotonin levels showed positive relations with offsprings’ SFP at one week and offsprings’ anxiety at one and five weeks of age. Disruption and limitation of litter supply at an early age on the rearing farms increased SFP, feather damage and fearfulness. These effects were most prominent in the brown hybrid. It appeared that hens from a brown hybrid are more affected by environmental conditions, while hens from a white hybrid were more strongly affected by parental effects. These results are important for designing measures to prevent the development of SFP, which may require a different approach in brown and white flocks. PMID:24603500

  18. IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden.

    PubMed

    van der Zee, Marten; Sacchetti, Andrea; Cansoy, Medine; Joosten, Rosalie; Teeuwssen, Miriam; Heijmans-Antonissen, Claudia; Ewing-Graham, Patricia C; Burger, Curt W; Blok, Leen J; Fodde, Riccardo

    2015-09-01

    Cancer stem-like cells (CSC) may be critical to maintain the malignant behavior of solid and hematopoietic cancers. Recently, patients with endometrial cancer whose tumors expressed high levels of aldehyde dehydrogenase (ALDH), a detoxifying enzyme characteristic of many progenitor and stem cells, exhibited a relative reduction in survival compared with patients with low levels of ALDH. Given evidence of its role as a CSC marker, we hypothesized that high level of ALDH activity (ALDH(hi)) in a tumor might positively correlate with the presence of stem- and progenitor-like tumor cells in this disease setting. In support of this hypothesis, ALDH could be used to enrich for CSC in endometrial cancer cell lines and primary tumors, as illustrated by the increased tumor-initiating capacity of ALDH(hi) cells in immunodeficient mice. ALDH(hi) cells also exhibited greater clonogenic and organoid-forming capacity compared with ALDH(lo) cells. Notably, the number of ALDH(hi) cells in tumor cell lines and primary tumors inversely correlated with differentiation grade. Expression analysis revealed upregulation of IL6 receptor subunits and signal transducers CD126 and GP130 in ALDH(hi) endometrial cancer cells. Accordingly, targeted inhibition of the IL6 receptor and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth. Overall, our results provide a preclinical rationale to target IL6 or its effector functions as a novel therapeutic option in endometrial cancer.

  19. Staff development and secondary science teachers: Factors that affect voluntary participation

    NASA Astrophysics Data System (ADS)

    Corley, Theresa Roebuck

    2000-10-01

    A researcher-designed survey assessed the perceptions of Alabama secondary science public school teachers toward the need for staff development and toward certain staff development strategies and programs. Factors that encouraged or discouraged attendance at voluntary staff development programs and opinions regarding effective and ineffective features of programs were identified. Data were analyzed using descriptive techniques. Percentages and frequencies were noted. Average rankings were computed for the staff development techniques considered most and least effective and for the preferred designs of future staff development offerings. Chi squares were computed to respond to each of the 4 research hypotheses. Narrative discussions and tables were utilized to report the data and provide clarification. This study related demographic information to the research hypotheses. Analysis of the research hypotheses revealed that experienced teachers agree more strongly about the features of staff development programs that they consider effective and about the factors that may affect participation in staff development programs. Analysis of the research questions revealed that secondary science teachers in Alabama agree that staff development is a personal responsibility but that the school systems are responsible for providing staff development opportunities. Teachers believe that staff development is needed annually in both science content and teaching strategies and favor lengthening the school year for staff development. Teachers identified interest level, graduate credit, ability to implement material, scheduling factors, and the reputation of the organizer as the most important factors in determining participation in voluntary staff development programs. Hands-on workshops were identified as the most effective type of voluntary staff development and teachers requested that future staff development experiences include hands-on workshops, networking, curriculum

  20. Tumor growth affects the metabonomic phenotypes of multiple mouse non-involved organs in an A549 lung cancer xenograft model

    PubMed Central

    Xu, Shan; Tian, Yuan; Hu, Yili; Zhang, Nijia; Hu, Sheng; Song, Dandan; Wu, Zhengshun; Wang, Yulan; Cui, Yanfang; Tang, Huiru

    2016-01-01

    The effects of tumorigenesis and tumor growth on the non-involved organs remain poorly understood although many research efforts have already been made for understanding the metabolic phenotypes of various tumors. To better the situation, we systematically analyzed the metabolic phenotypes of multiple non-involved mouse organ tissues (heart, liver, spleen, lung and kidney) in an A549 lung cancer xenograft model at two different tumor-growth stages using the NMR-based metabonomics approaches. We found that tumor growth caused significant metabonomic changes in multiple non-involved organ tissues involving numerous metabolic pathways, including glycolysis, TCA cycle and metabolisms of amino acids, fatty acids, choline and nucleic acids. Amongst these, the common effects are enhanced glycolysis and nucleoside/nucleotide metabolisms. These findings provided essential biochemistry information about the effects of tumor growth on the non-involved organs. PMID:27329570

  1. Misexpression of BRE gene in the developing chick neural tube affects neurulation and somitogenesis

    PubMed Central

    Wang, Guang; Li, Yan; Wang, Xiao-Yu; Chuai, Manli; Yeuk-Hon Chan, John; Lei, Jian; Münsterberg, Andrea; Lee, Kenneth Ka Ho; Yang, Xuesong

    2015-01-01

    The brain and reproductive expression (BRE) gene is expressed in numerous adult tissues and especially in the nervous and reproductive systems. However, little is known about BRE expression in the developing embryo or about its role in embryonic development. In this study, we used in situ hybridization to reveal the spatiotemporal expression pattern for BRE in chick embryo during development. To determine the importance of BRE in neurogenesis, we overexpressed BRE and also silenced BRE expression specifically in the neural tube. We established that overexpressing BRE in the neural tube indirectly accelerated Pax7+ somite development and directly increased HNK-1+ neural crest cell (NCC) migration and TuJ-1+ neurite outgrowth. These altered morphogenetic processes were associated with changes in the cell cycle of NCCs and neural tube cells. The inverse effect was obtained when BRE expression was silenced in the neural tube. We also determined that BMP4 and Shh expression in the neural tube was affected by misexpression of BRE. This provides a possible mechanism for how altering BRE expression was able to affect somitogenesis, neurogenesis, and NCC migration. In summary, our results demonstrate that BRE plays an important role in regulating neurogenesis and indirectly somite differentiation during early chick embryo development. PMID:25568339

  2. Mathematical modeling of capillary formation and development in tumor angiogenesis: penetration into the stroma.

    PubMed

    Levine, H A; Pamuk, S; Sleeman, B D; Nilsen-Hamilton, M

    2001-09-01

    The purpose of this paper is to present a mathematical model for the tumor vascularization theory of tumor growth proposed by Judah Folkman in the early 1970s and subsequently established experimentally by him and his coworkers [Ausprunk, D. H. and J. Folkman (1977) Migration and proliferation of endothelial cells in performed and newly formed blood vessels during tumor angiogenesis, Microvasc Res., 14, 53-65; Brem, S., B. A. Preis, ScD. Langer, B. A. Brem and J. Folkman (1997) Inhibition of neovascularization by an extract derived from vitreous Am. J. Opthalmol., 84, 323-328; Folkman, J. (1976) The vascularization of tumors, Sci. Am., 234, 58-64; Gimbrone, M. A. Jr, R. S. Cotran, S. B. Leapman and J. Folkman (1974) Tumor growth and neovascularization: an experimental model using the rabbit cornea, J. Nat. Cancer Inst., 52, 413-419]. In the simplest version of this model, an avascular tumor secretes a tumor growth factor (TGF) which is transported across an extracellular matrix (ECM) to a neighboring vasculature where it stimulates endothelial cells to produce a protease that acts as a catalyst to degrade the fibronectin of the capillary wall and the ECM. The endothelial cells then move up the TGF gradient back to the tumor, proliferating and forming a new capillary network. In the model presented here, we include two mechanisms for the action of angiostatin. In the first mechanism, substantiated experimentally, the angiostatin acts as a protease inhibitor. A second mechanism for the production of protease inhibitor from angiostatin by endothelial cells is proposed to be of Michaelis-Menten type. Mathematically, this mechanism includes the former as a subcase. Our model is different from other attempts to model the process of tumor angiogenesis in that it focuses (1) on the biochemistry of the process at the level of the cell; (2) the movement of the cells is based on the theory of reinforced random walks; (3) standard transport equations for the diffusion of

  3. Prepubertal tamoxifen treatment affects development of heifer reproductive tissues and related signaling pathways.

    PubMed

    Al Naib, A; Tucker, H L M; Xie, G; Keisler, D H; Bartol, F F; Rhoads, R P; Akers, R M; Rhoads, M L

    2016-07-01

    Prepubertal exposure of the developing ovaries and reproductive tract (RT) to estrogen or xenoestrogens can have acute and long-term consequences that compromise the reproductive performance of cattle. This research examined effects of the selective estrogen receptor modulator tamoxifen (TAM) on gene and protein abundance in prepubertal ovaries and RT, with a particular focus on signaling pathways that affect morphology. Tamoxifen was administered to Holstein heifer calves (n=8) daily (0.3mg/kg subcutaneously) from 28 to 120 d of age, when tissues were collected. Control calves (n=7) received an equal volume of excipient. Weight, gross measurements, and samples of reproductive tissues were collected, and protein and mRNA were extracted from snap-frozen samples of vagina, cervix, uterus, oviduct, ovary, and liver. Neither estradiol nor insulin-like growth factor I (IGFI) concentrations in the serum were affected by TAM treatment. Tamoxifen treatment reduced ovarian weight independently from effects on antral follicle populations, as there was no difference in visible antral follicle numbers on the day of collection. Estrogen receptor α (ESR1) and β (ESR2) mRNA, ESR1 protein, IGFI, progesterone receptor, total growth hormone receptor, WNT4, WNT5A, and WNT7A mRNA, in addition to mitogen-activated protein kinase (MAPK) and phosphorylated MAPK proteins were affected differently depending on the tissue examined. However, neither IGFI receptor mRNA nor protein abundance were affected by TAM treatment. Results indicate that reproductive development in prepubertal Holstein heifer calves is TAM-sensitive, and that bovine RT and ovarian development are supported, in part, by estrogen receptor-dependent mechanisms during the period studied here. Potential long-term consequences of such developmental disruption remain to be defined. PMID:27085397

  4. Early-Life Environmental Variation Affects Intestinal Microbiota and Immune Development in New-Born Piglets

    PubMed Central

    Zhang, Ling-li; Vastenhouw, Stéphanie A.; Heilig, Hans G. H. J.; Smidt, Hauke; Rebel, Johanna M. J.; Smits, Mari A.

    2014-01-01

    Background Early-life environmental variation affects gut microbial colonization and immune competence development; however, the timing and additional specifics of these processes are unknown. The impact of early-life environmental variations, as experienced under real life circumstances, on gut microbial colonization and immune development has not been studied extensively so far. We designed a study to investigate environmental variation, experienced early after birth, to gut microbial colonization and intestinal immune development. Methodology/Principal Findings To investigate effects of early-life environmental changes, the piglets of 16 piglet litters were divided into 3 groups per litter and experimentally treated on day 4 after birth. During the course of the experiment, the piglets were kept with their mother sow. Group 1 was not treated, group 2 was treated with an antibiotic, and group 3 was treated with an antibiotic and simultaneously exposed to several routine, but stressful management procedures, including docking, clipping and weighing. Thereafter, treatment effects were measured at day 8 after birth in 16 piglets per treatment group by community-scale analysis of gut microbiota and genome-wide intestinal transcriptome profiling. We observed that the applied antibiotic treatment affected the composition and diversity of gut microbiota and reduced the expression of a large number of immune-related processes. The effect of management procedures on top of the use of an antibiotic was limited. Conclusions/Significance We provide direct evidence that different early-life conditions, specifically focusing on antibiotic treatment and exposure to stress, affect gut microbial colonization and intestinal immune development. This reinforces the notion that the early phase of life is critical for intestinal immune development, also under regular production circumstances. PMID:24941112

  5. The Use of Narrative in Understanding how Cancer Affects Development: The Stories of One Cancer Survivor

    PubMed Central

    LEE, CHRISTINA SUNMI

    2010-01-01

    Although cancer disrupts development, the experience of having cancer is often understood using developmental theories that do not assume serious illness at an early age. This article presents a narrative analysis of one patient’s story of survivorship. She tells three interrelated stories: how others have reacted to her illness; her struggles to understand her illness; and how it has changed her priorities. Taken together, her stories comprise an account of how the experience has affected her development. Her story is an example of how individuals integrate unusual life events into their development. It suggests that focusing more on how unusual life experiences contribute to development may expand and enrich our understanding of developmental processes. PMID:21151860

  6. Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology.

    PubMed

    Selby, Mark J; Engelhardt, John J; Johnston, Robert J; Lu, Li-Sheng; Han, Minhua; Thudium, Kent; Yao, Dapeng; Quigley, Michael; Valle, Jose; Wang, Changyu; Chen, Bing; Cardarelli, Pina M; Blanset, Diann; Korman, Alan J

    2016-01-01

    The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies. PMID:27610613

  7. Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology

    PubMed Central

    Selby, Mark J.; Engelhardt, John J.; Johnston, Robert J.; Lu, Li-Sheng; Han, Minhua; Thudium, Kent; Yao, Dapeng; Quigley, Michael; Valle, Jose; Wang, Changyu; Chen, Bing; Cardarelli, Pina M.; Blanset, Diann; Korman, Alan J.

    2016-01-01

    The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies. PMID:27610613

  8. Phyllodes tumor of the breast: role of Axl and ST6GalNAcII in the development of mammary phyllodes tumors.

    PubMed

    Ren, Dongliang; Li, Yanyan; Gong, Yanxin; Xu, Jingchao; Miao, Xiaolong; Li, Xiangnan; Liu, Chen; Jia, Li; Zhao, Yongfu

    2014-10-01

    Phyllodes tumor exhibits an aggressive growth. The expression of many biological markers has been explored to discriminate between different grades of phyllodes tumor and to predict their behavior. The purpose of this study was to evaluate the implications of Axl and ST6GalNAcII in phyllodes tumors. Real-time PCR, Western blot, and immunohistochemical were used to analyze differential expression of ST6GalNAcII and Axl in phyllodes tumor (PT) cell lines and tissue specimens. RNAi assay, ECM invasion assay, and tumorigenicity assay were used to analyze the altered expression of ST6GalNAcII gene effects on the expression of Axl and invasive ability of phyllodes tumor cells in vitro and in vivo. Compared to benign tumors, borderline and malignant ones showed a remarkable increase in mRNA levels of Axl and ST6GalNAcII gene, and it was higher in malignant tumor cells than in borderline tumor cells. When ST6GalNAcII was silenced, compared to the control, the expression level of Axl was significantly reduced in malignant tumor cell transfectants and knockdown of ST6GalNAcII gene significantly inhibited invasive activity in malignant tumor cells. The high expression of ST6GalNAcII and Axl was significantly correlated with tumor grade and distance metastasis by immunohistochemical analysis. Axl and ST6GalNAcII expression increases with increasing tumor grade in mammary phyllodes tumors. ST6GalNAc II might be participated in the glycosylation of Axl, and this Axl glycosylation may mediate the tumorigenicity, invasion, and distant metastasis of PT cells.

  9. Paving the Road to Tumor Development and Spreading: Myeloid-Derived Suppressor Cells are Ruling the Fate

    PubMed Central

    Meirow, Yaron; Kanterman, Julia; Baniyash, Michal

    2015-01-01

    Cancer development is dependent on intrinsic cellular changes as well as inflammatory factors in the tumor macro and microenvironment. The inflammatory milieu nourishes the tumor and contributes to cancer progression. Numerous studies, including ours, have demonstrated that the tumor microenvironment is immunosuppressive, impairing the anticancer immune responses. Chronic inflammation was identified as the key process responsible for this immunosuppression via induction of immature myeloid-derived suppressor cells (MDSCs). Upon a prolonged immune response, MDSCs are polarized toward immunosuppressive cells meant to control the exacerbated immune response. In cancer, the chronic inflammatory response renders the MDSCs harmful. Polarized MDSCs suppress T-cells and natural killer cells, as well as antigen-presenting cells, abrogating the beneficial immune response. These changes in the immunological milieu could also lead to high frequency of mutations, enhanced cancer cell stemness, and angiogenesis, directly supporting tumor initiation, growth, and spreading. The presence of MDSCs in cancer poses a serious obstacle in a variety of immune-based therapies, which rely on the stimulation of antitumor immune responses. Cumulative data, including our own, suggest that the selection of an appropriate and effective anticancer therapy must take into consideration the host’s immune status as well as tumor-related parameters. Merging biomarkers for immune monitoring into the traditional patient’s categorization and follow-up can provide new predictive and diagnostic tools to the clinical practice. Chronic inflammation and MDSCs could serve as novel targets for therapeutic interventions, which can be combined with conventional cancer treatments such as chemotherapy, radiotherapy, and cancer cell-targeted and immune-based therapies. Intervention in environmental and tumor-specific inflammatory mechanisms will allow better clinical management of cancer toward more efficient

  10. Molecular characterization of patient-derived human pancreatic tumor xenograft models for preclinical and translational development of cancer therapeutics.

    PubMed

    Mattie, Mike; Christensen, Ashley; Chang, Mi Sook; Yeh, William; Said, Suzanne; Shostak, Yuriy; Capo, Linnette; Verlinsky, Alla; An, Zili; Joseph, Ingrid; Zhang, Yi; Kumar-Ganesan, Sathish; Morrison, Karen; Stover, David; Challita-Eid, Pia

    2013-10-01

    Preclinical evaluation of novel cancer agents requires models that accurately reflect the biology and molecular characteristics of human tumors. Molecular profiles of eight pancreatic ductal adenocarcinoma patient tumors were compared to corresponding passages of xenografts obtained by grafting tumor fragments into immunocompromised mice. Molecular characterization was performed by copy number analysis, gene expression and microRNA microarrays, mutation analysis, short tandem repeat (STR) profiling, and immunohistochemistry. Xenografts were found to be highly representative of their respective tumors, with a high degree of genetic stability observed by STR profiling and mutation analysis. Copy number variation (CNV) profiles of early and late xenograft passages were similar, with recurrent losses on chromosomes 1p, 3p, 4q, 6, 8p, 9, 10, 11q, 12p, 15q, 17, 18, 20p, and 21 and gains on 1q, 5p, 8q, 11q, 12q, 13q, 19q, and 20q. Pearson correlations of gene expression profiles of tumors and xenograft passages were above 0.88 for all models. Gene expression patterns between early and late passage xenografts were highly stable for each individual model. Changes observed in xenograft passages largely corresponded to human stromal compartment genes and inflammatory processes. While some differences exist between the primary tumors and corresponding xenografts, the molecular profiles remain stable after extensive passaging. Evidence for stability in molecular characteristics after several rounds of passaging lends confidence to clinical relevance and allows for expansion of models to generate the requisite number of animals required for cohorts used in drug screening and development studies.

  11. Institutional Guidance of Affective Bonding: Moral Values Development in Brazilian Military Education.

    PubMed

    Wortmeyer, Daniela Schmitz; Branco, Angela Uchoa

    2016-09-01

    In this article, our aim is to analyze institutional practices guided to promote the development of moral values within the context of military education of Brazilian Army combatant commissioned officers. From a cultural psychological approach, we discuss how social guidance within military culture operates at different levels of the affective-semiotic regulation of individuals, structuring complex experiences that give rise to hypergeneralized meaning fields regarding morality and military values. For this goal, we first introduce some theoretical topics related to values development, emphasizing their affective roots and role in the emergence, maintenance, amplification and attenuation of all relations between the person and the environment. Following a brief discussion on how social institutions try to promote changes in personal values, we provide an overview of values present in the military culture and socialization. Finally, the text focuses on the education of Brazilian Army combatant commissioned officers, describing how practices related to different levels of affective-semiotic experience combine in order to promote the internalization and externalization of specific moral values. We conclude suggesting issues for future investigation. PMID:26960934

  12. Institutional Guidance of Affective Bonding: Moral Values Development in Brazilian Military Education.

    PubMed

    Wortmeyer, Daniela Schmitz; Branco, Angela Uchoa

    2016-09-01

    In this article, our aim is to analyze institutional practices guided to promote the development of moral values within the context of military education of Brazilian Army combatant commissioned officers. From a cultural psychological approach, we discuss how social guidance within military culture operates at different levels of the affective-semiotic regulation of individuals, structuring complex experiences that give rise to hypergeneralized meaning fields regarding morality and military values. For this goal, we first introduce some theoretical topics related to values development, emphasizing their affective roots and role in the emergence, maintenance, amplification and attenuation of all relations between the person and the environment. Following a brief discussion on how social institutions try to promote changes in personal values, we provide an overview of values present in the military culture and socialization. Finally, the text focuses on the education of Brazilian Army combatant commissioned officers, describing how practices related to different levels of affective-semiotic experience combine in order to promote the internalization and externalization of specific moral values. We conclude suggesting issues for future investigation.

  13. Tumor-Induced Myeloid-Derived Suppressor Cells.

    PubMed

    De Sanctis, Francesco; Bronte, Vincenzo; Ugel, Stefano

    2016-06-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous, immune-suppressive leukocyte population that develops systemically and infiltrates tumors. MDSCs can restrain the immune response through different mechanisms including essential metabolite consumption, reactive oxygen and nitrogen species production, as well as display of inhibitory surface molecules that alter T-cell trafficking and viability. Moreover, MDSCs play a role in tumor progression, acting directly on tumor cells and promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. Many biological and pharmaceutical drugs affect MDSC expansion and functions in preclinical tumor models and patients, often reversing host immune dysfunctions and allowing a more effective tumor immunotherapy.

  14. Management and outcomes of intramedullary spinal cord tumors: A single center experience from a developing country

    PubMed Central

    Bakhshi, Saqib K.; Waqas, Muhammad; Shakaib, Baila; Enam, Syed A.

    2016-01-01

    Background: Intraoperative neurophysiology, high magnification microscopes, and ultrasonic aspirators are considered essential aid for the safe resection of intramedullary spinal cord tumors (IMSCTs). Most centers in developing countries such as Pakistan still lack these facilities. The purpose of this study was to review the management of IMSCTs at our hospital and to determine factors associated with the outcomes of surgery. Methods: This was a retrospective review of medical records of adult patients undergoing surgery for IMSCT over 12 years. The institutional ethical review committee approved this study. Data were collected regarding demographics, clinical and radiological features, and surgical details. Modified McCormick Scale was used to grade patients’ neurological status at admission, discharge, and follow-up. Statistical analysis was performed using the Statistical Package for Social Sciences version 22. Results: Forty three cases were reviewed. Mean age was 33.8 ± 15.1 years whereas median follow-up was 5 months (range: 0.25–96 months). Most patients had ependymoma (n = 16; 73%). Cervical region was the most commonly involved (n = 15; 34.9%). Gross total resection (GTR) was achieved in 30 cases (69.8%). The preoperative McCormick grade was significantly associated with follow-up McCormick grade (P value = 0.002). Eight patients (18.6%) underwent intraoperative electrophysiological monitoring, out of which GTR was achieved in all cases, and none had disease progression or recurrence. Ten patients received postoperative radiotherapy. Thirty five patients (81.4%) had progression free survival at last follow-up. Conclusions: We achieved a GTR rate of 68.9% for IMSCTs with limited resources. In few cases, where intraoperative electrophysiology was used, the rate of GTR was 100%. Preoperative neurological status was associated with better postoperative McCormick score.

  15. Management and outcomes of intramedullary spinal cord tumors: A single center experience from a developing country

    PubMed Central

    Bakhshi, Saqib K.; Waqas, Muhammad; Shakaib, Baila; Enam, Syed A.

    2016-01-01

    Background: Intraoperative neurophysiology, high magnification microscopes, and ultrasonic aspirators are considered essential aid for the safe resection of intramedullary spinal cord tumors (IMSCTs). Most centers in developing countries such as Pakistan still lack these facilities. The purpose of this study was to review the management of IMSCTs at our hospital and to determine factors associated with the outcomes of surgery. Methods: This was a retrospective review of medical records of adult patients undergoing surgery for IMSCT over 12 years. The institutional ethical review committee approved this study. Data were collected regarding demographics, clinical and radiological features, and surgical details. Modified McCormick Scale was used to grade patients’ neurological status at admission, discharge, and follow-up. Statistical analysis was performed using the Statistical Package for Social Sciences version 22. Results: Forty three cases were reviewed. Mean age was 33.8 ± 15.1 years whereas median follow-up was 5 months (range: 0.25–96 months). Most patients had ependymoma (n = 16; 73%). Cervical region was the most commonly involved (n = 15; 34.9%). Gross total resection (GTR) was achieved in 30 cases (69.8%). The preoperative McCormick grade was significantly associated with follow-up McCormick grade (P value = 0.002). Eight patients (18.6%) underwent intraoperative electrophysiological monitoring, out of which GTR was achieved in all cases, and none had disease progression or recurrence. Ten patients received postoperative radiotherapy. Thirty five patients (81.4%) had progression free survival at last follow-up. Conclusions: We achieved a GTR rate of 68.9% for IMSCTs with limited resources. In few cases, where intraoperative electrophysiology was used, the rate of GTR was 100%. Preoperative neurological status was associated with better postoperative McCormick score. PMID:27656322

  16. Factors Affecting the Disposition of Research-Based Innovations in the Development of a Basal Reading Program: A Case Analysis.

    ERIC Educational Resources Information Center

    Wile, J. M.

    A study investigated how the beliefs of literacy scholars affect the development of basal reading programs, the roles literacy scholars play in the development of new reading programs, and some of the critical factors that affect the disposition of innovative ideas. Two literacy scholars who had actively collaborated on the development of separate…

  17. Notes for developing a molecular test for the full characterization of circulating tumor cells

    PubMed Central

    Rossi, Elisabetta; Facchinetti, Antonella

    2015-01-01

    The proved association between the circulating tumor cell (CTC) levels and the patients’ survival parameters has been growing interest to investigate the molecular profile of these neoplastic cells among which hide out precursors capable of initiating a new distant metastatic lesion. The full characterization of the tumor cells in peripheral blood of cancer patients is expected to be of help for understanding and (prospectively) for counteracting the metastatic process. The major hitch that is hampering the successful gaining of this result is the lack of a consensus onto standard operating procedures (SOPs) for performing what we generally define as the “liquid biopsy”. Here we review the more recent acquisitions in the analysis of CTCs and tumor related nucleic acids, looking to the main open questions that are hampering their definitive employ in the routine clinical practice. PMID:26543333

  18. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development.

    PubMed

    Stachura, Joanna; Wachowska, Malgorzata; Kilarski, Witold W; Güç, Esra; Golab, Jakub; Muchowicz, Angelika

    2016-07-01

    Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT).

  19. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

    PubMed Central

    Stachura, Joanna; Wachowska, Malgorzata; Kilarski, Witold W.; Güç, Esra; Golab, Jakub; Muchowicz, Angelika

    2016-01-01

    ABSTRACT Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT).

  20. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development

    PubMed Central

    Stachura, Joanna; Wachowska, Malgorzata; Kilarski, Witold W.; Güç, Esra; Golab, Jakub; Muchowicz, Angelika

    2016-01-01

    ABSTRACT Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT). PMID:27622039

  1. The dual role of tumor lymphatic vessels in dissemination of metastases and immune response development.

    PubMed

    Stachura, Joanna; Wachowska, Malgorzata; Kilarski, Witold W; Güç, Esra; Golab, Jakub; Muchowicz, Angelika

    2016-07-01

    Lymphatic vasculature plays a crucial role in the immune response, enabling transport of dendritic cells (DCs) and antigens (Ags) into the lymph nodes. Unfortunately, the lymphatic system has also a negative role in the progression of cancer diseases, by facilitating the metastatic spread of many carcinomas to the draining lymph nodes. The lymphatics can promote antitumor immune response as well as tumor tolerance. Here, we review the role of lymphatic endothelial cells (LECs) in tumor progression and immunity and mechanism of action in the newest anti-lymphatic therapies, including photodynamic therapy (PDT). PMID:27622039

  2. Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice

    PubMed Central

    Wu, Kong-Yan; Zuo, Guo-Long; Li, Xiao-Feng; Ye, Qing; Deng, Yong-Qiang; Huang, Xing-Yao; Cao, Wu-Chun; Qin, Cheng-Feng; Luo, Zhen-Ge

    2016-01-01

    The recent Zika virus (ZIKV) epidemic in Latin America coincided with a marked increase in microcephaly in newborns. However, the causal link between maternal ZIKV infection and malformation of the fetal brain has not been firmly established. Here we show a vertical transmission of ZIKV in mice and a marked effect on fetal brain development. We found that intraperitoneal (i.p.) injection of a contemporary ZIKV strain in pregnant mice led to the infection of radial glia cells (RGs) of dorsal ventricular zone of the fetuses, the primary neural progenitors responsible for cortex development, and caused a marked reduction of these cortex founder cells in the fetuses. Interestingly, the infected fetal mice exhibited a reduced cavity of lateral ventricles and a discernable decrease in surface areas of the cortex. This study thus supports the conclusion that vertically transmitted ZIKV affects fetal brain development and provides a valuable animal model for the evaluation of potential therapeutic or preventative strategies. PMID:27174054

  3. Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice.

    PubMed

    Wu, Kong-Yan; Zuo, Guo-Long; Li, Xiao-Feng; Ye, Qing; Deng, Yong-Qiang; Huang, Xing-Yao; Cao, Wu-Chun; Qin, Cheng-Feng; Luo, Zhen-Ge

    2016-06-01

    The recent Zika virus (ZIKV) epidemic in Latin America coincided with a marked increase in microcephaly in newborns. However, the causal link between maternal ZIKV infection and malformation of the fetal brain has not been firmly established. Here we show a vertical transmission of ZIKV in mice and a marked effect on fetal brain development. We found that intraperitoneal (i.p.) injection of a contemporary ZIKV strain in pregnant mice led to the infection of radial glia cells (RGs) of dorsal ventricular zone of the fetuses, the primary neural progenitors responsible for cortex development, and caused a marked reduction of these cortex founder cells in the fetuses. Interestingly, the infected fetal mice exhibited a reduced cavity of lateral ventricles and a discernable decrease in surface areas of the cortex. This study thus supports the conclusion that vertically transmitted ZIKV affects fetal brain development and provides a valuable animal model for the evaluation of potential therapeutic or preventative strategies.

  4. Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice.

    PubMed

    Wu, Kong-Yan; Zuo, Guo-Long; Li, Xiao-Feng; Ye, Qing; Deng, Yong-Qiang; Huang, Xing-Yao; Cao, Wu-Chun; Qin, Cheng-Feng; Luo, Zhen-Ge

    2016-06-01

    The recent Zika virus (ZIKV) epidemic in Latin America coincided with a marked increase in microcephaly in newborns. However, the causal link between maternal ZIKV infection and malformation of the fetal brain has not been firmly established. Here we show a vertical transmission of ZIKV in mice and a marked effect on fetal brain development. We found that intraperitoneal (i.p.) injection of a contemporary ZIKV strain in pregnant mice led to the infection of radial glia cells (RGs) of dorsal ventricular zone of the fetuses, the primary neural progenitors responsible for cortex development, and caused a marked reduction of these cortex founder cells in the fetuses. Interestingly, the infected fetal mice exhibited a reduced cavity of lateral ventricles and a discernable decrease in surface areas of the cortex. This study thus supports the conclusion that vertically transmitted ZIKV affects fetal brain development and provides a valuable animal model for the evaluation of potential therapeutic or preventative strategies. PMID:27174054

  5. Resolving Tumor Heterogeneity: Genes Involved in Chordoma Cell Development Identified by Low-Template Analysis of Morphologically Distinct Cells

    PubMed Central

    Wagner, Karin; Meditz, Katharina; Kolb, Dagmar; Feichtinger, Julia; Thallinger, Gerhard G.; Quehenberger, Franz; Liegl-Atzwanger, Bernadette; Rinner, Beate

    2014-01-01

    The classical sacrococcygeal chordoma tumor presents with a typical morphology of lobulated myxoid tumor tissue with cords, strands and nests of tumor cells. The population of cells consists of small non-vacuolated cells, intermediate cells with a wide range of vacuolization and large heavily vacuolated (physaliferous) cells. To date analysis was only performed on bulk tumor mass because of its rare incidence, lack of suited model systems and technical limitations thereby neglecting its heterogeneous composition. We intended to clarify whether the observed cell types are derived from genetically distinct clones or represent different phenotypes. Furthermore, we aimed at elucidating the differences between small non-vacuolated and large physaliferous cells on the genomic and transcriptomic level. Phenotype-specific analyses of small non-vacuolated and large physaliferous cells in two independent chordoma cell lines yielded four candidate genes involved in chordoma cell development. UCHL3, coding for an ubiquitin hydrolase, was found to be over-expressed in the large physaliferous cell phenotype of MUG-Chor1 (18.7-fold) and U-CH1 (3.7-fold) cells. The mannosyltransferase ALG11 (695-fold) and the phosphatase subunit PPP2CB (18.6-fold) were found to be up-regulated in large physaliferous MUG-Chor1 cells showing a similar trend in U-CH1 cells. TMEM144, an orphan 10-transmembrane family receptor, yielded contradictory data as cDNA microarray analysis showed up- but RT-qPCR data down-regulation in large physaliferous MUG-Chor1 cells. Isolation of few but morphologically identical cells allowed us to overcome the limitations of bulk analysis in chordoma research. We identified the different chordoma cell phenotypes to be part of a developmental process and discovered new genes linked to chordoma cell development representing potential targets for further research in chordoma tumor biology. PMID:24503940

  6. Relations between different coping strategies for social stress, tumor development and neuroendocrine and immune activity in male mice.

    PubMed

    Azpiroz, A; De Miguel, Z; Fano, E; Vegas, O

    2008-07-01

    This study analyzes the effects of acute social stress and different coping strategies employed in response to it on the development of B16F10 melanoma pulmonary metastases, the activation of the HPA axis and the NKG2D receptor expression. To this end, male OF1 mice were subjected to 24h of social stress using the sensorial contact model. This model includes three 5-min sessions of direct social interaction with resident cagemates selected for consistent levels of aggression. Subjects' behavior was videotaped and assessed. Six days after the first social interaction (1st social stress), the animals were inoculated with tumor cells or vehicle, and six days later, both tumor-bearing and non tumor-bearing mice were subjected to a second 24h sensorial contact social stress session (2nd social stress). One hour after the 2nd social interaction, corticosterone levels and NKG2D receptor expression were determined. Lung metastatic foci numbers were determined 21 days after inoculation (15 days post-stress). Social stress increased the number of pulmonary metastases and the serum corticosterone level. A combination of cluster and discriminant analyses established the existence of two types of coping strategies: (1) a passive-reactive strategy characterized by subjects dedicating a greater percentage of time to submission, flee and avoidance behaviors; and (2) an active-proactive strategy, characterized by subjects dedicating a greater percentage of time to attack and non social exploration behaviors. Subjects belonging to the passive-reactive group were found to have a higher number of tumor foci, a higher level of corticosterone and a lower NKG2D receptor expression than subjects in the active-proactive group. These data indicate the relationship between different coping strategies for social stress and tumor development. PMID:18061400

  7. Decision analysis and risk models for land development affecting infrastructure systems.

    PubMed

    Thekdi, Shital A; Lambert, James H

    2012-07-01

    Coordination and layering of models to identify risks in complex systems such as large-scale infrastructure of energy, water, and transportation is of current interest across application domains. Such infrastructures are increasingly vulnerable to adjacent commercial and residential land development. Land development can compromise the performance of essential infrastructure systems and increase the costs of maintaining or increasing performance. A risk-informed approach to this topic would be useful to avoid surprise, regret, and the need for costly remedies. This article develops a layering and coordination of models for risk management of land development affecting infrastructure systems. The layers are: system identification, expert elicitation, predictive modeling, comparison of investment alternatives, and implications of current decisions for future options. The modeling layers share a focus on observable factors that most contribute to volatility of land development and land use. The relevant data and expert evidence include current and forecasted growth in population and employment, conservation and preservation rules, land topography and geometries, real estate assessments, market and economic conditions, and other factors. The approach integrates to a decision framework of strategic considerations based on assessing risk, cost, and opportunity in order to prioritize needs and potential remedies that mitigate impacts of land development to the infrastructure systems. The approach is demonstrated for a 5,700-mile multimodal transportation system adjacent to 60,000 tracts of potential land development.

  8. Prenatal sodium arsenite affects early development of serotonergic neurons in the fetal rat brain.

    PubMed

    Senuma, Mika; Mori, Chisato; Ogawa, Tetsuo; Kuwagata, Makiko

    2014-11-01

    Prenatal arsenite exposure has been associated with developmental disorders in children, including reduced IQ and language abnormalities. Animal experiments have also shown that exposure to arsenite during development induced developmental neurotoxicity after birth. However, the evidence is not enough, and the mechanism is poorly understood, especially on the exposure during early brain development. This study assessed effects of sodium (meta) arsenite shortly after exposure on early developing fetal rat brains. Pregnant rats were administered 50 mg/L arsenite in their drinking water or 20 mg/kg arsenite orally using a gastric tube, on gestational days (GD) 9-15. Fetal brains were examined on GD16. Pregnant rats administered 20 mg/kg arsenite showed reductions in maternal body weight gain and food consumption during treatment, but not with 50 mg/L arsenite. Arsenite did not affect fetal development, as determined by body weight, mortality and brain size. Arsenite also did not induce excessive cell death or affect neural cell division in any region of the fetal neuroepithelium. Thyrosine hydroxylase immunohistochemistry revealed no difference in the distribution of catecholaminergic neurons between fetuses of arsenite treated and control rats. However, reductions in the number of serotonin positive cells in the fetal median and dorsal raphe nuclei were observed following maternal treatment with 20mg/kg arsenite. Image analysis showed that the serotonin positive areas decreased in all fetal mid- and hind-brain areas without altering distribution patterns. Maternal stress induced by arsenite toxicity did not alter fetal development. These results suggest that arsenite-induced neurodevelopmental toxicity involves defects in the early development of the serotonin nervous system.

  9. Atrazine exposure affects longevity, development time and body size in Drosophila melanogaster.

    PubMed

    Marcus, Sarah R; Fiumera, Anthony C

    2016-01-01

    Atrazine is the one of the most widely used herbicides in the United States and non-target organisms may encounter it in the environment. Atrazine is known to affect male reproduction in both vertebrates and invertebrates but less is known about its effects on other fitness traits. Here we assessed the effects of five different chronic exposure levels on a variety of fitness traits in Drosophila melanogaster. We measured male and female longevity, development time, proportion pupated, proportion emerged, body size, female mating rate, fertility and fecundity. Atrazine exposure decreased the proportion pupated, the proportion emerged and adult survival. Development time was also affected by atrazine and exposed flies pupated and emerged earlier than controls. Although development time was accelerated, body size was actually larger in some of the exposures. Atrazine exposure had no effect on female mating rate and the effects on female fertility and fecundity were only observed in one of the two independent experimental blocks. Many of the traits showed non-monotonic dose response curves, where the intermediate concentrations showed the largest effects. Overall this study shows that atrazine influences a variety of life history traits in the model genetic system, D. melanogaster, and future studies should aim to identify the molecular mechanisms of toxicity. PMID:27317622

  10. Insight on Genes Affecting Tuber Development in Potato upon Potato spindle tuber viroid (PSTVd) Infection.

    PubMed

    Katsarou, Konstantina; Wu, Yun; Zhang, Runxuan; Bonar, Nicola; Morris, Jenny; Hedley, Pete E; Bryan, Glenn J; Kalantidis, Kriton; Hornyik, Csaba

    2016-01-01

    Potato (Solanum tuberosum L) is a natural host of Potato spindle tuber viroid (PSTVd) which can cause characteristic symptoms on developing plants including stunting phenotype and distortion of leaves and tubers. PSTVd is the type species of the family Pospiviroidae, and can replicate in the nucleus and move systemically throughout the plant. It is not well understood how the viroid can affect host genes for successful invasion and which genes show altered expression levels upon infection. Our primary focus in this study is the identification of genes which can affect tuber formation since viroid infection can strongly influence tuber development and especially tuber shape. In this study, we used a large-scale method to identify differentially expressed genes in potato. We have identified defence, stress and sugar metabolism related genes having altered expression levels upon infection. Additionally, hormone pathway related genes showed significant up- or down-regulation. DWARF1/DIMINUTO, Gibberellin 7-oxidase and BEL5 transcripts were identified and validated showing differential expression in viroid infected tissues. Our study suggests that gibberellin and brassinosteroid pathways have a possible role in tuber development upon PSTVd infection.

  11. Insight on Genes Affecting Tuber Development in Potato upon Potato spindle tuber viroid (PSTVd) Infection

    PubMed Central

    Zhang, Runxuan; Bonar, Nicola; Morris, Jenny; Hedley, Pete E.; Bryan, Glenn J.; Kalantidis, Kriton; Hornyik, Csaba

    2016-01-01

    Potato (Solanum tuberosum L) is a natural host of Potato spindle tuber viroid (PSTVd) which can cause characteristic symptoms on developing plants including stunting phenotype and distortion of leaves and tubers. PSTVd is the type species of the family Pospiviroidae, and can replicate in the nucleus and move systemically throughout the plant. It is not well understood how the viroid can affect host genes for successful invasion and which genes show altered expression levels upon infection. Our primary focus in this study is the identification of genes which can affect tuber formation since viroid infection can strongly influence tuber development and especially tuber shape. In this study, we used a large-scale method to identify differentially expressed genes in potato. We have identified defence, stress and sugar metabolism related genes having altered expression levels upon infection. Additionally, hormone pathway related genes showed significant up- or down-regulation. DWARF1/DIMINUTO, Gibberellin 7-oxidase and BEL5 transcripts were identified and validated showing differential expression in viroid infected tissues. Our study suggests that gibberellin and brassinosteroid pathways have a possible role in tuber development upon PSTVd infection. PMID:26937634

  12. Insight on Genes Affecting Tuber Development in Potato upon Potato spindle tuber viroid (PSTVd) Infection.

    PubMed

    Katsarou, Konstantina; Wu, Yun; Zhang, Runxuan; Bonar, Nicola; Morris, Jenny; Hedley, Pete E; Bryan, Glenn J; Kalantidis, Kriton; Hornyik, Csaba

    2016-01-01

    Potato (Solanum tuberosum L) is a natural host of Potato spindle tuber viroid (PSTVd) which can cause characteristic symptoms on developing plants including stunting phenotype and distortion of leaves and tubers. PSTVd is the type species of the family Pospiviroidae, and can replicate in the nucleus and move systemically throughout the plant. It is not well understood how the viroid can affect host genes for successful invasion and which genes show altered expression levels upon infection. Our primary focus in this study is the identification of genes which can affect tuber formation since viroid infection can strongly influence tuber development and especially tuber shape. In this study, we used a large-scale method to identify differentially expressed genes in potato. We have identified defence, stress and sugar metabolism related genes having altered expression levels upon infection. Additionally, hormone pathway related genes showed significant up- or down-regulation. DWARF1/DIMINUTO, Gibberellin 7-oxidase and BEL5 transcripts were identified and validated showing differential expression in viroid infected tissues. Our study suggests that gibberellin and brassinosteroid pathways have a possible role in tuber development upon PSTVd infection. PMID:26937634

  13. Development of bone-targeted catalase derivatives for inhibition of bone metastasis of tumor cells in mice.

    PubMed

    Zheng, Yunlong; Nishikawa, Makiya; Ikemura, Mai; Yamashita, Fumiyoshi; Hashida, Mitsuru

    2012-02-01

    Removal of hydrogen peroxide by delivering catalase to the vicinity of metastasizing tumor cells is a promising approach for inhibiting tumor metastasis. To inhibit bone metastasis, catalase was conjugated with 3,5-di(ethylamino-2,2-bisphosphono)benzoic acid (Bip), a derivative of bone-seeking bisphosphonates, polyethylene glycol (PEG), or both. Bip-conjugated catalase derivatives, that is, catalase-Bip and PEG-catalase-Bip, exhibited a higher affinity for bone matrix as compared with their counterparts without Bip. The tissue distribution of (111) In-labeled catalase derivatives indicated that the accumulation of radioactivity in bones was increased by conjugation of either Bip or PEG with catalase. An experimental bone metastasis model was developed by injecting male C57BL/6 mice with murine melanoma B16-BL6/Luc cells, which stably express firefly luciferase into left ventricle. Repeated injections of catalase to tumor-bearing mice had no significant effect on the number of melanoma cells in tibiae and femurs, whereas injections of catalase-Bip, PEG-catalase, or PEG-catalase-Bip significantly reduced the number. These results indicate that targeted delivery of catalase to the bones can be achieved by conjugating the enzyme with either Bip or PEG, and this delivery is effective in inhibiting the bone metastasis of tumor cells. PMID:21953593

  14. Factors affecting the development of somatic cell nuclear transfer embryos in Cattle.

    PubMed

    Akagi, Satoshi; Matsukawa, Kazutsugu; Takahashi, Seiya

    2014-01-01

    Nuclear transfer is a complex multistep procedure that includes oocyte maturation, cell cycle synchronization of donor cells, enucleation, cell fusion, oocyte activation and embryo culture. Therefore, many factors are believed to contribute to the success of embryo development following nuclear transfer. Numerous attempts to improve cloning efficiency have been conducted since the birth of the first sheep by somatic cell nuclear transfer. However, the efficiency of somatic cell cloning has remained low, and applications have been limited. In this review, we discuss some of the factors that affect the developmental ability of somatic cell nuclear transfer embryos in cattle.

  15. Can Breast Tumors Affect the Oxidative Status of the Surrounding Environment? A Comparative Analysis among Cancerous Breast, Mammary Adjacent Tissue, and Plasma.

    PubMed

    Panis, C; Victorino, V J; Herrera, A C S A; Cecchini, A L; Simão, A N C; Tomita, L Y; Cecchini, R

    2015-01-01

    In this paper, we investigated the oxidative profile of breast tumors in comparison with their normal adjacent breast tissue. Our study indicates that breast tumors present enhanced oxidative/nitrosative stress, with concomitant augmented antioxidant capacity when compared to the adjacent normal breast. These data indicate that breast cancers may be responsible for the induction of a prooxidant environment in the mammary gland, in association with enhanced TNF-α and nitric oxide. PMID:26697139

  16. Can Breast Tumors Affect the Oxidative Status of the Surrounding Environment? A Comparative Analysis among Cancerous Breast, Mammary Adjacent Tissue, and Plasma.

    PubMed

    Panis, C; Victorino, V J; Herrera, A C S A; Cecchini, A L; Simão, A N C; Tomita, L Y; Cecchini, R

    2015-01-01

    In this paper, we investigated the oxidative profile of breast tumors in comparison with their normal adjacent breast tissue. Our study indicates that breast tumors present enhanced oxidative/nitrosative stress, with concomitant augmented antioxidant capacity when compared to the adjacent normal breast. These data indicate that breast cancers may be responsible for the induction of a prooxidant environment in the mammary gland, in association with enhanced TNF-α and nitric oxide.

  17. Development of a diagnosis index of tropical cyclones affecting the Korean Peninsula

    NASA Astrophysics Data System (ADS)

    Choi, Jae-Won; Cha, Yumi

    2016-06-01

    This study has developed the index for diagnosis on possibility that tropical cyclones (TCs) affect Korean Peninsula. This index is closely related to the strength of the western North Pacific subtropical high (WNPSH), which is calculated as a difference in meridional wind between at the highest correlation area (around Korean Peninsula) and at the lowest correlation area (sea southeast of Japan) through a correlation analysis between TC frequency that affects Korean Peninsula and 500 hPa meridional wind. In low frequency years that selected from Korea affecting TC index, anomalous northeasterly is strengthened from Korea to the South China Sea because the center of anomalous anticyclonic circulation is located to northwest of Korean Peninsula. Thus, TCs tend to move westward from the sea east of the Philippines to the mainland China. On the other hand, in high frequency years, anomalous southwesterly serves as steering flow that more TCs move toward Korean Peninsula because the center of anomalous anticyclonic circulation is located to sea east of Japan. Consequently, this study suggests that if this index is calculated using real time 500 hPa meridional winds that forecasted by dynamic models during the movement of TCs, the possibility that TCs approach Korean Peninsula can be diagnosed in real time.

  18. Small molecule screen for compounds that affect vascular development in the zebrafish retina

    PubMed Central

    Kitambi, Satish S.; McCulloch, Kyle J.; Peterson, Randall T.; Malicki, Jarema J.

    2009-01-01

    Blood vessel formation in the vertebrate eye is a precisely regulated process. In the human retina, both an excess and a deficiency of blood vessels may lead to a loss of vision. To gain insight into the molecular basis of vessel formation in the vertebrate retina and to develop pharmacological means of manipulating this process in a living organism, we further characterized the embryonic zebrafish eye vasculature, and performed a small molecule screen for compounds that affect blood vessel morphogenesis. The screening of approximately 2000 compounds revealed four small molecules that at specific concentrations affect retinal vessel morphology but do not produce obvious changes in trunk vessels, or in the neuronal architecture of the retina. Of these, two induce a pronounced widening of vessel diameter without a substantial loss of vessel number, one compound produces a loss of retinal blood vessels accompanied by a mild increase of their diameter, and finally one other generates a severe loss of retinal vessels. This work demonstrates the utility of zebrafish as a screening tool for small molecules that affect eye vasculature and presents several compounds of potential therapeutic importance. PMID:19445054

  19. Interstitial laser thermotherapy: developments in the treatment of small deep-seated brain tumors.

    PubMed

    Menovsky, T; Beek, J F; Roux, F X; Bown, S G

    1996-12-01

    New technical advances have made feasible the utilization of laser to destroy deep-seated brain tumors under real-time monitoring. Experience with interstitial laser thermotherapy (ILTT) in animal and clinical studies has been obtained. These studies are summarized and the future potential of ILTT in neurosurgery is discussed.

  20. Development affects in vitro vascular tone and calcium sensitivity in ovine cerebral arteries

    PubMed Central

    Geary, Greg G; Osol, George J; Longo, Lawrence D

    2004-01-01

    We have shown recently that development from neonatal to adult life affects cerebrovascular tone of mouse cerebral arteries through endothelium-derived vasodilatory mechanisms. The current study tested the hypothesis that development from fetal to adult life affects cerebral artery vascular smooth muscle (VSM) [Ca2+]i sensitivity and tone through a mechanism partially dependent upon endothelium-dependent signalling. In pressurized resistance sized cerebral arteries (∼150 μm) from preterm (95 ± 2 days gestation (95 d)) and near-term (140 ± 2 days gestation (140 d)) fetuses, and non-pregnant adults, we measured vascular diameter (μm) and [Ca2+]i (nm) as a function of intravascular pressure. We repeated these studies in the presence of inhibition of nitric oxide synthase (NOS; with l-NAME), cyclo-oxygenase (COX; with indomethacin) and endothelium removal (E–). Cerebrovasculature tone (E+) was greater in arteries from 95 d fetuses and adults compared to 140 d sheep. Ca2+ sensitivity was similar in 95 d fetuses and adults, but much lower in 140 d fetuses. Removal of endothelium resulted in a reduction in lumen diameter as a function of pressure (greater tone) in all treatment groups. [Ca2+]i sensitivity differences among groups were magnified after E–. NOS inhibition decreased diameter as a function of pressure in each age group, with a significant increase in [Ca2+]i to pressure ratio only in the 140 d fetuses. Indomethacin increased tone and increased [Ca2+]i in the 140 d fetuses, but not the other age groups. Development from near-term to adulthood uncovered an interaction between NOS- and COX-sensitive substances that functioned to modulate artery diameter but not [Ca2+]i. This study suggests that development is associated with significant alterations in cerebral vascular smooth muscle (VSM), endothelium, NOS and COX responses to intravascular pressure. We speculate that these changes have important implications in the regulation of cerebral blood flow in

  1. Vagotomy Affects the Development of Oral Tolerance and Increases Susceptibility to Develop Colitis Independently of α-7 Nicotinic Receptor

    PubMed Central

    Di Giovangiulio, Martina; Bosmans, Goele; Meroni, Elisa; Stakenborg, Nathalie; Florens, Morgane; Farro, Giovanna; Gomez-Pinilla, Pedro J; Matteoli, Gianluca; Boeckxstaens, Guy E

    2016-01-01

    Vagotomy (VGX) increases the susceptibility to develop colitis suggesting a crucial role for the cholinergic anti-inflammatory pathway in the regulation of the immune responses. Since oral tolerance and the generation of regulatory T cells (Tregs) are crucial to preserve mucosal immune homeostasis, we studied the effect of vagotomy and the involvement of α7 nicotinic receptors (α7nAChR) at the steady state and during colitis. Therefore, the development of both oral tolerance and colitis (induced by dextran sulfate sodium (DSS) or via T cell transfer) was studied in vagotomized mice and in α7nAChR-/- mice. VGX, but not α7nAChR deficiency, prevented oral tolerance establishment. This effect was associated with reduced Treg conversion in the lamina propria and mesenteric lymphnodes. To the same extent, vagotomized mice, but not α7nAChR-/- mice, developed a more severe DSS colitis compared with control mice treated with DSS, associated with a decreased number of colonic Tregs. However, neither VGX nor absence of α7nAChR in recipient mice affected colitis development in the T cell transfer model. In line, deficiency of α7nAChR exclusively in T cells did not influence the development of colitis induced by T cell transfer. Our results indicate a key role for the vagal intestinal innervation in the development of oral tolerance and colitis, most likely by modulating induction of Tregs independently of α7nAChR. PMID:27341335

  2. Children affected by HIV/AIDS: SAFE, a model for promoting their security, health, and development.

    PubMed

    Betancourt, Theresa S; Fawzi, Mary K S; Bruderlein, Claude; Desmond, Chris; Kim, Jim Y

    2010-05-01

    A human security framework posits that individuals are the focus of strategies that protect the safety and integrity of people by proactively promoting children's well being, placing particular emphasis on prevention efforts and health promotion. This article applies this framework to a rights-based approach in order to examine the health and human rights of children affected by HIV/AIDS. The SAFE model describes sources of insecurity faced by children across four fundamental dimensions of child well-being and the survival strategies that children and families may employ in response. The SAFE model includes: Safety/protection; Access to health care and basic physiological needs; Family/connection to others; and Education/livelihoods. We argue that it is critical to examine the situation of children through an integrated lens that effectively looks at human security and children's rights through a holistic approach to treatment and care rather than artificially limiting our scope of work to survival-oriented interventions for children affected by HIV/AIDS. Interventions targeted narrowly at children, in isolation of their social and communal environment as outlined in the SAFE model, may in fact undermine protective resources in operation in families and communities and present additional threats to children's basic security. An integrated approach to the basic security and care of children has implications for the prospects of millions of children directly infected or indirectly affected by HIV/AIDS around the world. The survival strategies that young people and their families engage in must be recognized as a roadmap for improving their protection and promoting healthy development. Although applied to children affected by HIV/AIDS in the present analysis, the SAFE model has implications for guiding the care and protection of children and families facing adversity due to an array of circumstances from armed conflict and displacement to situations of extreme poverty.

  3. Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells.

    PubMed

    Oliveira-Costa, Joao Paulo; de Carvalho, Alex Fiorini; da Silveira, da Giorgia Gobbi; Amaya, Peter; Wu, Yongqi; Park, Kyoung-Joo Jenny; Gigliola, Mabel Pinilla; Lustberg, Maryam; Buim, Marcilei Eliza Cavicchioli; Ferreira, Elisa Napolitano; Kowalski, Luiz Paulo; Chalmers, Jeffrey J; Soares, Fernando Augusto; Carraro, Dirce Maria; Ribeiro-Silva, Alfredo

    2015-08-28

    Oral squamous cell carcinoma (OSCC) is the most common tumor of the oral cavity and has been associated with poor prognosis. Scarce prognostic markers are available for guiding treatment and/or sub-classifying patients. This study aims to identify biomarkers by searching for genes whose expression is increased or decreased during tumor progression (through T1 to T4 stages). Thirty-six samples from all tumor size stages (from T1 to T4) were analyzed using cDNA microarrays. Selected targets were analyzed by immunohistochemistry and in circulating tumor cells by immunofluorescence and Nanostring. Correlation was shown between PD-L1 and tumor size and lymph node metastasis, HOXB9 and tumor size, BLNK and perineural invasion, and between ZNF813 and perineural invasion. PD-L1 positivity was an independent prognostic factor in this cohort (p = 0.044, HH = 0.426). In CTCs from patients with locally advanced OSCC, we found a strong cytoplasmatic expression of PD-L1. PD-L1 is a ligand of PD-1 and is believed to limit T cell activity in inflammatory responses and limit autoimmune diseases. We demonstrated an important role for PD-L1 in primary tumors according to tumor size, and in disease specific survival. Therefore, we could further determine individuals with PD-L1+ CTCs, and possibly follow treatment using CTCs. PMID:26041877

  4. Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells

    PubMed Central

    Oliveira-Costa, Joao Paulo; de Carvalho, Alex Fiorini; da Silveira, Giorgia Gobbi; Amaya, Peter; Wu, Yongqi; Park, Kyoung-Joo Jenny; Gigliola, Mabel Pinilla; Lustberg, Maryam; Buim, Marcilei Eliza Cavicchioli; Ferreira, Elisa Napolitano; Kowalski, Luiz Paulo; Chalmers, Jeffrey J.; Soares, Fernando Augusto; Carraro, Dirce Maria; Ribeiro-Silva, Alfredo

    2015-01-01

    Oral squamous cell carcinoma (OSCC) is the most common tumor of the oral cavity and has been associated with poor prognosis. Scarce prognostic markers are available for guiding treatment and/or sub-classifying patients. This study aims to identify biomarkers by searching for genes whose expression is increased or decreased during tumor progression (through T1 to T4 stages). Thirty-six samples from all tumor size stages (from T1 to T4) were analyzed using cDNA microarrays. Selected targets were analyzed by immunohistochemistry and in circulating tumor cells by immunofluorescence and Nanostring. Correlation was shown between PD-L1 and tumor size and lymph node metastasis, HOXB9 and tumor size, BLNK and perineural invasion, and between ZNF813 and perineural invasion. PD-L1 positivity was an independent prognostic factor in this cohort (p = 0.044, HH = 0.426). In CTCs from patients with locally advanced OSCC, we found a strong cytoplasmatic expression of PD-L1. PD-L1 is a ligand of PD-1 and is believed to limit T cell activity in inflammatory responses and limit autoimmune diseases. We demonstrated an important role for PD-L1 in primary tumors according to tumor size, and in disease specific survival. Therefore, we could further determine individuals with PD-L1+ CTCs, and possibly follow treatment using CTCs. PMID:26041877

  5. Imaging hypoxia in tumors.

    PubMed

    Ballinger, J R

    2001-10-01

    For many years, it has been known that hypoxia affects the response to radiotherapy in human cancers. Hypoxic regions can develop as a tumor grows beyond the ability of its blood supply to deliver oxygen to the full extent of the tumor, exacerbated by vascular spasm or compression caused by increased interstitial fluid pressure. However, hypoxia is heterogeneous, and tumors that appear identical by clinical and radiographic criteria can vary greatly in their extent of hypoxia. Several invasive procedures to measure hypoxia in tumors have been developed and are predictive of response to therapy, but none of these is in routine clinical use because of technical complexity, inconvenience, and inability to obtain repeated measures. Noninvasive imaging with a hypoxia-directed radiopharmaceutical could be of great clinical utility. Most such radiopharmaceuticals under development use 2-nitroimidazole as the targeting moiety. 2-Nitroimidazole, which is selectively reduced and bound in hypoxic tissues, has been labeled with F-18, Cu-64/67, I-123, and Tc-99m. Of these, F-18-fluoromisonidazole and I-123-iodoazomycin arabinoside (IAZA) have been most widely studied clinically. Non-nitro-containing bioreductive complexes, such as the Cu-60/62/64 thiosemicarbazone ATSM and Tc-99m butylene amineoxime (BnAO or HL91), have also been evaluated. In particular, 1-123-IAZA and Cu-60-ATSM have shown correlation with response to radiotherapy in preliminary clinical studies. However, more preclinical studies comparing imaging with validated invasive methods and clinical studies with outcome measures are required. Nuclear medicine is poised to play an important role in optimizing the therapy of patients with hypoxic tumors.

  6. Estrogen-related receptor α in normal adrenal cortex and adrenocortical tumors: involvement in development and oncogenesis

    PubMed Central

    Felizola, Saulo J.A.; Nakamura, Yasuhiro; Hui, Xiao-Gang; Satoh, Fumitoshi; Morimoto, Ryo; Midorikawa, Sanae; Suzuki, Shinichi; Rainey, William E.; Sasano, Hironobu

    2014-01-01

    Aims The nuclear hormone receptor estrogen-related receptor α (ERRα) regulates the activation of mitochondrial genes in various human tissues, but its role in the adrenal gland and its disorders has not been defined. Therefore, we examined ERRα expression in both normal adrenal cortex (NAC) and adrenocortical tumors (ACT) in order to study the possible correlation of ERRα with adrenal development and tumor development. Methods Human adrenal specimens (non-pathological fetal n=7; non-pathological post-birth n=40; aldosterone producing adenoma (APA) n=11; cortisol producing adenoma (CPA) n=11; adrenocortical carcinoma (ACC) n=8) were immunohistochemically examined in this study. NAC (n=13) and ACT (n=14) frozen tissue specimens were also available for studying ERRα mRNA levels. Key findings In fetal NAC tissues, ERRα labeling index (LI) in fetal zone (FC) was significantly higher that that in neocortex (NC), and the difference among age groups for overall mean LI was statistically significant when analyzed by cortical layer. ERRα LI was also significantly higher in adrenocortical carcinomas (ACCs) than in other types of ACTs. ACC tended to have the highest mRNA levels for ERRα compared to other adrenocortical tumors. Significance Results of our present study suggest a possible role of ERRα in adrenal development and ACC. PMID:23123734

  7. MSX2 in pancreatic tumor development and its clinical application for the diagnosis of pancreatic ductal adenocarcinoma

    PubMed Central

    Satoh, Kennichi; Hamada, Shin; Shimosegawa, Tooru

    2012-01-01

    MSX2, a member of the homeobox genes family, is demonstrated to be the downstream target for ras signaling pathway and is expressed in a variety of carcinoma cells, suggesting its relevance to the development of ductal pancreatic tumors since pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary-mucinous neoplasia (IPMN) harbor frequent K-ras gene mutations. Recent studies revealed the roles of MSX2 in the development of carcinoma of various origins including pancreas. Among gastrointestinal tumors, PDAC is one of the most malignant. PDAC progresses rapidly to develop metastatic lesions, frequently by the time of diagnosis, and these tumors are usually resistant to conventional chemotherapy and radiation therapy. The molecular mechanisms regulating the aggressive behavior of PDAC still remain to be clarified. On the other hand, IPMN of the pancreas is distinct from PDAC because of its intraductal growth in the main pancreatic duct or secondary branches with rare invasion and metastasis to distant organs. However, recent evidence indicated that once IPMN showed stromal invasion, it progresses like PDAC. Therefore, it is important to determin how IPMN progresses to malignant phenotype. In this review, we focus on the involvement of MSX2 in the enhancement of malignant behavior in PDAC and IPMN, and further highlight the clinical approach to differentiate PDAC from chronic pancreatitis by evaluating MSX2 expression level. PMID:23162473

  8. Pathogenesis of pituitary tumors.

    PubMed

    Yu, Run; Melmed, Shlomo

    2010-01-01

    Pituitary tumors are common and mostly benign neoplasia which cause excess or deficiency of pituitary hormones and compressive damage to adjacent organs. Oncogene activation [e.g. PTTG (pituitary tumor-transforming gene) and HMGA2], tumor suppressor gene inactivation (e.g. MEN1 and PRKAR1A), epigenetic changes (e.g. methylation) and humoral factors (e.g. ectopic production of stimulating hormones) are all possible pituitary tumor initiators; the micro-environment of pituitary tumors including steroid milieu, angiogenesis and abnormal cell adhesion further promote tumor growth. Senescence, a cellular defence mechanism against malignant transformation, may explain the benign nature of at least some pituitary tumors. We suggest that future research on pituitary tumor pathogenesis should incorporate systems approaches, and address regulatory mechanisms for pituitary cell proliferation, development of new animal models of pituitary tumor and isolation of functional human pituitary tumor cell lines. PMID:20541667

  9. Tumor necrosis factor-alpha and interleukin-17 differently affects Langerhans cell distribution and activation in an innovative three-dimensional model of normal human skin.

    PubMed

    Prignano, Francesca; Arnaboldi, Francesca; Cornaghi, Laura; Landoni, Federica; Tripo, Lara; Preis, Franz William Baruffaldi; Donetti, Elena

    2015-02-01

    Among the several cytokines involved in the psoriasis pathogenesis, tumor necrosis factor (TNF)-alpha and interleukin (IL)-17 play a central role. Many biomolecular steps remain unknown due to difficulty to obtain psoriatic models. To investigate the effect of TNF-alpha and IL-17 on the ultrastructure, immunophenotype, and number of epidermal Langerhans cells (LCs), human skin explants (n=7) were cultured air-liquid interface in a Transwell system. Four different conditions were used: medium alone (control), medium added with 100 ng/ml TNF-alpha or 50 ng/ml IL-17 or a combination of both cytokines. Samples were harvested 24 and 48 h after cytokine addition and were frozen. Samples harvested at 24h were also processed for transmission electron microscopy (TEM). By immunofluorescence analysis with anti-human Langerin antibody (three experiments/sample) we calculated the percentage of LCs/mm(2) of living epidermis after 24 and 48 h of incubation (considering control as 100%). At 24h LC number was significantly higher in samples treated with both cytokines (216.71+15.10%; p<0.001) and in TNF-alpha (125.74+26.24%; p<0.05). No differences were observed in IL-17-treated samples (100.14+38.42%). After 48 h, the number of epidermal Langerin-positive cells in IL-17- and TNF-alpha treated samples slightly decreased (94.99+36.79% and 101.37+23% vs. their controls, respectively). With the combination of both cytokines epidermal LCs strongly decreased (120+13.36%). By TEM, upon TNF-alpha stimulus LCs appeared with few organelles, mostly mitochondria, lysosomes, and scattered peripherical BGs. Upon IL-17 stimulus, LCs showed a cytoplasm with many mitochondria and numerous BGs close to the perinuclear space and Golgi apparatus, but also at the periphery, at the beginning of the dendrites. The addition of both cytokines did not affect LC ultrastructure. Our study showed that IL-17 induced significant changes in LC ultrastructure, while the combination of both cytokines seems to

  10. Type of Inflammation Differentially Affects Expression of Interleukin 1β and 6, Tumor Necrosis Factor-α and Toll-Like Receptors in Subclinical Endometritis in Mares.

    PubMed

    Siemieniuch, Marta J; Szóstek, Anna Z; Gajos, Katarzyna; Kozdrowski, Roland; Nowak, Marcin; Okuda, Kiyoshi

    2016-01-01

    Mares that fail to conceive or lose their embryos, without showing typical signs of clinical endometritis, should be suspected of subclinical endometritis (SE). In this study, the question was addressed: does SE fully activate selected mechanisms of innate immunity in mares? For this aim, expression of mRNAs for Toll-like Receptor 2 and 4 (TLR 2/4), interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor α (TNF) was examined in control mares versus either mares suffering from chronic endometritis (ChE) or subacute suppurative endometritis (SSE). The concentrations of IL-1β, IL-6 and TNF-α in supernatants from endometrial tissue cultures after 4 h incubation were measured using the enzyme immunoassay (EIA) method. Eighty-two warmblood mares, of known breeding history, were enrolled in this study. Based on histopathological assessment, mares were classified as suffering from ChE, SSE or as being healthy. In addition, immuno-localization of both TLR2 and TLR4 as well as TNF-α was investigated in the equine endometria. The mRNA expression of TLR2 (P < 0.01), IL-1β (P < 0.0001), IL-6 (P < 0.0001) and TLR4 and TNF (P < 0.05) was up-regulated in endometria of mares suffering from SSE compared with unaffected mares. Concentrations of IL-6 and TNF-α were increased only in mares exhibiting SSE, compared with unaffected (P < 0.01 for both) and ChE mares (P < 0.05 for both). Immuno-localization of TNF-α and TLRs was confirmed, both in unaffected and SE-affected endometria, and was present in the luminal and glandular epithelia and stromal cells. The severity of inflammation impacts the immune response and fosters activation of innate immunity mechanisms, as observed in the endometria of mares. The intracellular localization of TLRs and TNF-α in the endometria indicates a key role of endometrial epithelial and stromal cells in the immune response and inflammation. PMID:27152525

  11. Type of Inflammation Differentially Affects Expression of Interleukin 1β and 6, Tumor Necrosis Factor-α and Toll-Like Receptors in Subclinical Endometritis in Mares

    PubMed Central

    Szóstek, Anna Z.; Gajos, Katarzyna; Kozdrowski, Roland; Nowak, Marcin; Okuda, Kiyoshi

    2016-01-01

    Mares that fail to conceive or lose their embryos, without showing typical signs of clinical endometritis, should be suspected of subclinical endometritis (SE). In this study, the question was addressed: does SE fully activate selected mechanisms of innate immunity in mares? For this aim, expression of mRNAs for Toll-like Receptor 2 and 4 (TLR 2/4), interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor α (TNF) was examined in control mares versus either mares suffering from chronic endometritis (ChE) or subacute suppurative endometritis (SSE). The concentrations of IL-1β, IL-6 and TNF-α in supernatants from endometrial tissue cultures after 4 h incubation were measured using the enzyme immunoassay (EIA) method. Eighty-two warmblood mares, of known breeding history, were enrolled in this study. Based on histopathological assessment, mares were classified as suffering from ChE, SSE or as being healthy. In addition, immuno-localization of both TLR2 and TLR4 as well as TNF-α was investigated in the equine endometria. The mRNA expression of TLR2 (P < 0.01), IL-1β (P < 0.0001), IL-6 (P < 0.0001) and TLR4 and TNF (P < 0.05) was up-regulated in endometria of mares suffering from SSE compared with unaffected mares. Concentrations of IL-6 and TNF-α were increased only in mares exhibiting SSE, compared with unaffected (P < 0.01 for both) and ChE mares (P < 0.05 for both). Immuno-localization of TNF-α and TLRs was confirmed, both in unaffected and SE-affected endometria, and was present in the luminal and glandular epithelia and stromal cells. The severity of inflammation impacts the immune response and fosters activation of innate immunity mechanisms, as observed in the endometria of mares. The intracellular localization of TLRs and TNF-α in the endometria indicates a key role of endometrial epithelial and stromal cells in the immune response and inflammation. PMID:27152525

  12. Minute dosages of alpha(nu)beta3-targeted fumagillin nanoparticles impair Vx-2 tumor angiogenesis and development in rabbits.

    PubMed

    Winter, Patrick M; Schmieder, Anne H; Caruthers, Shelton D; Keene, Jeffery L; Zhang, Huiying; Wickline, Samuel A; Lanza, Gregory M

    2008-08-01

    Fumagillin suppresses angiogenesis in cancer models and clinical trials, but it is associated with neurotoxicity at systemic doses. In this study, alpha(nu)beta(3)-targeted fumagillin nanoparticles were used to suppress the neovasculature and inhibit Vx-2 adenocarcinoma development using minute drug doses. Tumor-bearing rabbits were treated on days 6, 9, and 12 postimplantation with alpha(nu)beta(3)-targeted fumagillin nanoparticles (30 microg/kg), alpha(nu)beta(3)-targeted nanoparticles without drug, nontargeted fumagillin nanoparticles (30 microg/kg) or saline. On day 16, MRI was performed with alpha(nu)beta(3)-targeted paramagnetic nanoparticles to quantify tumor size and assess neovascularity. Tumor volume was reduced among rabbits receiving alpha(nu)beta(3)-targeted fumagillin nanoparticles (470+/-120 mm(3)) compared with the three control groups: nontargeted fumagillin nanoparticles (1370+/-300 mm(3), P<0.05), alpha(nu)beta(3)-targeted nanoparticles without drug (1080+/-180 mm(3), P<0.05) and saline (980+/-80 mm(3), P<0.05). MR molecular imaging of control rabbits (no fumagillin) revealed a predominant peripheral distribution of neovascularity representing 7.2% of the tumor rim volume, which decreased to 2.8% (P<0.05) with alpha(nu)beta(3)-targeted fumagillin nanoparticle treatment. Microscopically, the tumor parenchyma tended to show T-cell infiltration after targeted fumagillin treatment, which was not appreciated in control animals. These results suggest that alpha(nu)beta(3)-targeted fumagillin nanoparticles could provide a safe and effective means to deliver MetAP2 inhibitors alone or in combination with cytotoxic or immunotherapy.

  13. GPI/AMF inhibition blocks the development of the metastatic phenotype of mature multi-cellular tumor spheroids.

    PubMed

    Gallardo-Pérez, Juan Carlos; Rivero-Segura, Nadia Alejandra; Marín-Hernández, Alvaro; Moreno-Sánchez, Rafael; Rodríguez-Enríquez, Sara

    2014-06-01

    Epithelial-mesenchymal transition (EMT) and cellular invasiveness are two pivotal processes for the development of metastatic tumor phenotypes. The metastatic profile of non-metastatic MCF-7 cells growing as multi-cellular tumor microspheroids (MCTSs) was analyzed by determining the contents of the EMT, invasive and migratory proteins, as well as their migration and invasiveness potential and capacity to secrete active cytokines such as the glucose phosphate isomerase/AMF (GPI/AMF). As for the control, the same analysis was also performed in MCF-7 and MDA-MB-231 (highly metastatic, MDA) monolayer cells, and in stage IIIB and IV human metastatic breast biopsies. The proliferative cell layers (PRL) of mature MCF-7 MCTSs, MDA monolayer cells and metastatic biopsies exhibited increased cellular contents (2-15 times) of EMT (β-catenin, SNAIL), migratory (vimentin, cytokeratin, and fibronectin) and invasive (MMP-1, VEGF) proteins versus MCF-7 monolayer cells, quiescent cell layers of mature MCF-7 MCTS and non-metastatic breast biopsies. The increase in metastatic proteins correlated with substantially elevated cellular abilities for migration (18-times) and invasiveness (13-times) and with the higher level (6-times) of the cytokine GPI/AMF in the extracellular medium of PRL, as compared to MCF-7 monolayer cells. Interestingly, the addition of the GPI/AMF inhibitors erythrose-4-phosphate or 6-phosphogluconate at micromolar doses significantly decreased its extracellular activity (>80%), with a concomitant diminution in the metastatic protein content and migratory tumor cell capacity, and with no inhibitory effect on tumor lactate production or toxicity on 3T3 mouse fibroblasts. The present findings provide new insights into the discovery of metabolic inhibitors to be used as complementary therapy against metastatic and aggressive tumors.

  14. Polycyclic aromatic hydrocarbons affect survival and development of common snapping turtle (Chelydra serpentina) embryos and hatchlings.

    PubMed

    Van Meter, Robin J; Spotila, James R; Avery, Harold W

    2006-08-01

    Polycyclic aromatic hydrocarbons (PAHs) are toxic compounds found in the John Heinz National Wildlife Refuge in Philadelphia, Pennsylvania. We assessed the impact of PAHs and crude oil on snapping turtle development and behavior by exposing snapping turtle eggs from the Refuge and from three clean reference sites to individual PAHs or a crude oil mixture at stage 9 of embryonic development. Exposure to PAHs had a significant effect on survival rates in embryos from one clean reference site, but not in embryos from the other sites. There was a positive linear relationship between level of exposure to PAHs and severity of deformities in embryos collected from two of the clean reference sites. Neither righting response nor upper temperature tolerance (critical thermal maximum, CTM) of snapping turtle hatchlings with no or minor deformities was significantly affected by exposure to PAHs. PMID:16360251

  15. Perinatal Environmental Exposures Affect Mammary Development, Function, and Cancer Risk in Adulthood*

    PubMed Central

    Fenton, Suzanne E.; Reed, Casey; Newbold, Retha R.

    2012-01-01

    Puberty is an important transition that enables reproduction of mammalian species. Precocious puberty, specifically early thelarche (the appearance of breast “buds”), in girls of multiple ethnic backgrounds is a major health problem in the United States and other countries. The cause for a continued decrease in the age of breast development in girls is unknown, but environmental factors likely play a major role. Laboratory and epidemiological studies have identified several individual environmental factors that affect breast development, but further progress is needed. Current research needs include increased attention to and recording of prenatal and neonatal environmental exposures, testing of marketed chemicals for effects on the mammary gland, and understanding of the mammary gland–specific mechanisms that are altered by chemicals. Such research is required to halt the increasing trend toward puberty at earlier ages. PMID:22017681

  16. 7-Rhamnosylated Flavonols Modulate Homeostasis of the Plant Hormone Auxin and Affect Plant Development.

    PubMed

    Kuhn, Benjamin M; Errafi, Sanae; Bucher, Rahel; Dobrev, Petre; Geisler, Markus; Bigler, Laurent; Zažímalová, Eva; Ringli, Christoph

    2016-03-01

    Flavonols are a group of secondary metabolites that affect diverse cellular processes. They are considered putative negative regulators of the transport of the phytohormone auxin, by which they influence auxin distribution and concomitantly take part in the control of plant organ development. Flavonols are accumulating in a large number of glycosidic forms. Whether these have distinct functions and diverse cellular targets is not well understood. The rol1-2 mutant of Arabidopsis thaliana is characterized by a modified flavonol glycosylation profile that is inducing changes in auxin transport and growth defects in shoot tissues. To determine whether specific flavonol glycosides are responsible for these phenotypes, a suppressor screen was performed on the rol1-2 mutant, resulting in the identification of an allelic series of UGT89C1, a gene encoding a flavonol 7-O-rhamnosyltransferase. A detailed analysis revealed that interfering with flavonol rhamnosylation increases the concentration of auxin precursors and auxin metabolites, whereas auxin transport is not affected. This finding provides an additional level of complexity to the possible ways by which flavonols influence auxin distribution and suggests that flavonol glycosides play an important role in regulating plant development.

  17. Paternal benzo[a]pyrene exposure affects gene expression in the early developing mouse embryo.

    PubMed

    Brevik, Asgeir; Lindeman, Birgitte; Rusnakova, Vendula; Olsen, Ann-Karin; Brunborg, Gunnar; Duale, Nur

    2012-09-01

    The health of the offspring depends on the genetic constitution of the parental germ cells. The paternal genome appears to be important; e.g., de novo mutations in some genes seem to arise mostly from the father, whereas epigenetic modifications of DNA and histones are frequent in the paternal gonads. Environmental contaminants which may affect the integrity of the germ cells comprise the polycyclic aromatic hydrocarbon, benzo[a]pyrene (B[a]P). B[a]P has received much attention due to its ubiquitous distribution, its carcinogenic and mutagenic potential, and also effects on reproduction. We conducted an in vitro fertilization (IVF) experiment using sperm cells from B[a]P-exposed male mice to study effects of paternal B[a]P exposure on early gene expression in the developing mouse embryo. Male mice were exposed to a single acute dose of B[a]P (150 mg/kg, ip) 4 days prior to isolation of cauda sperm, followed by IVF of oocytes from unexposed superovulated mice. Gene expression in fertilized zygotes/embryos was determined using reverse transcription-qPCR at the 1-, 2-, 4-, 8-, and blastocyst cell stages of embryo development. We found that paternal B[a]P exposure altered the expression of numerous genes in the developing embryo especially at the blastocyst stage. Some genes were also affected at earlier developmental stages. Embryonic gene expression studies seem useful to identify perturbations of signaling pathways resulting from exposure to contaminants, and can be used to address mechanisms of paternal effects on embryo development.

  18. Protective role of taurine in developing offspring affected by maternal alcohol consumption

    PubMed Central

    Ananchaipatana-Auitragoon, Pilant; Ananchaipatana-Auitragoon, Yutthana; Siripornpanich, Vorasith; Kotchabhakdi, Naiphinich

    2015-01-01

    Maternal alcohol consumption is known to affect offspring growth and development, including growth deficits, physical anomalies, impaired brain functions and behavioral disturbances. Taurine, a sulfur-containing amino acid, is essential during development, and continually found to be protective against neurotoxicity and various tissue damages including those from alcohol exposure. However, it is still unknown whether taurine can exert its protection during development of central nervous system and whether it can reverse alcohol damages on developed brain later in life. This study aims to investigate protective roles of taurine against maternal alcohol consumption on growth and development of offspring. The experimental protocol was conducted using ICR-outbred pregnant mice given 10 % alcohol, with or without maternal taurine supplementation during gestation and lactation. Pregnancy outcomes, offspring mortality and successive bodyweight until adult were monitored. Adult offspring is supplemented taurine to verify its ability to reverse damages on learning and memory through a water maze task performance. Our results demonstrate that offspring of maternal alcohol exposure, together with maternal taurine supplementation show conserved learning and memory, while that of offspring treated taurine later in life are disturbed. Taurine provides neuroprotective effects and preserves learning and memory processes when given together with maternal alcohol consumption, but not shown such effects when given exclusively in offspring. PMID:26648819

  19. Development of a K-edge micro CT for the study of tumor angiogenesis in small animals

    NASA Astrophysics Data System (ADS)

    Baldazzi, G.; Bollini, D.; Gambaccini, M.; Golfieri, R.; Lollini, P. L.; Margotti, A.; Masetti, S.; Nicoletti, G.; Pancaldi, G.; Roma, L.; Rossi, P. L.; Zuffa, M.

    2006-03-01

    A new micro scanner CT for small animals - based on a couple of parallel quasi-monochromatic X-ray beams with different energies selectable - is under development. The aim of the study is the in vivo imaging of the tumor neo-angiogenesis pattern in an earlier diagnostic phase and the analysis of cancer growth and metastasis development in different tumor types on mice. As previously demonstrated1, the imaging system based on dual energy quasi- monochromatic X-ray beams provides higher sensitivity in detecting low concentrations of iodine contrast medium if compared to traditional polychromatic X-ray equipment. The K-edge dual energy radiology is a realistic candidate to recognize tumor neo- angiogenesis process in a very earlier stage, in which conventional systems are very poor in sensitivity. Moreover, the capability to select the energy of quasi-monochromatic beams enables the use of the Multi-Energy Quasi-Monochromatic technique. Tuning properly the energies allows maximizing the difference between linear absorption coefficients of healthy and pathological tissues increasing the contrast of pathologies. In order to optimize the contrast with this technique, one should know the X-ray energy regions where the absorption of healthy and pathological tissues eventually differs and that for each type of tumor under study. For this reason, the systematic X-ray characterization of many types of healthy and neoplastic human and mice tissues is in progress. The goal of this work is to obtain a catalog of liner attenuation coefficients of a variety of pathological tissues for respect to the healthy ones, finding any energy windows of radiological differentiation. In this paper, the theoretical methods are presented with development works and preliminary results.

  20. New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: Part I--Formulation development and in-vitro characterization.

    PubMed

    Tinkov, Steliyan; Winter, Gerhard; Coester, Conrad; Bekeredjian, Raffi

    2010-04-01

    Despite high antitumor efficacy and a broad application spectrum, clinical treatment with anthracycline chemotherapeutics is often limited by severe adverse effects such as cardiotoxicity and myelosupression. In recent years, tumor drug targeting has evolved as a promising strategy to increase local drug concentration and reduce systemic side effects. One recent approach for targeting solid tumors is the application of microbubbles, loaded with chemotherapeutic drugs. These advanced drug carriers can be safely administered to the patient by intravenous infusion, and will circulate through the entire vasculature. Their drug load can be locally released by ultrasound targeted microbubble destruction. In addition, tumors can be precisely localized by diagnostic ultrasound since microbubbles act as contrast agents. In the present work a novel microbubble carrier for doxorubicin has been developed and characterized in-vitro. In contrast to many recent tumor-targeting MB designs the newly developed doxorubicin-loaded microbubbles possess a soft but stable phospholipid monolayer shell. Importantly, the active drug is embedded in the microbubble shell and is complexed to the phospholipids by both electrostatic and hydrophobic interactions. Despite their drug load, these novel microbubbles retained all important physical characteristics for ultrasound targeted microbubble destruction, comparable with the commercially available ultrasound contrast agents. In cell culture studies doxorubicin-loaded microbubbles in combination with ultrasound demonstrated an about 3 fold increase of the anti-proliferative activity compared to free doxorubicin and doxorubicin-loaded liposomes. For the first time in the literature the intracellular partition of free doxorubicin and phospholipid-complexed doxorubicin were compared. In conclusion, new doxorubicin-loaded microbubbles with ideal physical characteristics were developed. In-vitro studies show enhanced cytotoxic activity compared to

  1. Development of Hospital Information Systems: User Participation and Factors Affecting It

    PubMed Central

    Rahimi, Bahlol; Safdari, Reza; Jebraeily, Mohamad

    2014-01-01

    Introduction: Given the large volume of data generated in hospitals, in order to efficiently management them; using hospital information system (HIS) is critical. User participation is one of the major factors in the success of HIS that in turn leads Information needs and processes to be correctly predicted and also their commitment to the development of HIS to be augmented. The purpose of this study is to investigate the participation rate of users in different stages of HIS development as well as to identify the factors affecting it. Method and materials: This is a descriptive–cross sectional study which was inducted in 2014. The study population consists of 140 HIS users (from different types of job including physicians, nurses, laboratory, radiology and HIM staffs) from Teaching Hospitals Affiliated to Urmia University of Medical Sciences. Data were collected using a self-structured questionnaire which was estimated as both reliable and valid. The data were analyzed by SPSS software descriptive statistics and analytical statistics (t-test and chi-square). Results: The highest participation rate of users in the four-stage development of the HIS was related to the implementation phase (2.88) and the lowest participation rate was related to analysis (1.23). The test results showed that the rate of user participation was not satisfactory in none of the stages of development (P< 0.05). The most important factors in increasing user participation include established teamwork from end-users and the support of top managers from HIS development. Conclusion: According to the results obtained from the study, it seems that health care administrators must have a detailed plan for user participation prior to the development and purchase of HIS so that they identify the real needs as well as increase their commitment and motivations to develop, maintain and upgrade the system, and in this way, the success of the system will be assured. PMID:25684849

  2. Development and biophysical characterization of HK polymer for siRNA delivery to tumor in a mouse model

    NASA Astrophysics Data System (ADS)

    Chou, Szu-Ting

    Delivery has been the major obstacle for nucleic acid therapeutics, including the RNA interference (RNAi) approach. Mixson's lab has been focused on the development of a non-viral peptide-based delivery system, HK (histidine-lysine) polymers, which have shown promise as carriers of plasmids and small interference RNA (siRNA) in several cell lines and in tumor-bearing models. In a previous study, a four-branched peptide, denoted H3K(+H)4b, with the predominant repeating -HHHK- sequence in the branch, has been shown to be the most effective and least toxic carrier in vitro and in vivo.. Building on these results, I utilized different approaches including several structure and stability molecular characterization methods to study polyplex and to develop more effective carriers for improved therapy with siRNAs targeting malignancies. To understand the role of histidine in the stability of the H3K(+H)4b/siRNA polyplex, the physicochemical properties were investigated. With the use of isothermal titration calorimetry and heteronuclear single quantum coherence NMR, histidines were shown to form hydrogen bonds with siRNA, which enhanced the stability and biological activity of the polyplexes. In addition, to enhance resistance to nucleases and to target the tumors selectively, H3K(+H)4b was chemically modified with different patterns of polyethylene glycol (PEG) and cyclic RGD (Arg-Gly-Asp, cRGD) peptide conjugates. The luciferase marker gene expressed stably by tumor xenografts in mouse models was targeted in order to evaluate the efficacy of HK carriers of siRNA that differed in location and number of cRGD-PEG attachments. The most effective carrier was (RGD-PEG)4H3K(+H) (RP-HK), which has a cRGD-PEG on each of its four terminal branches. Consistent with its prolonged stability, as observed by pharmacokinetic studies, the RP-HK polyplex down-regulated luciferase activity in tumor xenografts by nearly 70% compared with the untreated group. Subsequently, the RP-HK polyplex

  3. Development of tumor lysis syndrome (TLS): A potential risk factor in cancer patients receiving anticancer therapy

    PubMed Central

    Rasool, Mahmood; Malik, Arif; Qureshi, Muhammad Saeed; Ahmad, Riaz; Manan, Abdul; Asif, Muhammad; Naseer, Muhammad Imran; Pushparaj, Peter Natesan

    2014-01-01

    Tumor lysis syndrome (TLS) is characterized by hyperuricaemia, hyperphosphatemia, hyperkalaemia, as well as hypocalcaemia due to the breakdown of tumor cells undergoing cancer therapy (chemo/radio). Therefore it is of interest to evaluate oxidative stress using selective biological markers [Malondialdehyde (MDA), Superoxide Dismutase (SOD), Glutathione (GSH) and Catalase (CAT)] in TLS. We report the marked differences (statistically significant with control) observed among a selected set of biomarkers of oxidative stress (MDA = 8.66±1.37; SOD = 0.15±0.11; GSH = 2.25±.77; CAT = 0.76±.57) in TLS patients in addition to other conventional biomarkers. Moreover, correlation was investigated among the parameters of oxidative stress and other circulating biomarkers of TLS. Data suggest the use of SOD, MDA, and GSH as potential diagnostic biomarker for TLS with other biomarkers. PMID:25512688

  4. [Effects of organic fluorosilicone compounds on the development of tumors in mice].

    PubMed

    Snegireva, A E; Shaposhnikova, G M; Ignatenko, M A; Shevliagin, V Ia; Dobrynin, Ia V; Nikolaeva, T G; Borovskiĭ, Iu V; Karabach, O S

    1990-02-01

    The influence of new synthesized fluoro-silicium-organic complexes on the virus-induced Rauscher leukosis and cell-transferred MX-11 mouse sarcoma was studied. We also studied the cytotoxic effects of these complexes in vitro in the human CaOv cells. Two complexes from seven studied were cytotoxic for CaOv cells. Five complexes from seven studied diminished the mortality of animals with MX-11 tumors on the 27-th day of observation, but the total life duration of the animals in the experimental group was the same as in controls. One complex from seven studied increased the life duration of mice with MX-11 tumors. No effects were noted in relation to mice virus-induced Rauscher leukosis.

  5. Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells

    PubMed Central

    Yun, Jihye; Rago, Carlo; Cheong, Ian; Pagliarini, Ray; Angenendt, Philipp; Rajagopalan, Harith; Schmidt, Kerstin; Wilson, James K. V.; Markowitz, Sandy; Zhou, Shibin; Diaz, Luis A.; Velculescu, Victor; Lengauer, Christoph; Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas

    2010-01-01

    Tumor progression is driven by genetic mutations, but little is known about the environmental conditions that select for these mutations. Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, we found that GLUT1, encoding glucose transporter-1, was one of three genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wild-type KRAS alleles were subjected to a low glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1 and 4% of these survivors had acquired new KRAS mutations. The glycolysis inhibitor, 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Together, these data suggest that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors. PMID:19661383

  6. Desferrioxamine enhances AIDS-associated Kaposi's sarcoma tumor development in a xenograft model.

    PubMed

    Simonart, Thierry; Boelaert, Johan R; Andrei, Graciela; van den Oord, Joost J; Degraef, Chantale; Hermans, Philippe; Noel, Jean-Christophe; Van Vooren, Jean-Paul; Heenen, Michel; De Clercq, Erik; Snoeck, Robert

    2002-07-10

    Iron is suspected to be involved in the induction and/or progression of various human tumors. More particularly, we have previously shown that iron may be involved in the pathogenesis of Kaposi's sarcoma (KS). We have also shown that the iron chelator desferrioxamine (DFO) has a potent anti-KS activity in vitro, suggesting that it may represent a potential therapeutic approach for the treatment of KS. The present study was designed to investigate the effect of DFO on the growth of human KS xenografts in immunodeficient mice. Unexpectedly, we found that mice treated with DFO (400 mg/kg, 3 times weekly) (n = 30) exhibited a marked enhancement of tumor growth compared with control mice (n = 33) (230 +/- 134 mm(2) versus 143 +/- 70 mm p < 0.01). No enhancement of tumor growth was seen in mice treated with iron-saturated DFO. At least 2 findings suggest that this paradoxic pro-KS activity occurred independently of mice iron stores. First, treatment with DFO had only a marginal effect on ferritin and hematocrit levels. Second, induction of effective iron depletion by an iron-poor diet (6.7 mg iron/kg diet) (n = 23) did not have a deleterious effect on the growth of the KS xenografts. The lesions obtained from the DFO-treated animals exhibited a significantly decreased apoptotic index (p < 0.05), indicating that some antiapoptotic mechanism induced by DFO may be operating in vivo to favour tumor growth. In conclusion, our data show that DFO has a stimulatory effect on KS growth in immunodeficient mice, suggesting that this drug is not indicated in patients with KS.

  7. Targeting the tumor microenvironment

    PubMed Central

    Bournazou, Eirini; Bromberg, Jacqueline

    2013-01-01

    Persistent JAK-STAT3 signaling is implicated in many aspects of tumorigenesis. Apart from its tumor-intrinsic effects, STAT3 also exerts tumor-extrinsic effects, supporting tumor survival and metastasis. These involve the regulation of paracrine cytokine signaling, alterations in metastatic sites rendering these permissive for the growth of cancer cells and subversion of host immune responses to create an immunosuppressive environment. Targeting this signaling pathway is considered a novel promising therapeutic approach, especially in the context of tumor immunity. In this article, we will review to what extent JAK-STAT3-targeted therapies affect the tumor microenvironment and whether the observed effects underlie responsiveness to therapy. PMID:24058812

  8. P-element mutations affecting embryonic peripheral nervous system development in Drosophila melanogaster

    SciTech Connect

    Kania, A.; Salzberg, A.; Bhat, M.

    1995-04-01

    The Drosophila embryonic peripheral nervous system (PNS) is an excellent model system to study the molecular mechanisms governing neural development. To identify genes controlling PNS development, we screened 2000 lethal P-element insertion strains. The PNS of mutant embryos was examined using the neural specific marker MAb 22C10, and 92 mutant strains were retained for further analysis. Genetic and cytological analysis of these strains shows that 42 mutations affect previously isolated genes that are known to be required for PNS development: longitudinals lacking (19), mastermind (15), numb (4), big brain (2), and spitz (2). The remaining 50 mutations were classified into 29 complementation groups and the P-element insertions were cytologically mapped. The mutants were classified in five major classes on the basis of their phenotype: gain of neurons, loss of neurons, organizational defects, pathfinding defects and morphological defects. Herein we report the preliminary phenotypic characterization of each of these complementation groups as well as the embryonic lacZ expression pattern of each P-element strain. Our analysis indicates that in most of the P-element insertion strains, the lacZ reporter gene is not expressed in the developing PNS. 52 refs., 5 figs., 5 tabs.

  9. Melatonin, But not auxin, affects postnatal reproductive development in the marsh rice rat (Oryzomys palustris).

    PubMed

    Edmonds, Kent E

    2013-06-01

    Melatonin and the plant hormone auxin (indole-3-acetic acid) have some structural similarity and, may thus exert comparable physiological effects on reproduction and growth. To test this possibility, I examined the effects of melatonin and auxin administration on reproductive and non-reproductive organ development in an animal model, the marsh rice rat Oryzomys palustris. Juvenile males housed under 14L:10D conditions were injected daily for four weeks with saline, melatonin, auxin, or melatonin and auxin, and the development of the testes and other organs was assessed. Melatonin alone significantly inhibited the development of the testes, seminal vesicles, Harderian glands, and overall somatic growth, but not the spleen. Auxin did not affect any endpoint measured. When melatonin was administered simultaneously with auxin, the melatonin effects dominated in suppressing reproduction and growth. The administration of melatonin or auxin in the drinking water produced results similar to the effects of melatonin and auxin injections reported herein. Lastly, both melatonin and auxin in the drinking water failed to alter any short photoperiod-induced reproductive inhibition. These data suggest that structural similarities between melatonin and auxin do not result in similar postnatal effects on reproductive and non-reproductive organ development on a long photoperiod and further suggest that melatonin and auxin do not operate through a common physiological mechanism.

  10. Pollen development and tube growth are affected in the symbiotic mutant of Lotus japonicus, crinkle.

    PubMed

    Tansengco, Myra L; Imaizumi-Anraku, Haruko; Yoshikawa, Makoto; Takagi, Shingo; Kawaguchi, Masayoshi; Hayashi, Makoto; Murooka, Yoshikatsu

    2004-05-01

    The symbiotic mutant of Lotus japonicus, crinkle (crk), exhibits abnormal nodulation and other alterations in the root hairs, trichomes, and seedpods. Defective nodulation in crk mutant is due to the arrested infection thread growth from the epidermis into the cortex. Here, we describe that crk is also affected in male fertility that causes the production of small pods with few seeds. Under in vitro conditions, pollen germination and tube growth were markedly reduced in the crk mutant. A swollen tip phenotype with disorganized filamentous actin (F-actin) was observed in the mutant pollen tubes after prolonged in vitro culture. During pollen development, the striking difference noted in the mutant was the small size of the microspores that remained spherical. Histological examination of ovule development, as well as outcrosses of the mutant as female to wild type as male, showed no evidence of abnormality in the female gametophyte development. Based on these findings, the Crk gene, aside from its role in the infection process during nodulation, is also involved in male gametophyte development and function. Therefore, this gene represents a connection between nodule symbiosis, polar tip growth, and other plant developmental processes.

  11. White matter development in adolescence: the influence of puberty and implications for affective disorders.

    PubMed

    Ladouceur, Cecile D; Peper, Jiska S; Crone, Eveline A; Dahl, Ronald E

    2012-01-01

    There have been rapid advances in understanding a broad range of changes in brain structure and function during adolescence, and a growing interest in identifying which of these neurodevelopmental changes are directly linked with pubertal maturation—at least in part because of their potential to provide insights into the numerous emotional and behavioral health problems that emerge during this developmental period. This review focuses on what is known about the influence of puberty on white matter development in adolescence.We focus on white matter because of its role in providing the structural architectural organization of the brain and as a structural correlate of communication within complex neural systems. We begin with a review of studies that report sex differences or sex by age interactions in white matter development as these findings can provide, although indirectly,information relevant to puberty-related changes. Studies are also critically reviewed based on methodological procedures used to assess pubertal maturation and relations with white matter changes. Findings are discussed in light of their implications for the development of neural systems underlying the regulation of emotion and behavior and how alterations in the development of these systems may mediate risk for affective disorders in vulnerable adolescents.

  12. White Matter Development in Adolescence: The Influence of Puberty and Implications for Affective Disorders

    PubMed Central

    Ladouceur, Cecile D.; Peper, Jiska S.; Crone, Eveline A.; Dahl, Ronald E.

    2011-01-01

    There have been rapid advances in understanding a broad range of changes in brain structure and function during adolescence, and a growing interest in identifying which of these neurodevelopmental changes are directly linked with pubertal maturation—at least in part because of their potential to provide insights into the numerous emotional and behavioral health problems that emerge during this developmental period. This review focuses on what is known about the influence of puberty on white matter development in adolescence. We focus on white matter because of its role in providing the structural architectural organization of the brain and as a structural correlate of communication within complex neural systems. We begin with a review of studies that report sex differences or sex by age interactions in white matter development as these findings can provide, although indirectly, information relevant to puberty-related changes. Studies are also critically reviewed based on methodological procedures used to assess pubertal maturation and relations with white matter changes. Findings are discussed in light of their implications for the development of neural systems underlying the regulation of emotion and behavior and how alterations in the development of these systems may mediate risk for affective disorders in vulnerable adolescents. PMID:22247751

  13. Early history of development of boron neutron capture therapy of tumors.

    PubMed

    Sweet, W H

    1997-05-01

    The stable isotope 10B has a peculiarly marked avidity to capture slow neutrons whereupon it disintegrates into a lithium and a helium atom. These give up the 2.4 MeV of disintegration energy which they share within 5 and 9 microns of the 10B atom respectively. This means that the cell closest to the 10B atom bears the brunt of its atomic explosion. The objective of the tumor therapist is to find a carrier molecule for the boron atom which will concentrate in the tumor. Although a number of investigators saw the peculiar advantage of this selective tactic to achieve destruction of a species of unwanted cells, no success in animal studies was achieved until 1950. Sweet and colleagues found that the capillary blood-brain barrier keeps many substances out of the normal brain but that the gliomas had much less of such a barrier. He, Brownell, Soloway and Hatanaka in Boston together with Farr. Godwin, Robertson, Stickley. Konikowski and others at the Brookhaven. National Laboratory worked partially in collaboration and partly independently. We irradiated at 3 nuclear reactors several series of glioma patients with no long-term remission, much less a cure being achieved. Hatanaka on his return to Japan kept BNCT alive by treating a total of 140 patients with various brain tumors. Beginning in 1972, Mishima and colleagues have achieved useful concentrations of 10B-borono-phenylalanine, an analogue of the melanin precursor tyrosine, for BNCT of melanomas.

  14. Role and molecular mechanism of heterogeneous nuclear ribonucleoprotein K in tumor development and progression

    PubMed Central

    LU, JING; GAO, FENG-HOU

    2016-01-01

    Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a member of the hnRNP family, which exists in the nucleus and the cytoplasm simultaneously. It is a multifunctional protein that can participate in a variety of regulatory progressions of gene expression and signal transduction, such as chromatin remodeling, transcription, RNA alternative splicing and translation. hnRNP K not only directly binds to the kinases, but also recruits the associated factors regarding transcription, splicing and translation to control gene expression, and therefore, it serves as a docking platform for integrating transduction pathways to nucleic acid-directed processes. Numerous studies also show that abnormal expression of hnRNP K is closely associated with the tumor formation. This protein is overexpressed in numerous types of cancer and its aberrant cytoplasmic localization is also associated with a worse prognosis for patients. These results consistently indicate that hnRNP K has a key role in cancer progression. To understand the hnRNP K pathophysiological process in tumor disease, the previous research results regarding the association between hnRNP K and tumors were reviewed. PMID:27284403

  15. Decreased Zinc Availability Affects Glutathione Metabolism in Neuronal Cells and in the Developing Brain

    PubMed Central

    Omata, Yo; Salvador, Gabriela A.; Oteiza, Patricia I.

    2013-01-01

    A deficit in zinc (Zn) availability can increase cell oxidant production, affect the antioxidant defense system, and trigger oxidant-sensitive signals in neuronal cells. This work tested the hypothesis that a decreased Zn availability can affect glutathione (GSH) metabolism in the developing rat brain and in neuronal cells in culture, as well as the capacity of human neuroblastoma IMR-32 cells to upregulate GSH when challenged with dopamine (DA). GSH levels were low in the brain of gestation day 19 (GD19) fetuses from dams fed marginal Zn diets throughout gestation and in Zn-deficient IMR-32 cells. γ-Glutamylcysteine synthetase (GCL), the first enzyme in the GSH synthetic pathway, was altered by Zn deficiency (ZD). The protein and mRNA levels of the GCL modifier (GCLM) and catalytic (GCLC) subunits were lower in the Zn-deficient GD19 fetal brain and in IMR-32 cells compared with controls. The nuclear translocation of transcription factor nuclear factor (erythroid-derived 2)-like 2, which controls GCL transcription, was impaired by ZD. Posttranslationally, the caspase-3-dependent GCLC cleavage was high in Zn-deficient IMR-32 cells. Cells challenged with DA showed an increase in GCLM and GCLC protein and mRNA levels and a consequent increase in GSH concentration. Although Zn-deficient cells partially upregulated GCL subunits after exposure to DA, GSH content remained low. In summary, results show that a low Zn availability affects the GSH synthetic pathway in neuronal cells and fetal brain both at transcriptional and posttranslational levels. This can in part underlie the GSH depletion associated with ZD and the high sensitivity of Zn-deficient neurons to pro-oxidative stressors. PMID:23377617

  16. Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro.

    PubMed

    Fan, Lir-Wan; Bhatt, Abhay; Tien, Lu-Tai; Zheng, Baoying; Simpson, Kimberly L; Lin, Rick C S; Cai, Zhengwei; Kumar, Praveen; Pang, Yi

    2015-05-01

    patterns of contactin-associated protein (Caspr) clustering were observed at the sites of Node of Ranvier, suggesting that 5-HT exposure may affect other axon-derived factors for myelination. In summary, this is the first study to demonstrate that manipulation of serotonin levels affects OL development and myelination, which may contribute to altered neural connectivity noted in SSRIs-treated animals. The current in vitro study demonstrated that exposure to high level of serotonin (5-HT) led to aberrant oligodendrocyte (OL) development, cell injury, and myelination deficit. We propose that elevated extracellular serotonin levels in the fetal brain, such as upon the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, may adversely affect OL development and/or myelination, thus contributing to altered neural connectivity seen in Autism Spectrum Disorders. OPC = oligodendrocyte progenitor cell.

  17. Development of Y-shaped peptide for constructing nanoparticle systems targeting tumor-associated macrophages in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Yan, Lu; Gao, Yunxiang; Pierce, Ryan; Dai, Liming; Kim, Julian; Zhang, Mei

    2014-04-01

    Tumor-associated macrophage (TAM) is increasingly being viewed as a target of great interest in tumor microenvironment due to its important role in the progression and metastasis of cancers. It has been shown that TAM indeed overexpresses unique surface marker legumain. In this study, we designed and synthesized a Y-shaped legumain-targeting peptide (Y-Leg) with functional groups allowing for further conjugation with imaging and therapeutic moieties (vide infra). The in vitro cell experiments using FITC-conjugated Y-Leg revealed its specific and selective interaction with M2-polarized macrophages (i.e., TAMs) with preference to M1 macrophages, and that the interaction was not interfered with by conjugating FITC to its functional group. Further, we constructed a nanotube system by grafting Y-Leg onto oxidized carbon nanotubes (OCNTs) loaded with paramagnetic Fe3O4 nanoparticles. The intravenous injection of the resultant Y-Leg-OCNT/Fe3O4 nanotubes to 4T1 mammary tumor-bearing mouse led to the magnetic resonance imaging (MRI) of TAM-infiltrated tumor microenvironment, revealing the targeting specificity of Y-Leg-conjugated nanotubes in vivo. The Y shape of peptide and its functional groups containing amines and imidazole can protonate at different pHs, contributing to the in vitro and in vivo targeting specificity. This study represents the first development of novel peptide and peptide-grafted nanotube system targeting M2-polarized TAMs in vivo. The methodology developed in this study is applicable to the construction of various multifunctional nanoparticle systems for selectively targeting, imaging and manipulating of TAMs for the diagnosis and treatment of cancers and inflammatory diseases identified with macrophage-infiltrated disease tissue.

  18. Factors affecting the development of instructional skills in preservice middle and secondary school science teachers

    NASA Astrophysics Data System (ADS)

    Yilmaz, Ozgul

    The purposes of this study were to explore the factors affecting the development of instructional skills in preservice middle and secondary school science teachers (PSTs), determine PSTs' dispositions about utilization of different instructional methods while they were taking methods course, and examine PSTs' ideas about adaptability of these methods for their future teaching. Qualitative case study methodology was applied to this study. The science methods course at a Midwestern university was used as the study site. The findings of this study revealed that even though PSTs had true conceptions about different instructional methods, they had difficulty in implementing that knowledge in real classroom settings. PSTs had the biggest struggle especially when they implemented the student-centered methods. Failing to develop necessary instructional skills played an important role in having unsuccessful teaching experience. Further analysis suggested there were outside factors that influenced the development of PSTs' instructional skills. Different components of the science methods course, students, cooperating teachers, and setting for authentic practice were the factors that influenced the development of PSTs' instructional skills. PSTs' belief systems and their previous experiences as students also influenced the development of instructional skills. At the end of science methods course, PSTs decided the adaptability of different instructional methods for their future teaching. The student-centered methods were seemed as less likely to adapt for future teaching by PSTs. In order to help PSTs handle these factors effectively, prolonged professional development opportunities need to be provided to them during the science methods courses. PSTs' beliefs need to be determined during science methods courses and an environment for PSTs should be provided to change their beliefs.

  19. The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer

    PubMed Central

    Jiang, Hongchao; Chen, Ceshi; Sun, Qiangming; Wu, Jing; Qiu, Lijuan; Gao, Change; Liu, Weiqing; Yang, Jun; Jun, Nie; Dong, Jian

    2016-01-01

    Background Semaphorin 4D (Sema4D) is highly expressed in certain types of tumors and functions in the regulation of tumor angiogenesis and growth. However, it is still not clear regarding the roles of Sema4D in breast cancer. This study was designed to explore the effects of Sema4D on proliferation, cell cycle progression, apoptosis, invasion, migration, tumor growth, and angiogenesis in breast cancer. Materials and methods The expression level of Sema4D was investigated in MCF10A, 184A1, HCC1937, MDA-MB-468, MDA-MB-231, Hs578T, BT474, MCF-7, and T47D breast cancer cell lines by Western blotting analysis. Sema4D downregulation or overexpression was established by infection with lentiviruses-encoding Sema4D short hairpin RNA (shRNA) or Sema4D. To evaluate the effects of Sema4D on cell proliferation, cell cycle progression, apoptosis, invasion, and migration of MDA-MB-231 and MDA-MB-468 cells, methods including MTT assay, flow cytometry, wound healing assay, and transwell experiments were applied. BALB/c nude mice were injected with MDA-MB-231 cells, which were respectively infected with lentiviruses-encoding Sema4D, Sema4D shRNA, and GFP, followed by tumor angiogenesis assay. Results Sema4D was expressed at higher levels in breast cancer cell lines compared with the normal human breast epithelial cell lines, especially in MDA-MB-231 and MDA-MB-468 cells. Cell proliferation ability was remarkably inhibited in Sema4D downregulated condition, whereas the proportions of cells in the G0/G1 phase and apoptosis increased in MDA-MB-231 and MDA-MB-468 cells. In addition, the invasion and migration abilities of these cells were obviously reduced. Xenograft growth as well as angiogenesis was inhibited when infected with lentiviruses-encoding Sema4D shRNA in vivo. Conclusion Downregulation of Sema4D had notable influence on cell proliferation ability, invasion, migration, and apoptosis of both MDA-MB-231 and MDA-MB-468 cells. Furthermore, infection with lentiviruses

  20. Constitutive active/androstane receptor, peroxisome proliferator-activated receptor α, and cytotoxicity are involved in oxadiazon-induced liver tumor development in mice.

    PubMed

    Kuwata, Kazunori; Inoue, Kaoru; Ichimura, Ryohei; Takahashi, Miwa; Kodama, Yukio; Yoshida, Midori

    2016-02-01

    Oxadiazon (OX) is a protoporphyrinogen oxidase-inhibiting herbicide that induces porphyria and liver tumors in rodents. Although porphyria is generally considered to be a risk factor for liver tumor development, the mechanisms through which OX mediates tumor development are unclear. Therefore, in this study, we investigated the mechanisms of tumor development by focusing on constitutive active/androstane receptor (CAR), which is essential for the development of tumors in response to several chemicals. After 1, 4, or 13 weeks of dietary treatment with 1000 ppm OX, hepatic Cyp2b10 expression was induced in wild-type (WT) mice. However, this effect was blocked in CAR-knockout (CARKO) mice. Hepatic Cyp4a10 expression, indicative of peroxisome proliferator-activated receptor α (PPARα) activation, and cytotoxic changes in hepatocytes were also observed in both groups of mice. After initiation by diethylnitrosamine, 26-week treatment with OX resulted in an increase in proliferative lesions, including foci and adenomas, in both genotypes, and the incidence and multiplicity of proliferative lesions in CARKO mice were higher than those in control mice but lower than those in WT mice. These results suggested that CAR, PPARα activation, and cytotoxicity were involved in the development of liver tumors. Moreover, porphyrin was not apparently involved in OX-induced tumor development.

  1. Pleomorphic adenoma--unusual presentation of a salivary gland tumor in the neck of a child.

    PubMed

    Arunkumar, K V; Kumar, Sanjeev; Bansal, Vishal; Saxena, Susmita; Elhence, Poonam

    2011-01-01

    Ectopic salivary gland tumors are rare in children. When salivary gland tumors do develop, they preferentially affect major salivary glands and then minor salivary glands. Pleomorphic adenoma, also referred to as a benign mixed tumor, is the most common tumor of the salivary glands. Approximately 90% of these tumors occur in the parotid gland, while the remaining 10% affect the minor salivary glands. However, it is uncommon to find them elsewhere in the head and neck region. We report a rare case of pleomorphic adenoma in the upper neck, an unusual site in an 8-year-old boy.

  2. Diversity of dynamics and morphologies of invasive solid tumors

    NASA Astrophysics Data System (ADS)

    Jiao, Yang; Torquato, Salvatore

    2012-03-01

    Complex tumor-host interactions can significantly affect the growth dynamics and morphologies of progressing neoplasms. The growth of a confined solid tumor induces mechanical pressure and deformation of the surrounding microenvironment, which in turn influences tumor growth. In this paper, we generalize a recently developed cellular automaton model for invasive tumor growth in heterogeneous microenvironments [Y. Jiao and S. Torquato, PLoS Comput. Biol. 7, e1002314 (2011)] by incorporating the effects of pressure. Specifically, we explicitly model the pressure exerted on the growing tumor due to the deformation of the microenvironment and its effect on the local tumor-host interface instability. Both noninvasive-proliferative growth and invasive growth with individual cells that detach themselves from the primary tumor and migrate into the surrounding microenvironment are investigated. We find that while noninvasive tumors growing in "soft" homogeneous microenvironments develop almost isotropic shapes, both high pressure and host heterogeneity can strongly enhance malignant behavior, leading to finger-like protrusions of the tumor surface. Moreover, we show that individual invasive cells of an invasive tumor degrade the local extracellular matrix at the tumor-host interface, which diminishes the fingering growth of the primary tumor. The implications of our results for cancer diagnosis, prognosis and therapy are discussed.

  3. Sinus Tumors

    MedlinePlus

    ... Tumors Nasal Deformities Choanal Atresia Epiphora (Excessive Tearing) Disclosure Statement Printer Friendly Sinus Tumors Abtin Tabaee, MD Introduction Tumors of the nose and paranasal sinuses are rare, accounting for fewer than 1% of all tumors. These ...

  4. Ozone affects growth and development of Pieris brassicae on the wild host plant Brassica nigra.

    PubMed

    Khaling, Eliezer; Papazian, Stefano; Poelman, Erik H; Holopainen, Jarmo K; Albrectsen, Benedicte R; Blande, James D

    2015-04-01

    When plants are exposed to ozone they exhibit changes in both primary and secondary metabolism, which may affect their interactions with herbivorous insects. Here we investigated the performance and preferences of the specialist herbivore Pieris brassicae on the wild plant Brassica nigra under elevated ozone conditions. The direct and indirect effects of ozone on the plant-herbivore system were studied. In both cases ozone exposure had a negative effect on P. brassicae development. However, in dual-choice tests larvae preferentially consumed plant material previously fumigated with the highest concentration tested, showing a lack of correlation between larval preference and performance on ozone exposed plants. Metabolomic analysis of leaf material subjected to combinations of ozone and herbivore-feeding, and focussing on known defence metabolites, indicated that P. brassicae behaviour and performance were associated with ozone-induced alterations to glucosinolate and phenolic pools.

  5. Mixtures of environmentally relevant endocrine disrupting chemicals affect mammary gland development in female and male rats.

    PubMed

    Mandrup, Karen Riiber; Johansson, Hanna Katarina Lilith; Boberg, Julie; Pedersen, Anne Stilling; Mortensen, Mette Sidsel; Jørgensen, Jennifer Solgaard; Vinggaard, Anne Marie; Hass, Ulla

    2015-07-01

    Estrogenic chemicals are able to alter mammary gland development in female rodents, but little is known on the effects of anti-androgens and mixtures of endocrine disrupting chemicals (EDCs) with dissimilar modes of action. Pregnant rat dams were exposed during gestation and lactation to mixtures of environmentally relevant EDCs with estrogenic, anti-androgenic or dissimilar modes of action (TotalMix) of 100-, 200- or 450-fold high end human intake estimates. Mammary glands of prepubertal and adult female and male offspring were examined. Oestrogens increased mammary outgrowth in prepubertal females and the mRNA level of matrix metalloproteinase-3, which may be a potential biomarker for increased outgrowth. Mixtures of EDCs gave rise to ductal hyperplasia in adult males. Adult female mammary glands of the TotalMix group showed morphological changes possibly reflecting increased prolactin levels. In conclusion both estrogenic and anti-androgenic chemicals given during foetal life and lactation affected mammary glands in the offspring.

  6. Ozone affects growth and development of Pieris brassicae on the wild host plant Brassica nigra.

    PubMed

    Khaling, Eliezer; Papazian, Stefano; Poelman, Erik H; Holopainen, Jarmo K; Albrectsen, Benedicte R; Blande, James D

    2015-04-01

    When plants are exposed to ozone they exhibit changes in both primary and secondary metabolism, which may affect their interactions with herbivorous insects. Here we investigated the performance and preferences of the specialist herbivore Pieris brassicae on the wild plant Brassica nigra under elevated ozone conditions. The direct and indirect effects of ozone on the plant-herbivore system were studied. In both cases ozone exposure had a negative effect on P. brassicae development. However, in dual-choice tests larvae preferentially consumed plant material previously fumigated with the highest concentration tested, showing a lack of correlation between larval preference and performance on ozone exposed plants. Metabolomic analysis of leaf material subjected to combinations of ozone and herbivore-feeding, and focussing on known defence metabolites, indicated that P. brassicae behaviour and performance were associated with ozone-induced alterations to glucosinolate and phenolic pools. PMID:25645061

  7. A systems theory approach to career development: Exploring factors that affect science as a career choice

    NASA Astrophysics Data System (ADS)

    Liskey, Brian K.

    This research project was designed to examine the factors that affect students' choice in a career. Specifically, the factors of (a) achievement, (b) interest, (c) self-efficacy, (d) perceived preparation for a career, and (e) being informed about a career will be under investigation. Of key importance to the study is how these factors can affect a student's perception about choosing a science career. A quantitative analysis of secondary data from the 2006 and 2009 Program for International Student Assessment (PISA) international assessment and attitudinal questionnaire provided data on student perceptions and aptitude in science. The sample from PISA included over 400,000 15 year-old students from 57 countries. From the 57 countries, 30 countries, comprised by Organization for Economic and Cooperative Development (OECD), were isolated for analysis. Within this group of 30, 11 were selected for comparison based on their questionnaire response to expectations for a career in science at age 30. The Institute for Educational Science's, International Data Explorer was utilized to acquire and analyze data from the 2006 and 2009 PISA international tests and questionnaires to determine significance between scaled scores and PISA indices. Variables were chosen as factors affecting student's perception on various systems outlined by the Systems Theory of Career Development (Patton & McMahon, 1997) and the Systems Theory of Career Development Framework (Patton & McMahon, 1999). Four country groups were established based on student responses to question 30a from the 2006 PISA attitudinal questionnaire, which asks what career students expected to have at age 30. The results from comparing country groups showed that countries in Group A, which showed the highest values for students expecting a career in science, also had the highest average values for achievement on the PISA science literacy assessment. Likewise, countries that had the lowest values for expecting a career in

  8. Resistance of novel mouse strains different in MHC class I and the NKC domain to the development of experimental tumors.

    PubMed

    Fišerová, Anna; Richter, Jan; Čapková, Katarína; Bieblová, Jana; Mikyšková, Romana; Reiniš, Milan; Indrová, Marie

    2016-08-01

    To elucidate the immunological mechanisms critical for tumor progression, we bred novel mouse strains, different in the NKC and H-2D domains. We used inbreeding to generate hybrids of Balb/c and C57BL/6 of stable H-2Db+d-NK1.1neg and H-2Db-d+NK1.1high phenotypes. We analyzed the growth of three established MHC class I-deficient tumor cell lines: TC-1/A9 tumor (HPV-associated) and B16F10 melanoma, both syngeneic to C57BL/6, and the MCB8 (3-methycholanthrene-induced tumor) syngeneic to Balb/c. Furthermore, we induced colorectal carcinoma by azoxymethane-DSS treatment to test the susceptibility to chemically-induced primary cancer. We found that the novel strains spontaneously regressed the tumor transplants syngeneic to both Balb/c (MCB8) and C57BL/6 (B16F10 and TC-1/A9) mice. The H2-Db+d-NK1.1neg, but not the H2-Db-d+NK1.1high strain was also highly resistant to chemically-induced colorectal cancer in comparison to the parental mice. The immune changes during TC-1/A9 cancer development involved an increase of the NK cell distribution in the peripheral blood and spleen along with higher expression of NKG2D activation antigen; this was in correlation with the time-dependent rise of cytotoxic activity in comparison to C57BL/6 mice. The TC-1/A9 cancer regression was accompanied by higher proportion of B cells in the spleen and B220+/CD86+ activated antigen-presenting B cells distributed in the lymphoid organs, as well as in the periphery. The changes in the T-cell population were represented mainly by the prevalence of T helper cells reflected by grown CD4/CD8 ratio, most prominent in the b+d-NK1.1neg strain. The results of the present study imply usefulness of the two novel mouse strains as an experimental model for further studies of tumor resistance mechanisms. PMID:27279019

  9. Oakleaf: an S locus-linked mutation of Primula vulgaris that affects leaf and flower development.

    PubMed

    Cocker, Jonathan M; Webster, Margaret A; Li, Jinhong; Wright, Jonathan; Kaithakottil, Gemy; Swarbreck, David; Gilmartin, Philip M

    2015-10-01

    In Primula vulgaris outcrossing is promoted through reciprocal herkogamy with insect-mediated cross-pollination between pin and thrum form flowers. Development of heteromorphic flowers is coordinated by genes at the S locus. To underpin construction of a genetic map facilitating isolation of these S locus genes, we have characterised Oakleaf, a novel S locus-linked mutant phenotype. We combine phenotypic observation of flower and leaf development, with classical genetic analysis and next-generation sequencing to address the molecular basis of Oakleaf. Oakleaf is a dominant mutation that affects both leaf and flower development; plants produce distinctive lobed leaves, with occasional ectopic meristems on the veins. This phenotype is reminiscent of overexpression of Class I KNOX-homeodomain transcription factors. We describe the structure and expression of all eight P. vulgaris PvKNOX genes in both wild-type and Oakleaf plants, and present comparative transcriptome analysis of leaves and flowers from Oakleaf and wild-type plants. Oakleaf provides a new phenotypic marker for genetic analysis of the Primula S locus. We show that none of the Class I PvKNOX genes are strongly upregulated in Oakleaf leaves and flowers, and identify cohorts of 507 upregulated and 314 downregulated genes in the Oakleaf mutant.

  10. Language development and affecting factors in 3- to 6-year-old children.

    PubMed

    Muluk, Nuray Bayar; Bayoğlu, Birgül; Anlar, Banu

    2014-05-01

    The aim of this study was to assess factors affecting language developmental screening test results in 33.0- to 75.0-month-old children. The study group consists of 402 children, 172 (42.8%) boys and 230 (57.2%) girls, aged 33.0-75.0 months who were examined in four age groups: 3 years (33.0-39.0 months), 4 years (45.0-51.0 months), 5 years (57.0-63.0 months) and 6 years (69.0-75.0 months). Demographic data and medical history obtained by a standard questionnaire and Denver II Developmental Test results were evaluated. Maternal factors such as mother's age, educational level, and socioeconomic status (SES) correlated with language items in all age groups. Linear regression analysis indicated a significant effect of mother's education and higher SES on certain expressive and receptive language items at 3 and 4 years. Fine motor items were closely related to language items at all ages examined, while in the younger (3- and 4-year-old) group gross motor items also were related to language development. Maternal and socioeconomic factors influence language development in children: these effects, already discernible with a screening test, can be potential targets for social and educational interventions. The interpretation of screening test results should take into account the interaction between fine motor and language development in preschool children.

  11. Ozone affects gas exchange, growth and reproductive development in Brassica campestris (Wisconsin fast plants).

    PubMed

    Black, V J; Stewart, C A; Roberts, J A; Black, C R

    2007-01-01

    Exposure to ozone (O(3)) may affect vegetative and reproductive development, although the consequences for yield depend on the effectiveness of the compensatory processes induced. This study examined the impact on reproductive development of exposing Brassica campestris (Wisconsin Fast Plants) to ozone during vegetative growth. Plants were exposed to 70 ppb ozone for 2 d during late vegetative growth or 10 d spanning most of the vegetative phase. Effects on gas exchange, vegetative growth, reproductive development and seed yield were determined. Impacts on gas exchange and foliar injury were related to pre-exposure stomatal conductance. Exposure for 2 d had no effect on growth or reproductive characteristics, whereas 10-d exposure reduced vegetative growth and reproductive site number on the terminal raceme. Mature seed number and weight per pod and per plant were unaffected because seed abortion was reduced. The observation that mature seed yield per plant was unaffected by exposure during the vegetative phase, despite adverse effects on physiological, vegetative and reproductive processes, shows that indeterminate species such as B. campestris possess sufficient compensatory flexibility to avoid reductions in seed production. PMID:17803646

  12. Exposure to Sevoflurane Affects the Development of Parvalbumin Interneurons in the Main Olfactory Bulb in Mice

    PubMed Central

    Yang, Jing; Chen, Jing; Cai, Guohong; Lu, Rui; Sun, Tingting; Luo, Tingting; Wu, Shengxi; Ling, Shucai

    2016-01-01

    Sevoflurane is widely used in adult and pediatric patients during clinical surgeries. Although studies have shown that exposure to sevoflurane impairs solfactory memory after an operation, the neuropathological changes underlying this effect are not clear. This study detected the effect of sevoflurane exposure on the development of calcium-binding proteins-expressing interneurons in the main olfactory bulb (MOB). We exposed neonatal mice to 2% sevoflurane at two different developmental time points and found that exposing mice to sevoflurane at postnatal day (PD) 7 significantly decreased the expression of GAD67 and parvalbumin (PV) in the olfactory bulb (OB) but did not alter the expression of calretinin (CR) or calbindin D28k (CB). The number and dendritic morphology of PV-expressing interneurons in the MOB were impaired by exposure to sevoflurane at PD7. However, exposure to sevoflurane at PD10 had no effect on calcium-binding protein expression or the number and dendritic morphology of PV-expressing interneurons in the MOB. These results suggest that exposing neonatal mice to sevoflurane during a critical period of olfactory development affects the development of PV-expressing interneurons in the MOB. PMID:27445710

  13. Applying a Cognitive-Affective Model of Conceptual Change to Professional Development

    NASA Astrophysics Data System (ADS)

    Ebert, Ellen K.; Crippen, Kent J.

    2010-04-01

    This study evaluated Gregoire’s (2003) Cognitive-Affective Conceptual Change model (CAMCC) for predicting and assessing conceptual change in science teachers engaged in a long-term professional development project set in a large school district in the southwestern United States. A multiple case study method with data from three teacher participants was used to understand the process of integrating and applying a reform message of inquiry based science teaching. Data sources included: responses to example teaching scenarios, reflective essays, lesson plans, classroom observations, and action research projects. Findings show that the CAMCC functioned well in predicting how these teachers made decisions that impacted how they processed the reform message. When the reform message was communicated in such a way as to initiate stress appraisal, conceptual change occurred, producing changes in classroom practice. If the reform message did not initiate stress appraisal, teachers rejected the professional development message and developed heuristic responses. In order to further research and improve practice, propositions for assessments related to the CAMCC are provided.

  14. Overexpression of a glutamine synthetase gene affects growth and development in sorghum.

    PubMed

    Urriola, Jazmina; Rathore, Keerti S

    2015-06-01

    Nitrogen is a primary macronutrient in plants, and nitrogen fertilizers play a critical role in crop production and yield. In this study, we investigated the effects of overexpressing a glutamine synthetase (GS) gene on nitrogen metabolism, and plant growth and development in sorghum (Sorghum bicolor L., Moench). GS catalyzes the ATP dependent reaction between ammonia and glutamate to produce glutamine. A 1,071 bp long coding sequence of a sorghum cytosolic GS gene (Gln1) under the control of the maize ubiquitin (Ubq) promoter was introduced into sorghum immature embryos by Agrobacterium-mediated transformation. Progeny of the transformants exhibited higher accumulation of the Gln1 transcripts and up to 2.2-fold higher GS activity compared to the non-transgenic controls. When grown under optimal nitrogen conditions, these Gln1 transgenic lines showed greater tillering and up to 2.1-fold increase in shoot vegetative biomass. Interestingly, even under greenhouse conditions, we observed a seasonal component to both these parameters and the grain yield. Our results, showing that the growth and development of sorghum Gln1 transformants are also affected by N availability and other environmental factors, suggest complexity of the relationship between GS activity and plant growth and development. A better understanding of other control points and the ability to manipulate these will be needed to utilize the transgenic technology to improve nitrogen use efficiency of crop plants.

  15. Susceptible period of socio-emotional development affected by constant exposure to daylight.

    PubMed

    Koshiba, Mamiko; Senoo, Aya; Karino, Genta; Ozawa, Simpei; Tanaka, Ikuko; Honda, Yoshiko; Usui, Setsuo; Kodama, Tohru; Mimura, Koki; Nakamura, Shun; Kunikata, Tetsuya; Yamanouchi, Hideo; Tokuno, Hironobu

    2015-04-01

    As a diurnal experimental primate, the common marmoset (Callithrix jacchus) has recently contributed to numerous kinds of studies of neurobiological psychiatry as an essential pre-clinical model. The marmoset matures sexually within one or two years after birth. Thus, we can observe how the primate learns and develops psycho-cognitive functions through experiences in experimental environment for a much shorter period compared to that of humans. Longer daylight exposure may affect psychological development of children. In our research, we focus on raising marmosets under constant daylight from birth until various ages. In order to quantitatively evaluate the development of higher-ordered psychological functions, we designed a system of socio-behavioral tests and multivariate correlation analysis methods based on principal component analysis. With reference to the call and typical body movement expressed during a particular social context, we statistically inferred the emotional features of the subjects. In the current literature, we review our published results showing increased alert behaviors by constant light, and then, attempted to extend our additional analysis to seek age-dependent susceptibility to constant light. We then present the neurobiological mechanisms with reference to previous research reports. The current review suggests possible existence of a susceptible period earlier than three to five month-old in the environment-induced developmental disorder model, supposedly like attention deficit hyperactive disorders (ADHD) or oppositional defiant disorder (ODD).

  16. Unilateral deafness in children affects development of multi-modal modulation and default mode networks.

    PubMed

    Schmithorst, Vincent J; Plante, Elena; Holland, Scott

    2014-01-01

    Monaural auditory input due to congenital or acquired unilateral hearing loss (UHL) may have neurobiological effects on the developing brain. Using functional magnetic resonance imaging (fMRI), we investigated the effect of UHL on the development of functional brain networks used for cross-modal processing. Children ages 7-12 with moderate or greater unilateral hearing loss of sensorineural origin (UHL-SN; N = 21) and normal-hearing controls (N = 23) performed an fMRI-compatible adaptation of the Token Test involving listening to a sentence such as "touched the small green circle and the large blue square" and simultaneously viewing an arrow touching colored shapes on a video. Children with right or severe-to-profound UHL-SN displayed smaller activation in a region encompassing the right inferior temporal, middle temporal, and middle occipital gyrus (BA 19/37/39), evidencing differences due to monaural hearing in cross-modal modulation of the visual processing pathway. Children with UHL-SN displayed increased activation in the left posterior superior temporal gyrus, likely the result either of more effortful low-level processing of auditory stimuli or differences in cross-modal modulation of the auditory processing pathway. Additionally, children with UHL-SN displayed reduced deactivation of anterior and posterior regions of the default mode network. Results suggest that monaural hearing affects the development of brain networks related to cross-modal sensory processing and the regulation of the default network during processing of spoken language. PMID:24723873

  17. Ozone affects gas exchange, growth and reproductive development in Brassica campestris (Wisconsin fast plants).

    PubMed

    Black, V J; Stewart, C A; Roberts, J A; Black, C R

    2007-01-01

    Exposure to ozone (O(3)) may affect vegetative and reproductive development, although the consequences for yield depend on the effectiveness of the compensatory processes induced. This study examined the impact on reproductive development of exposing Brassica campestris (Wisconsin Fast Plants) to ozone during vegetative growth. Plants were exposed to 70 ppb ozone for 2 d during late vegetative growth or 10 d spanning most of the vegetative phase. Effects on gas exchange, vegetative growth, reproductive development and seed yield were determined. Impacts on gas exchange and foliar injury were related to pre-exposure stomatal conductance. Exposure for 2 d had no effect on growth or reproductive characteristics, whereas 10-d exposure reduced vegetative growth and reproductive site number on the terminal raceme. Mature seed number and weight per pod and per plant were unaffected because seed abortion was reduced. The observation that mature seed yield per plant was unaffected by exposure during the vegetative phase, despite adverse effects on physiological, vegetative and reproductive processes, shows that indeterminate species such as B. campestris possess sufficient compensatory flexibility to avoid reductions in seed production.

  18. Do early life factors affect the development of knee osteoarthritis in later life: a narrative review.

    PubMed

    Antony, Benny; Jones, Graeme; Jin, Xingzhong; Ding, Changhai

    2016-01-01

    Osteoarthritis (OA) mainly affects older populations; however, it is possible that early life factors contribute to the development of OA in later life. The aim of this review is to describe the association between childhood or early adulthood risk factors and knee pain, structural imaging markers and development of knee OA in later life. A narrative overview of the literature synthesising the findings of literature retrieved from searches of computerised databases and manual searches was conducted. We found that only a few studies have explored the long-term effect of childhood or early adulthood risk factors on the markers of joint health that predispose people to OA or joint symptoms. High body mass index (BMI) and/or overweight status from childhood to adulthood were independently related to knee pain and OA in later life. The findings regarding the association between strenuous physical activity and knee structures in young adults are still conflicting. However, a favourable effect of moderate physical activity and fitness on knee structures is reported. Childhood physical activity and performance measures had independent beneficial effects on knee structures including knee cartilage in children and young adults. Anterior knee pain syndrome in adolescence could lead to the development of patellofemoral knee OA in the late 40s. Furthermore, weak evidence suggests that childhood malalignment, socioeconomic status and physical abuse are associated with OA in later life. The available evidence suggests that early life intervention may prevent OA in later life. PMID:27623622

  19. A study of language development and affecting factors in children aged 5 to 27 months.

    PubMed

    Muluk, Nuray Bayar; Bayoğlu, Birgül; Anlar, Banu

    2016-01-01

    We conducted a study to assess the factors that affect language development in infants and toddlers using data obtained during developmental screening. Our study group consisted of 505 children-244 (48.3%) boys and 261 (51.7%) girls, aged 5 to 27 months. The children were divided into four age groups: group 1, which we designated as the "6 months" group (age range: 5 to 7 mo); group 2, designated as the "12 months" group (11 to 13 mo); group 3, designated as the "18 months" group (17 to 19 mo); and group 4, designated as the "24 months" group (23 to 27 mo). In addition to demographic data, we compiled data using the Denver II Developmental Screening Test, as well as neurologic examination findings and medical histories. At 6 months, the social item "Works for toy out of reach" was positively related to all language development items. Two gross motor development items-"Pull to sit, no head lag" and "Lifts chest with arm support"-were related to the "Turns to sound" and "Turns